(WCPG): Poster Abstracts: Saturday

ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] European Neuropsychopharmacology (2018) 000, 1–80

www.elsevier.com/locate/euroneuro

Abstracts of the 26th World Congress of Psychiatric Genetics

< Saturday, October 13, 2018 best at age 13.2 years, and with increasing age the prediction diverged increasingly from the observed diagnosis. PRS explained the most variance in ADHD-status in the ﬁrst 3 age-quantiles from 4 to 18 years (0.18 < r2 < 0.29; all P < 10- Poster Session II 8), and less from 18 to 30 years (r2 = 0.04; P = 0.04).

11:15 a.m. - 1:15 p.m. Discussion: Polygenic inﬂuences on ADHD change over time. Age-stratiﬁed and longitudinal studies are necessary to un- SA1 derstand the age- and trajectory-dependent genetic archi- THE POLYGENIC INFLUENCE ON ADHD DEPENDS ON tecture underlying ADHD. AGE AND CLINICAL TRAJECTORY Disclosure: Nothing to disclose.

Emma Sprooten 1, Nina Roth Mota 2, Janita Bralten 2, doi: 10.1016/j.euroneuro.2018.08.223 Jan Buitelaar 2, Barbara Franke 3

1 Donders Institute for Brain, Cognition & Behaviour 2 Radboud University Medical Center, Nijmegen SA2 3 Radboud University Medical Center, Donders Institute USING GENETIC INSTRUMENTS TO ASSESS CAUSAL PATHWAYS TO EDUCATIONAL ATTAINMENT IN ADHD Background: Attention-deficit/hyperactivity disorder AND AUTISM: EVIDENCE FROM A TWO SAMPLE (ADHD) is a neurodevelopmental disorder with a variable MENDELIAN RANDOMISATION STUDY developmental course of symptomatology. Polygenic common variation accounts for a significant portion of ADHD Christina Dardani 1, Beate Leppert 1, Lucy Riglin 2, heritability. Tw i n studies suggest that the genetic risk Dheeraj Rai 1, George Davey Smith 1, Kate Tilling 1, factors for ADHD depend on the age of onset and the degree Anita Thapar 2, Emma L. Anderson 1, Evie Stergiakouli 1 of persistence of the disorder. We investigated whether differential genetic effects are also discernable in polygenic 1 University of Bristol risk scores (PRS) derived from genotype data. 2 Cardiff University Methods: Genotype and clinical data were available for 951 individuals from the longitudinal NeuroIMAGE cohort Background: Attention Deficit/ Hyperactivity Disorder of individuals aged 4 to 30 years. The diagnostic status of (ADHD) and Autism Spectrum Disorders (ASD) show genetic ADHD changed between any two measurements in 14% of and phenotypic overlap (Satterstom et al., 2018; Stergiak- the sample. Illumina PsychArray-24-v1.1A genotypes were ouli et al., 2017). ADHD and ASD recently have been found processed and imputed using Ricopili. PRS were based on to have genetic links to one of the strongest predictors of European GWAS from the PGC-ADHD working group. We social and economic outcomes; educational attainment (De- investigated the age-by-PRS interaction on ADHD-status in montis et al., 2017; Grove et al., 2017). Observational ev- a generalized mixed-model with individual and family as idence indicates that children with ADHD or ASD, are at nested random effects. We also tested for associations of increased risk of poor school performance (Crump et al., ADHD-status with PRS within four age-quantiles. 2013). However, it is currently unknown whether the two Results: The generalized mixed-model showed an age-by- conditions have causal effects on educational attainment PRS interaction on ADHD-status (P = 0.007). A polynomial fit or whether these associations are a result of unmeasured to the residuals suggested that PRS predicted ADHD status or residual confounding. We examined the causal effect of

0924-977X ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 2 Abstracts liability for ADHD and ASD on educational attainment in a SA3 two- sample Mendelian Randomisation (MR) framework. STRUCTURAL BRAIN ALTERATIONS AND THEIR ASSO- Methods: We performed two MR analyses to test the causal CIATION WITH COGNITIVE FUNCTION AND SYMPTOMS effect of each exposure (ADHD and ASD) on years of school- IN ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ing. We considered as instrumental variables for ADHD, 12 FAMILIES genome-wide signiﬁcant SNPs, identiﬁed in the most recent

GWAS meta-analysis on ADHD (Demontis et al., 2017). In- Wenhao Jiang 1, Kuaikuai Duan 2, Jiayu Chen 3, struments for ASD were defined based on the latest GWAS Barbara Franke 4, Jan Buitelaar 5, Alejandro Arias-Vásquez 6, meta-analysis of ASD (Grove et al., 2017). To increase the Jingyu Liu 3, Jessica Turner 1 power of the ASD analysis, in addition to the 5 genome- wide significant SNPs, we utilized the 15 top SNPs identi- 1 Georgia State University • − fied in the ASD GWAS, with p- values ranging from 7 10 7 to 2 The University of New Mexico • − 1 10 7. For each of the main analyses, SNP- outcome coef- 3 Mind Research Network

ficients were extracted from the latest published GWAS on 4 Radboud University Medical Centre, Donders Institute educational attainment (Okbay et al., 2016). SNP- exposure 5 Radboud University and SNP- outcome coefficients were combined using an In- 6 Radboud University Medical Centre verse Variance Weighted approach. We performed sensitivity analyses to test the robustness of our findings and detect Background: Attention-deficit/Hyperactivity Disorder and account for pleiotropy. We also performed replication (ADHD) is a heritable neurodevelopmental disorder char- analyses using the largest forthcoming GWAS of educational acterized by inattention along with hyperactivity and attainment (Lee et al., to be published). impulsivity. Smaller whole brain volume, and gray matter Results: There was evidence consistent with a causal ef- abnormality in basal ganglia, fronto-striatal-parietal path- fect of liability to ADHD on 0.27 fewer years of schooling ways, and the cerebellum are the most consistent findings (95% CI: −0.43 to −0.12, p = 0.0003). The direction and in ADHD. We investigated 336 families from the Dutch magnitude of the causal effect estimate was consistent in NeuroIMAGE projects (von Rhein et al., 2015) in a multi- sensitivity analyses assessing pleiotropy, as well as in the variate analysis, to examine brain structure alterations and replication analysis with the most recent and largest educa- their association with symptoms and cognition among ADHD tional attainment GWAS. On the contrary, limited evidence subjects, their unaffected siblings, subthreshold cases, and was found in favor of a causal effect of liability to ASD on controls. years of schooling (b = 0.03, 95% CI: −0.053 to 0.125, p = Methods: 508 participants (aged from 7 to 18 years) from 0.432). The result was confirmed in the replication analy- 336 families from the NeuroIMAGE project were included in sis, although sensitivity analyses indicated strong evidence this study, with structural brain scans collected on two scan- of heterogeneity among the genetic variants used as instru- ners. ADHD subjects were diagnosed according to DSM-IV ments. or DSM-IV-TR, and inattention and hyperactivity/impulsivity Discussion: Our findings provide evidence for distinct causal symptom severity were assessed for all subjects. Subjects pathways for ADHD and ASD towards educational outcomes. were grouped into those with ADHD (N = 210), their unaf- Using two-sample MR, we found results were consistent with fected siblings (N = 108), subthreshold cases (N = 49), and liability to ADHD being a causal risk factor for poorer edu- non-ADHD controls (with no ADHD siblings, N = 141), accord- cational outcomes. This finding can provide support towards ing to previous designations. The WAIS Digit Span score, the improving current treatment approaches or support infras- Stop Signal Reaction time, the ratio of the Reaction Time tructure for children with ADHD, in order to enhance aca- Variability to its mean, and total Errors from a go/no-go task demic outcomes. On the contrary, there was lack of evi- were included. dence suggesting a causal effect of ASD on education. This All T1-weighted MRI images were segmented using SPM12 could be attributed to a number of factors, including the with a children-specific template (Wilke, Holland, Altaye, small effect size genetic variants, contributing to the broad & Gaser, 2008). The segmented, normalized, modulated, and heterogeneous expression of the ASD phenotype. Larger smoothed (6 mm FWHM), and gender- and site-corrected studies as well gender and phenotype stratified datasets are gray matter images were decomposed into 20 components needed in order to disentangle the associations among ASD and their loading coefficients using the Group ICA toolbox and educational attainment. (GIFT). Age and age ^ 2 effects were tested for effects on all components and included, when significant. To deter- Disclosure: Nothing to disclose. mine case/control effects, linear mixed models with fam- doi: 10.1016/j.euroneuro.2018.08.224 ily as random factors, diagnosis as a fixed factor, and relevant covariates were used. Similar models including age, gender, IQ, and medication status were used to test association with cognition and symptoms only in components that showed case/control effects. Results: Tw o components showed significant case/control effects with p-values corrected for False Discovery Rates (FDR), consistently showing lower loading coefficients in cases than controls. Component 1 included a maximum cluster in bilateral insula, and unaffected siblings showed ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 3 significantly reduced loadings relative to controls, similar Methods: We performed genome-wide association meta- to cases; subthreshold cases did not. analyses in 37,478 children ( < 18 years). The sample was col- No relationship was found with cognitive or symptom lected through collaborations from “Spit for Science” (Sick- scores. Component 2 (Crus II) only showed a case/control Kids, Canada), Brisbane Adolescent Study (QIMR, Australia), difference; subthreshold cases were intermediate between CATSS (Karolinska, Sweden), TEDS (King’s College, UK), The cases and unaffected siblings, who were similar to controls. Netherlands Tw i n Registry (NTR, the Netherlands), ALSPAC After correcting for IQ and medication status, component (Bristol, UK) and MoBa (FHI, Norway). The ADHD dimensions 2 showed a negative correlation with inattention symptoms were measured by scores summarizing each child’s hyperac- across the entire group (corrected p = 0.011, beta = -0.43, tive and inattentive behaviours based on established ques- VE = 1.4%). tionnaires (e.g. SWAN, SNAP, A-TAC, DAWBA and Conners’ Discussion: In a multivariate approach to gray matter net- Rating Scale). Scores from each measurement tool were work differences in ADHD, we identified two components first analysed individually, followed by fixed effect meta- showing significant gray matter reduction in ADHD, including analyses to combine the results. The heritability of each di- primarily insula and Crus II. The insula component showed mension as well as their genetic correlations between each a similar reduction in unaffected siblings, but no relation- other and with other common phenotypes were estimated ship to symptom severity or cognition. The cerebellar com- using LD score regression. ponent, in contrast, showed a relationship to inattention Results: Our first results indicate that both hyperactiv- regardless of clinical status, but the nonaffected siblings ity and inattention have low heritability attributable to were similar to controls. This approach suggests that areas common variants (inattention: h2 = 0.051 [SE = 0.015], hy- reflecting genetic liability within ADHD can be partly sepa- peractivity: h2 = 0.075 [SE = 0.013]). Nonetheless, geneti- rated from areas modulating symptom severity. cally, these dimensions reveal high correlation with a clinical ADHD diagnosis (rgADHD + hyperactivity = 0.91 [SE = 0.10, Disclosure: Nothing to disclose. p = 1.6E-20]; rgADHD + inattention = 0.93 [SE = 0.14, p = 7.50E- 11]). The genetic correlation between inattention and hy- doi: 10.1016/j.euroneuro.2018.08.225 peractivity was estimated to be 0.73 (SE = 0.08, p = 1.4E- 18). Evaluation of genetic correlations between the two ADHD dimensions and common psychiatric disorders in adults showed that, on average, inattention correlated

SA4 more strongly than hyperactivity. The individual genome-

GENOME-WIDE ASSOCIATION META-ANALYSES OF ADHD wide meta-analyses of each dimension did not reveal SYMPTOMATOLOGY: INATTENTION AND HYPERACTIV- any genome-wide signiﬁcant loci. The strongest signal for ITY/IMPULSIVITY inattention was observed at rs9425340 (Z = -5.42, p = 6.1E- 08) near EDEM3 gene and for hyperactivity at rs7994864 1 2 3 Tetyana Zayats , QIMR Group , SickKids Group , (Z = -4.91, p = 9.3E-07) in intron of RNF219-AS1 gene. 4 5 1 6 TEDS Group , CATSS Group , MoBa Group , NTR Group , Discussion: The exploration of genetics of ADHD dimen- 7 8 ALSPAC Group , ATGU Group sions and how those relate to ADHD diagnosis and common ADHD co-morbidities/co-occurring phenotypes will aid our

1 University of Bergen understanding of biological processes involved in ADHD

2 Berghofer Medical Research Institute symptomatology and, potentially, lead to better diagnosis,

3 SickKids Research Institute, University of Toronto treatment and prevention options for this disorder.

4 King’s College London

5 Karolinska Institutet Disclosure: Nothing to disclose.

6 VU Amsterdam doi: 10.1016/j.euroneuro.2018.08.226 7 University of Bristol

8 MGH and Stanley Center at BROAD

Background: Attention deﬁcit hyperactivity disorder SA5

(ADHD) is a common and highly heritable childhood on- GENES AND BRAIN CELL TYPES LINKED WITH SE- set psychiatric condition, presenting a multidimensional LECTIVE NEURONAL VULNERABILITY IN ADHD clinical picture, with two main symptom dimensions: inat- 1 1 2 tention and hyperactivity/impulsivity. As ADHD persists Jonathan Hess , Jameson Patak , Stephen J. Glatt , 2 into adulthood, hyperactive-impulsive symptoms tend to Stephen V. Faraone decline, whereas inattentive symptoms are more stable.

Furthermore, the various combinations of symptom dimen- 1 SUNY Upstate Medical University sions are associated with different clinical features (e.g. 2 Medical Genetics Research Center, SUNY Upstate Medical co-morbidities) and treatment outcomes of ADHD. So far, University the biology underlying symptomatology of ADHD is far from understood. In this study, we conducted a genome-wide Background: A series of large multi-site mega-analyses of exploration of genetics of ADHD dimensions and their structural brain imaging data led the Enhancing Neuroimag- genetic correlation with a variety of common phenotypes, ing Genetics through Meta-analysis (ENGIMA) Network reflecting common ADHD co-morbidities and other relevant found several brain regions that show significant volu- traits. metric reductions in individuals diagnosed with attention ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 4 Abstracts deficit hyperactivity disorder (ADHD). Some regions showed biota samples were collected over time and used to measure substantially greater loss than others, which might be an bacterial composition. indicator of selective neuronal vulnerability (SNV). Results: While ADHD core features were not observed, in- Methods: We hypothesized spatial variation in gene ex- creased anxiety was observed in mice colonized with ADHD pression levels across brain regions may explain this phe- microbiota. These mice also showed an increased functional nomenon. To test this hypothesis, we devised an approach connectivity between right motor cortex and right visual to that used RNA-sequencing data the Allen Brain Atlas to cortex and differences in Diffusion Tensor Imaging measures uncover gene sets and brain cell types associated with SNV in hippocampus and right internal capsule. The bacterial in ADHD. We targeted gene sets based on hypotheses de- composition predicted groups and multiple genera differed rived from prior work. significantly. Results: We identified statistically significant correlations Discussion: These data show that human gut ADHD micro- between volumetric loss in ADHD and expression levels of biota induces anxiety in mice and contribute to structural genes involved in reactive oxygen, autophagy, and apop- brain changes, which are both comparable to observations tosis. Furthermore, we uncovered a significant correlation in human ADHD. between abundance of three brain cell types (microglia, radial glia, and floorplate derived neuronal progenitor cells) Disclosure: Nothing to disclose. with brain volumetric changes associated with ADHD. Re- doi: 10.1016/j.euroneuro.2018.08.228 sults from conditional regression models suggested that the effect of brain cell abundance on volumetric loss in ADHD may be mediated by gene expression levels.

Discussion: We concluded that gene expression levels inﬂu- SA7 ence brain cell abundance, which in turn mediates liability DISENTANGLING CAUSE AND EFFECT IN NEURODE- for ADHD. VELOPMENTAL DISORDERS: A PHENOME-WIDE ASSOCI- ATION STUDY IN UK BIOBANK Disclosure: Nothing to disclose.

Beate Leppert 1, Louise Millard 1, Esther Walton 1, doi: 10.1016/j.euroneuro.2018.08.227 Lucy Riglin 2, George Davey Smith 1, Anita Thapar 2,

Kate Tilling 1, Evie Stergiakouli 1

SA6 1 University of Bristol

BRAIN AND BEHAVIORAL CHANGES IN MICE COLO- 2 Cardiff University NIZED WITH HUMAN ADHD GUT MICROBIOTA Background: Neurodevelopmental disorders are associated 1 1 1 Sarita Dam , Anouk Tengeler , Maximilian Wiesmann , with harmful lifestyle factors and health problems, such as 2 1 1 Clara Belzer , Jill Naaijen , Barbara Franke , smoking, heavy alcohol consumption and obesity as well as 1 3 1 Tamas Kocicz , Alejandro Arias-Vásquez , Amanda Kiliaan premature mortality. However, whether the observed associations with health risks are causal or due to a shared ge-

1 Donders Institute for Brain, Cognition and Behaviour, Rad- netic architecture or reverse causation is largely unknown. boud University Medical Center, Nijmegen We investigated whether genetic risk for neurodevelopmen-

2 Wageningen University & Research tal disorders can be causally linked to adverse health and

3 Radboud University Medical Centre lifestyle outcomes in the general population. Methods: We performed a phenome-wide association study Background: Microbes inhabiting our gastrointestinal in UK Biobank, including 334,977 unrelated participants of tracts, the gut microbiota, are involved in regulation of white British ancestry. We investigated causal effects of the gastrointestinal system, modulation of the immune, en- ADHD and autism polygenic risk scores on 21,800 traits, us- docrine and nervous systems by influencing the brain, mood ing the open-source phenome scan tool PHEnome Scan ANal- and stress regulation. Growing evidence indicates that an ysis Tool (PHESANT). We used genome-wide significant SNPs imbalance in microbiota have been observed in patients and from the most recent summary statistics from meta-analysis animal models of neurodevelopmental disorders. Specifi- of ADHD and autism to derive the polygenic risk scores. A cally, in Attention Deficit Hyperactivity Disorder (ADHD), Bonferroni correction was applied to correct for multiple the microbiome might mediate behavioral (dys)function via testing (p < 2.29 × 10-06). specific reward related networks (1). Our hypothesis is Results: Polygenic risk scores for ADHD showed associations that colonization of germ-free mice (young male wild type with 77 traits: 17 were related to an increased BMI/body C57BL/6JOlaHsd) with human gut microbiota from males weight or fat mass, 9 indicated a higher frequency of with ADHD influences the animals’ behavior, brain function cigarette smoking and alcohol intake, 7 were related to and structure to mimic ADHD-symptomatology. more or earlier sexual relations and 5 indicated a lower Methods: To test this hypothesis, mice were housed and be- educational attainment or socio-economic position. Poly- havioural tests (Open Field, Marble Burying and Novel Ob- genic risk scores for ADHD were also associated with an in- ject Recognition) were performed in gnotobiotic isolators creased count of white blood cells, neutrophils, eosinophils after colonization with either mixed microbiota from ADHD and thrombocytes, as well as an increased risk for wheezing. patients or healthy matched controls. Thereafter, the mice Polygenic risk scores for autism showed associations with underwent brain scanning with an 11.7 T MR scanner. Micro- 9 traits: 4 traits for reduced heel bone mineral density that ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 5 is associated with osteoporosis; 2 traits for reduced erythro- sation using two-sample Mendelian Randomisation (2-SMR) cyte and thrombocyte distribution width, 2 traits related to was conducted using all available SNPs for MDD, BD, SBP increased body height and reduced childhood body size and and DBP in non-overlapping samples. MDD and BD SNPs were 1 trait indicating higher risk of being a nervous person. used as instrumental variables for SBP and DBP outputs, and There was no overlap of associated traits between the vice versa. two disorders. Results: In PRS analysis, only the MDD PRS predicted the hy- Discussion: Our results highlight that neurodevelopmental pertension phenotype, although this was not supported by disorder polygenic risk scores are associated with various LDSR. Interestingly, BUHMBOX analysis noted heterogene- health and lifestyle measures in the general population. If ity of MDD SNPs within hypertension, and pleiotropic SNPs causal effects of ADHD or autism on these measures are were also noted by cFDR analysis with SNPs in the vicin- replicated it will provide a strong argument that early and ity of FURIN, IZUMO1, TEX41 and MICB significant for both appropriate intervention could impact on long term physical mood disorder and blood pressure phenotypes. 2-SMR, how- and mental health, as well as future wellbeing via educa- ever, did not find evidence of causality between MDD/BD tion and socio-economic position. That focusing prevention and SBP/DBP. of key risk factors for cardio vascular diseases (e.g. smok- Discussion: We identified evidence of common genetic ing and obesity) should be considered in people identified causality across MDD and blood pressure, rather than direct as having ADHD. causation between each phenotype. In addition, we found evidence of a heterogeneous MDD group within hypertension Disclosure: Nothing to disclose. and several novel pleiotropic SNPs. Further investigation of the heterogeneous hypertension-MDD group may contribute doi: 10.1016/j.euroneuro.2018.08.229 to stratified medicine approaches for mood disorders.

Disclosure: Nothing to disclose. SA8

INVESTIGATING SHARED GENETIC MECHANISMS BE- doi: 10.1016/j.euroneuro.2018.08.230 TWEEN MOOD DISORDERS AND BLOOD PRESSURE

Nicholas Graham, Joey Ward, Breda Cullen, Keira Johnston, SA9 Rona Strawbridge, Amy Ferguson, Daniel Mackay, GENOME-WIDE ASSOCIATION STUDY OF SUICIDALITY IN Laura Lyall, Donald Lyall, Richard Shaw, Mark Bailey, 122,935 UK BIOBANK PARTICIPANTS IDENTIFIES TWO Jill Pell, Jonathan Cavanagh, Sandosh Padmanabhan, GENOME-WIDE SIGNIFICANT LOCI AND SUBSTANTIAL Daniel Smith GENETIC CORRELATION WITH DEPRESSION-RELATED TRAITS University of Glasgow Joey Ward, Nicholas Graham, Rona Strawbridge, Background: An association between raised blood pressure Breda Cullen, Richard Shaw, Laura Lyall, Donald Lyall, and mood disorder has been reported in epidemiological Jill Pell, Robert Pearsall, Mark Bailey, Daniel Smith studies but the mechanisms underlying this are unclear. Pos- sible explanations include common biological and/or en- University of Glasgow vironmental vulnerabilities, as well as a causal relationship. Focusing on genetic aspects, we aimed to investigate Background: Suicidal thoughts and behaviours are currently whether a genetic overlap exists, and whether such an over- a major issue for global public health, with up to 1 mil- lap is due to pleiotropy, heterogeneous diagnostic groups lion individuals worldwide completing suicide each year. We and/or putative causal relationships between mood disor- investigated the genetic contribution to suicidality by con- ders and blood pressure. ducting the largest genome-wide association study (GWAS) Methods: This study involved three stages: i) Assessment to date in 122,935 individuals from UK Biobank (including of genetic correlation: Linkage disequilibrium score regres- 39,265 individuals with suicidality). sion (LDSR) compared summary statistics for Major Depres- Methods: Suicidality was classified as an ordinal variable sive Disorder (MDD) and Bipolar Disorder (BD) with those for comprising five categories of increasing severity: no sui- Systolic and Diastolic Blood Pressure (SBP and DBP respec- cidality; thoughts that life was not worth living; contem- tively). Also, Polygenic risk score (PRS) analysis was used plation of self-harm or suicide; actual self-harm; and at- to assess prediction of hypertension by MDD and BD PRS, tempted suicide. A model was run using the CLM function in with a similar analysis conducted in reverse; ii) Investiga- the ‘ordinal’ package in R, assuming additive allelic effects tion of pleiotropy and heterogeneity: Breaking Up Hetero- at each SNP and adjusting for 8 genetic PCs, age, sex and geneous Mixture Based On Cross-locus correlations (BUHM- genotyping chip. BOX) analysis was used to examine whether enrichment of Results: Tw o loci, including a total of 36 SNPs, were asso- MDD/BD risk alleles were present in all cases of Hyperten- ciated with suicidality at genome-wide significance. One sion or a just within a subset. Similarly, SBP and DBP SNPs locus on chromosome 11 (lead SNP rs598046; p = 1.1 × 10-8) were assessed for enrichment within MDD and BD cases. was located within CNTN5, a brain-expressed gene encoding Additionally, pleiotropy-informed conditional false discov- an immunoglobulin family protein involved in neuronal cell ery rate analysis (cFDR) was conducted between outputs for interactions. CNTN5 SNPs have previously been associated BD/MDD and SBP/DBP; iii) a bidirectional assessment of cau- with loneliness and with response to lithium treatment in ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 6 Abstracts bipolar disorder. The other locus on chromosome 9 (lead results with quantitative traits, we performed a gene- SNP rs62535711; p = 1.3 × 10-8) was located within the based association analysis with GCTA fastBAT. As a result, ZCCHC7 gene. Linkage disequilibrium Score Regression 24,679 genes have been mapped and ACTR6 gene, ubiqui- (LDSR) analysis of the GWAS summary statistics suggested tously expressed in brain, was found to be most significant a significant polygenic contribution and SNP heritability (p = 3.38 × 10 −4). estimated at 7.6%. Significant genetic correlations were Discussion: Our approaches such as genome-wide G × E in- identified with MDD (rg = 0.63), neuroticism (rg = 0.62), teraction analysis may be useful in identifying susceptibility mood instability (rg = 0.50) and anxiety (rg = 0.75). genes for depression in workplace. Discussion: These findings represent novel potential genetic vulnerabilities for suicidal thoughts and behavior and pro- Disclosure: Nothing to disclose. vide support for substantial shared biology between suici- doi: 10.1016/j.euroneuro.2018.08.232 dality and both mood and anxiety disorders. Future work building on these findings will inform the development of more effective preventative and stratified medicine approaches for a behaviour that is of major importance for SA11 global health. DO PRS FOR SQUIZOPHRENIA, BIPOLAR DISORDER Disclosure: Nothing to disclose. AND MAJOR DEPRESSION DISTINGUISH BETWEEN AFFECTIVE-PSYCHOSIS DIAGNOSTIC CATEGORIES? THE doi: 10.1016/j.euroneuro.2018.08.231 EUGEI STUDY

Victoria Rodríguez 1, Diego Quattrone 2, Giada Tripoli 1,

SA10 Marta Di Forti 2, Robin Murray 1, Evangelos Vassos 2 GENOME-WIDE GENE-ENVIRONMENT STUDY OF DE-

PRESSION IN JAPANESE EMPLOYEES 1 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

Takeshi Otowa 1, Mihoko Shimada 2, Norito Kawakami 1, 2 King’s College London

Akizumi Tsutsumi 3 Background: It is well-known that Bipolar Disorder (BD) and

1 University of Tokyo Major Depression Disorder (MDD) aggregate in families, with

2 Tokyo Metropolitan Institute of Medical Science heritability rates as high as 80 and 40% respectively. It is

3 Kitasato University School of Medicine believed that there are probably many hundreds or thousands of common alleles that influence susceptibility to the Background: Work-related stress has been reported to most common psychiatric disorders, where each gene con- be associated with depression in employees. Recently, in fers only a fractional risk. A newly developed method called Japan, work-related stress (“stress check”) in employees polygenic risk score (PRS) allows us to summarize individual must be assessed in companies with more than 50 employ- risks for an illness across those associated variants into a ees. The aim of the present study is to identify genes that quantitative score. However, the variance explained by PRS influence the association of work stress with depression. for identifying case-control status is lower than expected. Therefore, we performed a genome-wide gene–environment Apart from the heterogeneity, another major reason is at- (G × E) interaction analysis in Japanese employees. In addi- tributed to the shared genetic load between disorders. Us- tion, as a complementary approach to single-locus analysis, ing data from the EUGEI case-control study of first-episode we also conducted gene-based analyses. psychosis (FEP), we test whether PRS for schizophrenia (SZ), Methods: A genome-wide screen with 680 subjects was per- BP and MDD enable to distinguish between categorical diag- formed using the Illumina 300K microarray chip. Work stress nosis under the umbrella of affective psychosis beyond the (job demand) was assessed using a subscale of the Japanese genetic overlap. version of the Job Content Questionnaire (JCQ) and depres- Methods: DNA from blood tests or saliva sample was ob- sive state was assessed with self-rating questionnaires using tained from most participants at baseline (73.6% of 1130 the K6 scale. We applied two phenotypic approaches: (1) cases and 78.5% of 1499 controls) among 16 European cities categorical comparisons based upon depressive category (K6 as part of the EUGEI study. PRS for SZ, BD and MDD were > 13), and (2) quantitative traits using continuous K6 scale. built using data from the Psychiatric Genomic Consortium The p values for interaction between single nucleotide poly- (PGC). DSM-IV diagnoses were extracted from interviews morphisms (SNPs) and work stress were calculated using lo- and mental health records utilizing the Operational Criteria gistic or linear regression model adjusted for sex and age. Checklist at baseline and were grouped into diagnostic Results: After quality control of genotype data, a total of groups (Bipolar Disorder, Psychotic Depression, Affective 233,016 SNPs on autosomal chromosomes were further an- psychosis -combination of two previous-, Non-affective alyzed. Although none surpassed the level of the genome- psychosis -other psychosis-) for clinical status comparisons wide significance, several SNPs were found to be nominally (affective psychosis vs non-affective psychosis, affective associated with depression (top SNP in categorical compar- psychosis vs control, bipolar disorder vs psychotic depres- ison, p = 1.74 × 10 −5; continuous traits, p = 1.70 × 10 −6). sion, bipolar disorder vs control and psychotic depression vs Studying depression as quantitative traits may be more control). We built different logistic regression models using effective than categorical comparison. Therefore, using separately the different PRSs as predictors for each clinical ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 7 comparison, adjusted by population stratification using the Results: HWE test for control groups found that 4 loci first 10 principal components (PC). are out of HWE. Single loci association analysis with Results: PRS SZ was the only able to distinguish between phenotype of mood disorder found significant associa- affective and non-affective psychosis, showing an associations for 6 polymorphic loci. They are BHLHB2_rs6442925, tion with non-affective psychosis (OR = 0.36, 95% CI .19 - CLOCK_rs12504300, CSNK1E rs135745, PER2_rs2304669, .67, p = 0.001). Both PRS SZ (OR = 3.08, 95% CI 1.76 –5.37 TIMELESS_rs4630333, and TIMELESS_rs1082214. Gene to p > 0.001) and PRS BP (OR = 1.92 95% CI 1.39 –2.63 p < 0.001) gene interaction between CSNK1E_rs135745 and TIME- identified affective psychosis from controls, whereas PRS LESS_rs4630333 was the best model for two loci (Balanced MDD only showed a trend. When comparing bipolar disor- accuracy 68.67, Cross Validation Consistency 10 out of 10). der with psychotic depression PRS SZ was the only able to For three loci, gene interaction among BHLHB2_rs6442925, distinguish between categories, showing an association with CSNK1E_rs135745 and TIMELESS_rs4630333 was the best bipolar disorder (OR = 2.89 95% CI 1.01 – 8.24, p > 0.001). model (Balanced accuracy 69.49, Cross Validation Consis- Both PRS SZ (OR = 5.59 95% CI 2.52 – 12.36, p < 0.001) and tency 6 out of 10). PRS BD (OR = 2.33 95% CI 1.49 – 3.65, p < 0.001) were signifi- Discussion: Using the MDR method, we found a two-loci cantly associated with bipolar disorder when compared with (CSNK1E and TIMELESS) and three-loci (BHLHB2, CSNK1E and controls; but interestingly, only PRS BD was positively asso- TIMELESS) interaction for mood disorder as a broad pheno- ciated with psychotic depression against controls (OR = 1.63 type. These results support that gene-gene interaction of 95% CI 1.07 – 2.48, p = 0.022). PRS MDD failed to identify both clock genes are playing for mood disorder. Further analyses bipolar disorder and psychotic depression versus controls. for individual mood disorder with large sample are neces- Discussion: These results suggest that once the explained sary. variance becomes more significant, PRS could be a useful marker to help us understanding the architecture of af- Disclosure: Nothing to disclose. fective psychosis; for both positioning it on the spectrum doi: 10.1016/j.euroneuro.2018.08.234 of psychotic or mood disorders and delineating diagnostic boundaries. This potential use in High Risk or FEP settings may imply important differences in treatment and progno- sis prediction. SA13 FUNCTIONAL CHARACTERIZATION OF ATP2C2, A Disclosure: Nothing to disclose. RISK FACTOR FOR LANGUAGE DISORDERS doi: 10.1016/j.euroneuro.2018.08.233 Angela Martinelli, Rebeca Diaz, Irene Feliciotti, Samantha Pitt, Silvia Paracchini

University of St Andrews SA12

GENE-GENE INTERACTIONS OF CLOCK GENES FOR Background: Developmental Language Disorder (DLD) is a BROAD PHENOTYPE OF MOOD DISORDER common condition diagnosed when children show unex- pected difﬁculties in talking and understanding spoken lan- 1 2 1 1 Eun-Jeong Joo , Inyoung Jun , Kyu Young Lee , Mira Park , guage. DLD is highly heritable ( ∼70%) and affects up to 7% 1 Soon Ae Kim of pre-school children in the UK. Only a few genetic factors have been reported so far. Among those, ATP2C2 is a

1 Eulji University, School of Medicine strong candidate supported by associations with both com-

2 Korea University mon and rare variants. ATP2C2 is expressed in the brain and encodes for SPCA2, a transmembrane protein involved in Background: Mood disorder is a complex phenotype, which the transport of Ca2 + and Mn2 + . Calcium is involved in the may result from interactions between multiple genes with regulation of several neuronal processes (e.g. neural migra- small effects and environmental factors. Clock genes are tion, synaptic plasticity, working memory) and manganese known to be strong candidate genes for mood disorder. This accumulation is toxic to human cells. SPCA2 is predicted to study was performed to identify gene-gene interactions of pump metal ions and maintain low levels of cytosolic cal- various clock genes which could be associated with the risk cium and manganese, crucial for cell signaling and prevent- of mood disorder. ing neurodegeneration. However, its exact function remains Methods: We included 472 patients with mood disorder and poorly understood. The aim of this study is to investigate at 1298 normal controls. They are all unrelated Korean. In both the molecular and cellular level how genetic variants this study, we included major depressive disorder, bipolar in ATP2C2 influence the protein function and affect brain disorder, dysthymia, cyclothymia, and depressive disorder, and language development. NOS based on DSM-IV as a broad phenotype of mood disor- Methods: We used qRT-PCR, Western Blot and immunofluo- der. Total 20 different SNPs and 1 VNTR polymorphic loci rescence to study the expression pattern of ATP2C2 and its among 9 different clock genes. Clock genes studied in this cellular localization. study are BHLHB2, CLOCK, CSNBK1E, NR1D1, PER1, PER2, As a functional assay, we used the planar lipid bilayer PER3, TIMELESS, and TRPM2. We analyzed gene-gene inter- technique, an electrophysiological approach that allows to actions among 21 polymorphic loci using the multifactor- monitor the activity of single proteins, as ion transporters, dimensionality reduction (MDR) method. in an extremely well-controlled artificial environment. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 8 Abstracts

Through this technique we were able to test the effects ent assays. These included cell motility assays and the newly of individual parameters such as pH, voltage and ions on developed Elastic Resonator Interference Stress Microscopy SPCA2 activity. (ERISM) system which allows the study of mechanical forces, Results: Our results support the expression of ATP2C2 in such as cell-substrate interactions, at single cell level. the nervous system. Notably, we detected high levels of Results: Gene expression analysis in zebrafish revealed a mRNA transcripts in human pre-frontal cortex, a region of specific pattern restricted to particular developing struc- the brain involved in language processing. tures confirming a role in the brain and in the auditory We studied the cellular distribution of endogenous and and visual systems as well as in the notochord. In partic- overexpressed SPCA2 in different cell lines. Our results ular, expression in the notochord was specific to kiaa0319, showed localization in the Golgi, plasma membrane and in contrast to the signal in the other structures which was vesicles. We successfully detected the current generated by detected in its paralogue (kiaa0319-like). ERISM shows that the transport of calcium and manganese through the pla- KIAA0319 plays a role in cell motility, migration and attach- nar lipid bilayer technique demonstrating that this method ment, three processes mediated by the cytoskeleton. is an effective functional assay for the characterization of Discussion: Taken together, these data support a role for the kinetic properties of SPCA2. KIAA0319 in cytoskeleton dynamics, consistent with its Discussion: While genetic mapping is necessary to identify involvement in neuronal migration. However, such role is risk factors, functional characterization is essential to unlikely to extend beyond brain development and contribute derstand the underlying molecular mechanisms contributing also to the development of sensory organs and the noto- to diseases. Here we combine different methodologies to chord. The dyslexia associated genetic variants reside in build an experimental framework that can be used to study regulatory sequences and might affect the KIAA0319 tightly candidate genes for neurodevelopmental disorders. regulated spatial/temporal expression pattern observed in Our preliminary results show that ATP2C2 is expressed in zebrafish. These data contribute to our understanding of the pre-frontal cortex and the protein appears to localize in the role of genes and genetic variants in neurodevelopment the plasma membrane, Golgi apparatus and vesicles. In the and to pinpoint processes relevant to neurodevelopmental future we will focus on DLD associated variants and investi- disorders. gate their possible effect on the ion handling compared to the wildtype SPCA2 activity. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.236 Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.235 SA15 A LINKAGE STUDY OF PEDIATRIC OBSESSIVE- COMPULSIVE DISORDER (OCD): RELEVANCE OF ANXIETY SA14 AND NEUROPLASTICITY THE KIAA0319 DYSLEXIA SUSCEPTIBILITY GENE

PRESENTS A HIGHLY SPECIFIC EXPRESSION PATTERN Ella Caubo 1, Theodore Epstein 2, Yuan Yuan Ding 3,

DURING ZEBRAFISH DEVELOPMENT AND PLAYS A ROLE Marco Grados 4 IN CYTOSKELETON DYNAMICS

1 University of Amsterdam

Silvia Paracchini, Rebeca Diaz, Monika Gostic, 2 Yale University

Nils Kronenberg, Angela Martinelli, Keith Sillar, Javier Tello, 3 Johns Hopkins University

Malte Gather 4 Johns Hopkins University School of Medicine

University of St. Andrews Background: Etiologic genes for obsessive-compulsive disorder (OCD) are plausibly shared with OCD-related condi- Background: The association between the KIAA0319 gene tions, such as anxiety, tic, hoarding, anxiety and grooming and dyslexia was reported almost 15 years ago and has disorders. Prior linkage studies for OCD have not explored since been consistently replicated in a number of studies. the use of alternate phenotypes in pedigrees ascertained In spite of significant efforts the KIAA0319 function still re- for pediatric OCD probands. We undertook a genetic linkage mains poorly understood. Initial characterizations showed analysis in the effort to discover etiologic genes in families a specific expression in the human developing cortex, and of pediatric OCD probands using the OCD phenotype, as well in utero shRNA experiments in rats suggested a role in neu- as alternate phenotypes: an anxiety score, and a neurode- ronal migration. Conversely, recent studies in mice reported velopmental score. effects in the auditory system but not in neuronal migration. Methods: Probands with pediatric OCD and extended rel- Methods: To further elucidate the function of KIAA0319 atives were psychiatrically phenotyped using standardized we conducted a characterization based on a range of ap- measures: the Kiddie Schedule for Affective Disorders and proaches. A detail gene expression analysis throughout ze- Schizophrenia (K-SADS) for children and the Scheduled Clin- brafish development was conducted with RT-PCR, in situ ical Interview for DSM-IV (SCID) for adult. To test for QTL hybridization and the highly sensitive RNAscope technique linkage to OCD the following quantitative traits were used combined with light-sheet microscopy. To investigate the in MERLIN, a statistical software package for genetic anal- function of KIAA0319, we generated stable cellular knock- ysis: an OCD impairment score (0-5), an anxiety score (0- outs with CRISPR-Cas9 and characterized them with differ- 5; sum of anxiety disorders) and a neuropsychiatric score ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 9

(0-4; sum of attention-deficit hyperactivity disorder (ADHD), 3 University Hospital of Würzburg hoarding, skin picking and tics). Genotyping used the Illu- 4 Virginia Commonwealth University mina Linkage Panel 12 with the calling algorithm BeadStudio 5 University of Edinburgh version 3.3.7 on a total of 5,920 SNPs. Stringent quality con- 6 Institute of Psychiatry, Psychology & Neuroscience, King’s trol reported a mean call rate 0.9994 + /- 0.0019. Based on College London an exploratory hypothesis-generating approach, SNPs with LOD > 3 were identified genes (UCSC browser) within 150 kb Background: Anxiety disorders are common, complex psy- up- and downstream of the SNP with LOD > 3. Filtering for chiatric disorders with twin heritabilities of 30-60%. Al- brain expression (SAGE, GTEx, Illumina, BioGPS), annotating though many candidate gene studies of anxiety disorders for pathways (Kyoto Encyclopedia of Genes and Genomes; have been carried out, these associations have not proved KEGG) and testing for statistically overrepresented path- robust. As is the case with other psychiatric disorders, it ways (Protein Annotation Through Evolutionary Relation- is likely that a multitude of common genetic variants with ship; PANTHER) was completed. modest effects, in addition to environmental factors, un- Results: 23 families were informative for genetic linkage, derlie the risk for anxiety disorders. Analyses of significantly comprising 83 first-degree and 59 extended relatives (to- larger samples than have been utilized to date are required tal sample N = 142). Four genetic loci contained SNPs with to further our understanding of the underlying genetic ar- LOD scores > 3. Genes 150 bk from peak SNPs were: TLL1 chitecture of anxiety disorders and current anxiety symp- (Tolloid-like 1) at 4q32.3 (LOD 3.29, anxiety score); FAK (Fo- toms at the population level. cal Adhesion Kinase) at 8q24.3 (LOD 3.48, anxiety score); Methods: Selecting from 126,443 individuals in the UK MYH13, GAS7 at 17p13.1 (LOD 3.41, neuropsychiatric score) Biobank, we conducted a genome-wide association study and PKC-gamma, CACNG7, CACNG8, MYADM at 19q13.42 of self-reported "Any Anxiety Disorder" (n = 69,535) and, by (LOD 3.17, anxiety score). More broadly, a total of 27 SNPs way of internal replication, two additional questionnaire- had LOD scores > 3, identifying 132 brain-expressed genes based anxiety phenotypes (n = 14,031 and n = 77,125). We which included DLG4 (PSD-95) and NLNG2. KEGG annota- then meta-analyzed the most comparable analyses with two tion favored the tight junction pathway (9/132). Other high external case-control studies of anxiety. Using the summary ranked pathways included the interconnected MAPK and statistics from these analyses we performed gene-based as- oxytocin signaling (4/132) pathways. Statistical overrepre- sociation, assessed SNP based heritability and examined ge- sentation using PANTHER identified cytoskeletal regulation netic correlations between different definitions of anxiety, by Rho GTPase, nicotinic acetylcholine receptor signaling and external phenotypes. and Wnt signaling pathways. Results: The liability scale common variant heritability es- Discussion: Loci-derived genes in this linkage study code timate for "Any Anxiety Disorder" was 31.1%, and for the for key hub proteins in neuroplasticity, using primarily the combined sample meta-analysis was 13.8%. Three novel anxiety phenotype. Included are FAK, (8q24.3) and PKC- genome-wide significant loci were identified including an in- gamma (19q13.42), which interact in signal transduction tergenic region on chromosome 9 that has previously been pathways supporting dendritic arborization (dendritic spine associated with neuroticism. Anxiety showed significant ge- growth), as well as CACNG7 and CACNG8 (19q13.42) which netic correlations with depression and insomnia as well as are calcium-channel regulatory proteins critical in AMPA re- coronary artery disease, mirroring findings from epidemio- ceptor trafficking (consolidation of long-term potentiation). logical studies. MYH13 (17p13.1), a myosin protein, is part of a network of Discussion: We conclude that common genetic variation ac- MYH genes which includes non-brain myosin proteins iden- counts for a substantive proportion of the genetic architec- tified in structural neuroplastic changes through cytoskele- ture underlying anxiety. Anxiety appears to share much of ton regulation. Anxiety etiologic genes appear to support its variance with related disorders, including depression and a neuroplasticity mechanism, opening up new questions on neuroticism. pathophysiology and treatment of anxiety. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.238 doi: 10.1016/j.euroneuro.2018.08.237

SA17 SA16 EXTRACTING STABILITY INCREASES THE SNP HERI- A MAJOR ROLE FOR COMMON GENETIC VARIATION TABILITY OF EMOTIONAL PROBLEMS IN YOUNG PEOPLE IN ANXIETY DISORDERS

Thalia Eley 1, Rosa Cheesman 2, Major Depressive Disorder

Kirstin Purves 1, Jonathan Coleman 1, Sandra Meier 2, Working Group of the Psychiatric Genomics Consortium,

Christopher Rayner 1, Katrina Davis 1, Shing Wan Choi 1, Kirstin Purves 2, Jean-Baptiste Pingault 3, Gerome Breen 2,

Jurgen Deckert 3, Helena Alexandra Gaspar 1, Fruhling Rijsdijk 2, Robert Plomin 2

John Hettema 4, Christopher Hübel 1, Manuel Mattheisen 3,

Kristin Nicodemus 5, Gerome Breen 1, Thalia Eley 6 1 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

1 King’s College London 2 King’s College London

2 Aarhus University Hospital 3 University College London ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 10 Abstracts

Background: Tw i n studies have shown that emotional prob- mammalian species with specific evolved characteristics, in- lems (anxiety and depression) in childhood and adolescence cluding a species with highly unusual social behaviors. are moderately heritable ( ∼20-50%). In contrast, DNA-based Methods: Using a novel statistical analysis strategy (Shared ‘SNP heritability’ estimates are generally < 15% and non- Genomic Segments), we discovered 10 genomic regions with significant. One notable feature of emotional problems is significant evidence of familial sharing in large, high-risk that they can be somewhat transient, but the moderate sta- ASD families. ASD was diagnosed using gold standard clin- bility seen across time and across raters is predominantly in- ical interviews and observation. Genotypes from the Illu- fluenced by stable genetic influences. This suggests that by mina OmniExpress array were used to identify significant capturing what is in common across time and across raters, genomic segments shared by ASD cases in the high-risk fam- we might be more likely to tap into any underlying genetic ilies. Resulting significant shared segments were then inter- vulnerability. We therefore hypothesized that a phenotype rogated for harboring regions of accelerated evolution in capturing the pervasive stability of emotional problems will mammalian species that evolved various distinctive traits, show higher heritability. including elephant, microbat, orca, dolphin, naked mole Methods: We fitted single-factor latent trait models us- rat (NMR), ground squirrel, hamster, orangutan, and prairie ing 12 emotional problems measures across ages 7, 12 and vole. Evolved traits can map onto phenotypes of interest 16, rated by parents, teachers, and children themselves. for human disease; for example, cancer resistance in ele- Tw i n heritability estimates for stable emotional problems phants. (N = 6110 pairs and unrelated individuals, respectively) were Results: Shared genomic segments that segregate in high- compared to those for individual measures. risk ASD families were found to harbor significantly more ac- Results: Tw i n heritability increased from 45% on average celerated regions (ARs) in the NMR than expected by chance for individual measures to 76% (se = 0.023) by focusing on (p = 1.84E-14); no other species showed significant enrich- stable trait variance. SNP heritability rose from 5% on aver- ment in ASD regions. The NMR is one of two known eusocial age (n.s.) to 14% (se = 0.049; p = 0.002). Heritability was also mammals. The result was robust to simulations accounting higher for stable within-rater composites. Polygenic scores for nonrandom genomic distribution of ARs. for both adult anxiety and depression significantly predicted Discussion: We show that genomic regions linked to ASD variance in stable emotional problems (0.4%; p = 0.0001). risk are significantly enriched for ARs specifically in NMR, a The variance explained was more than in most individual species that evolved highly unusual social behaviors. Results measures. Stable emotional problems also showed signifi- reveal novel candidate genomic regions for shaping mam- cant genetic correlation with adult depression and anxiety malian sociability. Our results establish a combined phyloge- (average = 52%). nomics and human genetics approach to identify new ele- Discussion: These results demonstrate the value of exam- ments of genomic control for an aspect of human behavior ining stable emotional problems in gene-finding and predic- strongly associated with autism and other psychiatric disor- tion studies. ders.

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.239 doi: 10.1016/j.euroneuro.2018.08.240

SA19 SA18 SOCIAL AND NON-SOCIAL DOMAINS OF AUTISM ARE SIGNIFICANT OVERLAP OF GENOMIC REGIONS FROM GENETICALLY DISSOCIABLE EXTENDED HIGH-RISK AUTISM FAMILIES WITH EVOLU-

TIONARILY ACCELERATED REGIONS IN A SPECIES WITH Varun Warrier 1, Roberto Toro 2, Bhismadev Chakrabarti 3,

HIGHLY UNUSUAL SOCIAL BEHAVIOR Hyejung Won 4, iPSYCH-Broad Autism Consortium,

Anders Børglum 5, Jakob Grove 5, 23andMe, Inc. Research

Hilary Coon 1, Elliott Ferris 1, Todd Darlington 1, Team, David A. Hinds 6, Thomas Bourgeron 6,

Jubel Morgan 1, Rob Sargent 1, Alison Fraser 2, Ken R. Smith 2, Simon Baron-Cohen 1

Nicola J. Camp 1, Christopher Gregg 1

1 University of Cambridge

1 University of Utah School of Medicine 2 Institut Pasteur

2 Huntsman Cancer Institute 3 University of Reading

4 UNC Chapel Hill

Background: Genetic discoveries for Autism Spectrum Dis- 5 Aarhus University order (ASD) have been numerous in the past decade, with 6 Institut Pasteur, University Paris Diderot, Sorbonne Paris evidence for over 100 common and rare variants. However, Cité these discoveries account for only a portion of the genetic risk of ASD. Much of this remaining risk may reside in no- Background: The core diagnostic criteria of autism com- toriously elusive variants controlling gene regulation. To ad- prise strengths and difﬁculties in two domains: social dress this substantial knowledge gap, we compared genomic interaction and communication (the social domain) and results obtained from extended families at high risk for ASD unusually repetitive and restricted behaviour and nar- with genomic regions exhibiting accelerated evolution in row interests (the non-social domain). Multiple lines of ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 11 evidence, ranging from factor analysis to bivariate twin SA20 genetic correlation of autism related phenotypes, suggest COPY NUMBER VARIANTS AND POLYGENIC RISK SCORES that the social and non-social domains of autism are dis- IN ADULTS WITH AUTISM SPECTRUM DISORDER (ASD): sociable. This has implications for genetic, biological, and RESULTS FROM THE NCMH ADULT ASD COHORT clinical studies of autism as most studies have investigated autism as a unitary condition. To date, there has been no Jack Underwood, Kimberley Kendall, Jennifer Berrett, molecular genetic evidence in support of the hypothesis Richard Anney, Marianne Van Den Bree, Jeremy Hall that the two domains of autism are dissociable.

Methods: We leverage GWAS data from social traits related Cardiff University to autism (self-report empathy using the Empathy Quotient (EQ), and family relationship and friendship satisfaction Background: Autism Spectrum Disorders (ASD) are lifelong measures) and a GWAS of a non-social trait related to neurodevelopmental conditions characterised by persistent autism, called systemizing, and defined as the drive to difficulties in reciprocal social interaction, communication, analyze or build rule-based systems. These were used restricted interests, stereotypic behaviours and resistance to investigate if these two domains are dissociable using to change. The increasing recognition of adult ASD has re- genetic correlation, genomic structural equation modelling, sulted in the ongoing development of specialist services, and polygenic score regression. We first present the results some of which offer genetic testing for individuals with ASD. of the first GWAS of systemizing (N = 51,564), and subse- This study aims to examine i) the rate of rare neurodevelop- quently include data from multiple GWAS of phenotypes mental copy number variants (CNVs) and, ii) the polygenic that are genetically correlated with autism to demonstrate risk scores (PRS) of a cohort of individuals diagnosed with that social and non-social traits related to autism are ASD in adulthood. genetically dissociable. Methods: 90 individuals with ASD but without intellectual Results: We identified three genome-wide significant loci disability, and 60 age- and sex-matched controls were drawn and identify a SNP heritability of 12% ±1.2 (P = 1.2 × 10-20) from the National Centre for Mental Health (NCMH) sample. associated with systemizing. Systemizing was significantly Inclusion criteria were diagnosis of ASD at age ≥18 consis- enriched for chromatin marks in adult and fetal brain. As tent with ICD10 diagnostic criteria by secondary health care predicted by phenotypic correlations, we identified a pos- professional on casenote review, without comorbid intellec- itive genetic correlation between autism and systemizing tual disability. Clinical psychiatric, physical and social phe- (rg = 0.26 ±0.06; P = 3.35 × 10-5), which is independent of notypic data and DNA was retrieved. Genotyping was car- genetic contribution to educational attainment and cogni- ried out on two versions of the Illumina PsychChip. CNVs tive aptitude. Crucially, we demonstrate that systemizing were called from the 90% common content of the two chips is not genetically correlated with social traits related to using PennCNV run through a Galaxy pipeline. We then an- autism, empathy, and social relationship satisfaction. Hi- notated a list of 53 CNVs associated with neurodevelop- erarchical clustering of 15 phenotypes genetically corre- mental disorders. For PRS analysis, PRS scores for ASD, at- lated with autism identified three clusters: a social cluster, tention deficit hyperactivity disorder, bipolar affective dis- a psychiatric cluster, and an intelligence cluster. Systemiz- order, major depressive disorder, Alzheimer’s disease and ing clustered closely with the intelligence, whilst empathy, schizophrenia were generated following marker and individ- friendship satisfaction, and family satisfaction clustered to- ual quality control. gether, forming the social cluster. The combination of signif- Results: The rate of neurodevelopmental CNVs was 3.8% icant negative genetic correlation with empathy and friend- (n = 5) in individuals with ASD and 1.3% (n = 1) in control but ship satisfaction, and significant positive genetic correlation this difference was not statistically significant. The five neu- with systemizing, is unique to autism among nine psychiatric rodevelopmental CNVs detected were 2q13 deletion (n = 2), conditions tested, suggesting that this combination mirrors 15q13.3 duplication (n = 1), 16p13.11 duplication (n = 1) in the core DSM-5 criteria for autism. Finally, polygenic scores individuals with ASD and a 2p16.3 deletion in a control indi- for systemizing are significantly positively associated with vidual. Of the PRS scores calculated by presence or absence repetitive and restricted behaviour in 2,231 autistic individ- of ASD, only the PRS derived from the ASD GWAS showed uals (P_FDRcorrected = 0.03), but not with social difficul- statistically significant difference by caseness. We calculate ties. In contrast, polygenic scores for friendship satisfaction that approximately 0.1286 (P < .00001) of variance can be and empathy are associated negatively with social difficul- explained from PRS derived from linkage independent mark- ties (P_FDRcorrected = 0.03), but not with restrictive and ers showing association at P < 1e-3 in the ASD GWAS (SNPS repetitive behaviour. in model = 433). Discussion: We provide molecular genetic evidence con- Discussion: Individuals with ASD had an increased rate of firming the hypothesis that the social and non-social do- neurodevelopmental CNVs though this was not statistically mains of autism are genetically distinct. We demonstrate significant. A statistically significant increase in burden of the utility of investigating traits related to autism in the CNVs in this group might be confirmed in a larger sam- general population to understand the polygenic architec- ple. However, it appears that the CNV rate was lower than ture of autism. that reported in pediatric ASD populations, who may have a greater neurodevelopmental symptom profile. PRS anal- Disclosure: Nothing to disclose. ysis demonstrated a significant contribution of polygenic doi: 10.1016/j.euroneuro.2018.08.241 load of ASD-associated common variants, detectable even in this relatively small sample size. Taken together, these ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 12 Abstracts

results suggest that adults presenting with ASD may have a one SNP (rs10204) on 3 -UTR of PRRT2 gene releases consis- lower burden of rare penetrant variants and a higher poly- tently segregation in six NDD patients (‘‘C’’ genotype) and genic contribution of common risk alleles than childhood one healthy carrier (‘‘T” genotype). ASD populations, potentially reﬂecting less severe neurode- Discussion: This study gave the prevalence of 16p11.2 velopmental disability. deletion in Chinese children with NDD, which conﬁrmed the prevalence is similar to that in Western NDD patients Disclosure: Nothing to disclose. and hinted that 16p11.2 deletion is the same genomic pathogenicity of NDD as other known ones. The discordant doi: 10.1016/j.euroneuro.2018.08.242 phenotypes among seven deletion carriers from three Chi- nese families illustrated the complexity and heterogeneity of phenotype of 16p11.2 deletion. The 16p11.2 deletion

SA21 combined a SNP (rs10204) of PRRT2 on the hemizygous allele

EXPLORING THE NEURODEVELOPMENTAL TRAJECTORY may be the modiﬁer gene of NDD phenotypic penetrance AND MODIFIER GENE OF 16P11.2 MICRODELETION of 16p11.2 deletion. The hypothesis that the haploinsufﬁ- USING INTRA AND INTER-FAMILY CARRIERS ciency of neurodevelopmental candidate genes combining one SNP within the CNV boost the risk for neurodevelopmen- 1 1 1 2 1 Chen Liang , Hua Xie , Fang Liu , Nan Wu , Yu Zhang , tal phenotype, might help to account for the pathogenesis 3 4 5 1 Yiping Shen , James Gusella , Jian Wang , Xiaoli Chen of other neurodevelopment-related genomic arrangement.

1 Capital Institute of Pediatrics Disclosure: Nothing to disclose.

2 Peking Union Medical College Hospital, Peking Union Med- doi: 10.1016/j.euroneuro.2018.08.243 ical College, Chinese Academy of Medical Sciences

3 Shanghai Jiaotong University School of Medicine, Harvard Medical School, Massachusetts General Hospital

4 Massachusetts General Hospital SA22

5 Shanghai Jiaotong University School of Medicine INVESTIGATING PARENT-OF-ORIGIN EFFECTS IN AUTISM SPECTRUM DISORDER USING NEXT GENERATION SE- Background: Neurodevelopmental disorders (NDDs) are a QUENCING DATA group of pediatric disorders with severely affected behavioral features caused by alterations in early brain devel- Niamh Ryan, Louise Gallagher, Elizabeth Heron opment. Causative genetic variants in NDDs can range in size from the substitution, deletion or duplication of a sin- Trinity College Dublin gle base pair, to structural variants and to altered copy numbers of an entire chromosome (aneuploidy) or genome. Background: Autism Spectrum Disorder (ASD) is a neuro- The 600 kb deletion region at 16p11.2 between 29.5 and developmental condition characterised by a core triad of 30.1 Mb is a typical recurrent copy number variation (CNV), symptoms that include difficulties with social interactions, which has been implicated as an important genetic risk of language impairments and a tendency towards repetitive NDDs. 16p11.2 deletion carriers present heterogeneity of behaviours. Autism affects roughly 1% of the population, phenotype, from completely healthy to different degrees of with a marked bias between the number of boys and girls autism spectrum disorders (ASDs) or intellectual disability affected (4:1 boys vs girls with ASD). Heritability estimates (ID), and its potential pathogenesis is unknown. suggest that the genetic contribution to ASD risk ranges Methods: 718 Chinese children with unknown NDD were re- from 50 - 60%. However, the genetic architecture of ASD is cruited from the affiliated Children’s Hospital of Capital In- highly complex, with common, rare and de novo variants stitute of Pediatrics. The FMR1 CGG triplet-repeat primed (CNVs, and point mutations) all being implicated as con- (TP)–PCR assay was used to rule out FMR1 full mutation. tributing to disease aetiology. Furthermore, for a large pro- Array comparative genomic hybridization (aCGH) and Mul- portion of ASD cases the genetic cause has yet to be iden- tiplex Ligand-Dependent Probe Amplification (MLPA) were tified. Next generation sequencing (NGS) data is becoming used to identify 16p11.2 deletion in NDD children. Targeted more readily available and provides the opportunity to study sequencing for the 25 annotated genes in 16p11.2 interval both common and rare variations simultaneously. In addi- was performed in 16p11.2 deletion carriers, exploring the tion, NGS data from trios and quads provides an opportu- potential modifier gene involved in NDD phenotypic hetero- nity to study more complex genetic mechanisms that may geneity. be implicit in disease risk. One such mechanism, genomic Results: Seven children were identified as FMR1 full mu- imprinting, has been gathering support in the literature as tation (CGG repeats > 200) among this Chinese NDD cohort playing a role in ASD. and then were ruled out. Three independent children with Genomic imprinting is an epigenetic mechanism that 16p11.2 deletion was identified using aCGH or MLPA, giving leads to mono-allelic gene expression by silencing one allele that the prevalence of 16p11.2 deletion in Chinese NDD co- in a parent-of-origin manner; paternally imprinted genes hort is 0.42% (3/711). This three 16p11.2 deletions are all are silenced when inherited from the father but expressed parental inherited. Among the seven 16p11.2 deletion car- when inherited from the mother and maternally imprinted riers in these three families, six present neurodevelopmen- genes are silenced when inherited from the mother but ex- tal abnormalities and one is healthy. The result of targeted pressed when inherited from the father. If the expressed sequencing in seven 16p11.2 deletion carriers showed only copy carries a disease associated variant, this mono-allelic ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 13 expression can lead to disease, while the silenced copy side-effects (ANKK1, BDNF, CNR1, COMT, DAT1, DRD2, DRD3, will not have a disease effect. Therefore, transmission bias DRD4, HTR1A, HTR2A, ABCB1, CYP1A2, CYP2C19, CYP2D6 y might be observed in affected offspring where a parent-of- CYP3A5) were investigated. origin effect is present. Results: Statistical analyses, considering age and sex as co- Methods: We have implemented a Bayesian statistical variates, revealed nominal associations between polymor- framework to identify imprinting parent-of-origin effects phisms in the genes ANKK1 (rs1800497) and DRD4 (exon associated with ASD, within known imprinted loci. This 3VNTR) with treatment response (p = 0.02 and p = 0.03, model incorporates prior information on ASD risk and likely respectively). Additionally, association was observed be- imprinting effects. tween polymorphisms in the genes ANKK1 (rs1800497), BDNF Results: Using this approach, we have analyzed both com- (rs6265), COMT (rs4633 & rs4680), and CYP3A5 (rs776746) mon and rare variants from whole exome sequencing data and presence of adverse reactions (p < 0.05 for all compar- generated from the Simons Simplex Collection of ASD trios isons). Regarding weight gain, statistical analyses revealed and quads. marginal associations between BMI and genetic polymor- Discussion: We aim to use this method to analyze additional phisms in BDNF (p = 0.05), CNR1 (p = 0.03), DRD3 (p = 0.03), NGS ASD datasets to further our understanding of the ge- HTR2A (p = 0.02) and LEPR (p = 0.02). However, no clear as- netic basic of ASD. sociations were found with weight gain during treatment, except for a significant association with a DRD2 polymor- Disclosure: Nothing to disclose. phism (rs1801028, p = 0.002). Discussion: Our results suggest a genetic contribution to doi: 10.1016/j.euroneuro.2018.08.244 treatment variability and side-effects observed in ASD patients during pharmacological treatment. However, the clinical utility of these findings need further investigation. SA23 STUDY OF GENETIC INFLUENCE ON TREATMENT RE- Disclosure: Nothing to disclose. SPONSE IN AUTISM doi: 10.1016/j.euroneuro.2018.08.245 MJ Arranz, Guijarro Silvina, Laura Ibañez, Aitana Bigorra, Isabel Rueda, Marta Salgado, Marta Carulla, Sergi Bodas, Amanda Cercos, Martha Cancino, Javiera Uribe, SA24 Amaia Hervas NETBI-OMICS –DATA EXCHANGE FOR DISTRIBUTED BIOBANKS IN THE INVESTIGATION OF MENTAL ILLNESS Hospital Universitari Mutua Terrassa

Fanny Senner 1, Johannes Pung 2, Marcella Rietschel 3, 3 2 4 Background: Autism spectrum disorders (ASD) are severe Stephanie Witt , Otto Rienhoff , Thomas Schulze and chronic neurodevelopmental disorders that affect about

0.5-1% of the population. 50-60% of ASD sufferers are 1 Institute of Psychiatric Phenomics and Genomics (IPPG), treated with psychotropic drugs, including atypical antipsy- Medical Center of the University of Munich chotics, stimulants and antidepressants. However, about 2 University Medical Center Göttingen

30% of them do not respond adequately to treatment, and 3 Central Institute of Mental Health, University of Heidel- in some cases suffer a significant deterioration of symp- berg toms with subsequent treatment retrieval. Additionally, the 4 Institute of Psychiatric Phenomics and Genomics (IPPG); treatment-induced weight gain observed in ASD sufferers is Ludwig-Maximilians-University Munich higher than the observed in adult patients and carries a high risk of severe metabolic disorders. Treatment failure and Background: Mental illnesses are among the common dis- adverse reactions have a negative effect on patients’ prog- eases in Germany. In order to better understand and treat nosis, often leading to noncompliance. The identification of the development of mental illness, isolated research is no biomarkers for the prediction of clinical outcome and side longer sufficient. For this purpose, the Federal Ministry effects would help to improve treatment efficacy and safety of Education and Research (BMBF) supports psychiatric rein ASD patients. To date, only a few studies have focused on search in Germany. With a term from 2015 to 2019, the the genetic influence on treatment response in ASD. Previ- BMBF is funding a research network with a focus on men- ous studies have associated genetic polymorphism in sero- tal and psychiatric illnesses. The "Research Network for tonin receptors and metabolic enzymes with response to Mental Illness" funding initiative created research consor- pharmacological treatment. However, those findings need tia for the most common psychiatric illnesses. To allow confirmation. The main aim of our study is the identification data from these consortia to flow together, three common of pharmacogenetic markers for the prediction of response cross-sectional platforms for biomaterials, clinical data and to pharmacological treatment in ASD. imaging data were established. The cross-sectional project Methods: A candidate-gene association study was con- NetBi-omics should serve as a biobank. Biobanks have be- ducted in a cohort of 143 ASD probands (88% boys, 12% girls) come a crucial component of big data research in all fields treated with psychotropic drugs (113 methylphenidate, 30 of medicine, in particular as regards genomic approaches. antipsychotics, antidepressants, anxiolytics or mood sta- However, biobanking faces several non-trivial logistical and bilizers). Twenty-five polymorphisms within 15 genes pre- ethical questions, with the majority of logistical and con- viously associated with response to psychotropics and/or ceptual issues arising from the ethical challenges. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 14 Abstracts

Methods: Within a research network of this size a central re- trans-diagnostic approach. We sought to examine risk fac- quirement for processing any data stems from data protec- tors for endophenotypes and personality traits in individu- tion requirements. As a cross-sectional project performed als with depression that are associated with depression as on many study locations, the data has to be pseudonymised well as other psychiatric disorders: neuroticism, extrover- in the different projects and locations. Also, it has to pass sion, schizotypy, as well as positive and negative activation, every local ethics committee to get an ethics approval. using the machine learning algorithm Random Forest (RF). NetBi-omics explores three problem-solving approaches: (1) Variable importance measures (VIMs) quantify the strength providing a common privacy policy for the three cross- of association between predictors and outcome using RF, sectional platforms for submission to the ethics commit- which represent both main effects and interactions. How- tees, (2) implementing a usable common IT-infrastructure ever, there are nearly 20 different VIMs, and no guidance on to capture the data in a data protection compliant proce- which VIM should be preferred. Some VIMs explicitly model dure and (3) establish the processes needed to capture bio- interactions, whereas others provide support for quantifica- material on different study locations. tion of interactions but are based on a single predictor. Results: A data protection concept and a broad informed Methods: We performed an extensive simulation study, consent based on the national data protection guidelines varying strength of association and presence of correlated was developed which was positively assessed by the Mu- predictors, to assess the performance of the different VIMs nich ethics commission (LMU) and serves as an example including our newly-developed VIM called iBranch or ’inter- for further ethics commissions. This rating can now be action Branching’. Three of the VIMs including iBranch were used as a model for further ethics committees. The tech- able to provide joint importance measures for two or more nological heart is a central identity management. A spe- predictors; the rest were specific to a single predictor. We cial characteristic of NetBi-omics is that at no time during applied these methods to 778 individuals with Major Depres- this project identifying patient data are stored. Pseudonyms sive Disorder in the Generation Scotland Cohort Study, with used in each research consortium within the research net- ∼150 predictors (personality, cognition, lifestyle and health work are converted again into another pseudonym. This cre- and related polygenic scores (PGS)) using the abovemen- ates a chain of pseudonyms which only can be returned tioned outcomes. to the identifying data within the initial research consor- Results: There were highly significant differences in the tium. The generation of pseudonyms will occur at all sites performance of the VIMs, particularly when predictors were via a browser-based software using a laboratory informa- strongly correlated. The joint importance measures out- tion management system. The IT-infrastructure is managed performed single importance measures when interaction by the Department of Medical Informatics of the University was present. The RF models explained 36% of the vari- Medical Center Göttingen. ation in schizotypy and neuroticism scores, 19% of the Discussion: NetBi-omics is a cross-sectional biobank for variation in activation (overall), and 15% of the vari- the collection, storage and provision of biomaterials. ation in extroversion. Top predictors for schizotypy in- Networking and international collaborations have become cluded activation, extroversion, current psychological dis- indispensable for successful research. As we move towards tress and a PGS for depression. For neuroticism, the top collecting more detailed data and a large quantity of predictors included current psychological distress, extro- biomaterials, the risk of re-identification increases; As version, activation, and depression, neuroticism and autism measures to bypass technical solutions to data security and PGS. The top predictors for activation included schizo- encryption are likely to develop faster than such solutions, typy, current psychological distress, neuroticism, smoking the protection of personal rights will remain a challenge to and a PGS for autism. For extroversion, top predictors the field of biobanking. included neuroticism, current psychological distress, activation, cognition, depression, neuroticism, cross-disorder Disclosure: Nothing to disclose. and schizophrenia PGS. Several interactions were identified with PGS: extroversion-neuroticism PGS for schizo- doi: 10.1016/j.euroneuro.2018.08.246 typy, current psychological distress-depression, cognition and cross disorder PGS as well as extroversion-cognition SA25 PGS for neuroticism, schizotypy-depression PGS for activa-

RISK FACTORS FOR ENDOPHENOTYPES FOR MDD: tion and current psychological distress-cross disorder, neu-

INTERACTION DETECTION USING MACHINE LEARNING roticism, schizophrenia and depression PGS, as well as cognition PGS-neuroticism PGS interactions for extroversion. The number of significant interactions involving PGS varied Kristin Nicodemus 1, M. Iqbal Rosiadi 2, Joeri Meijsen 3, across endophenotype outcomes, with one interaction for Archie Campbell 1, Caroline Hayward 1, David Porteous 1 schizotypy to 16 for extroversion. Discussion: Variation explained for the four endopheno- 1 University of Edinburgh types among depression cases was significantly different 2 School of Informatics, University of Edinburgh from 0. Interactions identified using novel joint importance 3 Centre for Genomic and Experimental Medicine, IGMM, measures that included PGS ranked highly, despite the fact University of Edinburgh that PGS individually did not individually show strong association. The simulation study showed that joint measures

Background: The Research Domain Criteria (RDoC) initiative improve interpretation of results from RF. seeks to reframe research on mental ill health by taking a ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 15

Disclosure: Nothing to disclose. schizophrenia (n = 5), ADHD (n = 2) and Alzheimer’s disease (n = 3). The top educational attainment module (P = 1e-08; doi: 10.1016/j.euroneuro.2018.08.247 Z = 5.67) was enriched for DNA-repair pathways and also associated with IQ (Z = 2.9), ASD (Z = 2.06) and mean caudate brain volume (Z = -3.38). The top anorexia module (P = 2e-

SA26 08; Z = 5.6) was enriched for amyloid precursor metabolism

GENETIC PREDICTION OF TISSUE-SPECIFIC GENE CO- and was also associated with major depression (Z = 2.46) and EXPRESSION MODULES AIDS IN BIOLOGICAL INTERPRE- mean accumbens brain volume (Z = 2.04). TATION OF GENOME-WIDE ASSOCIATION STUDIES Discussion: In summary, we report a new method, NetX- can, that can identify disease associated gene-networks us- 1 2 2 Veera Rajagopal , Georgios Voloudakis , Wen Zhang , ing only GWAS summary statistics. NetXcan can complement 3 3 3 Mads Engel Hauberg , Anders Børglum , Ditte Demontis , approaches such as PrediXcan that performs imputation at 2 CommonMind Consortium, Eric E. Shadt , the gene level.

Johan L.M. Björkegren 2, Panos Roussos 2 Disclosure: Nothing to disclose.

1 Aarhus University doi: 10.1016/j.euroneuro.2018.08.248 2 Icahn School of Medicine at Mount Sinai

3 Aarhus University, Centre for Integrative Sequencing (iSEQ), The Lundbeck Foundation Initiative for Integrative

Psychiatric Research (iPSYCH) SA27 BIOINFORMATICS ANALYSES OF PARALOGS OF HU-

Background: Recently, transcriptomic imputation has been MAN ALDEHYDE DEHYDROGENASE ENCODING GENE widely used as a secondary analysis in genome wide associ- WHICH PARTICIPATES IN METABOLISM OF ALCOHOL ation studies (GWAS). Imputing individual gene-expressions 1 2 using cis-genotypes has many caveats: poor prediction per- Andrii Venger , Olga Kolesnyk formance and high false positives. Here, we report a new transcriptomic imputation approach, named NetXcan, 1 Odessa National Medical University where we collectively impute a set of genes that belong to 2 National Center of Seed and Cultivars Investigations the same gene co-expression network. Odessa Methods: RNAseq raw counts (N = ∼6000 samples) from 37 tissues, including eight brain tissues, generated by the CMC, Background: In humans the primary pathway of ethanol GTEx and STARNET consortia, were used. Briefly, after QC metabolism involves oxidation to acetaldehyde by the en- and calculation of expression residuals adjusted for poten- zyme alcohol dehydrogenase (ADH). The acetaldehyde then tial confounders, we generated co-expression networks us- is further oxidized by the enzyme aldehyde dehydroge- ing the ‘coexpp’ R-package. We measured the expression nase (ALDH) to acetate, which is either excreted in the of each module by extracting the first five principal com- urine or reincorporated into intermediary metabolism as ponents (PCs). We imputed genetic variants for all samples acetyl-CoA. The hydrogen atoms that are released during using the HRC reference panel in Michigan server. After QC, these reactions are used to generate a compound called re- we retained ∼6 million variants. We performed GWAS and duced nicotinamide dinucleotide (NADH), with two NADH identified variants associated with each module-PC at P < molecules produced per molecule of acetate generated. 0.0001. Using these variants as predictors and module-PCs The resulting NADH and acetate are thought to provide both as outcomes, we trained glmnet elastic regression models, the excess reducing equivalents and excess acetyl-CoA that an approach similar to PrediXcan. We constructed SNP-SNP are needed as starting material for fatty acid synthesis, covariance matrix using 1000 genomes EUR genotypes. We which results in the development of fatty liver disease if used MetaXcan to infer module associations with 18 traits high amounts of alcohol are ingested over time. Both ADH (Psychiatric = 7, cognitive = 2, subcortical brain volumes = 8 and ALDH exist in different variants with different levels and neurodegenerative = 1) using GWAS summary statistics. of activity, therefore resulting in different rates of ethanol We applied 5% FDR correction for each trait separately. metabolism. The executed research is devoted to estima- For the trait-associated modules, we extracted the module tion of divergence between sequences of human aldehyde genes and identified the biological pathways enriched with dehydrogenase (ALDH) encoding gene. The ALDH genes are these module genes using gene set enrichment analyses. not localized to a single chromosome. Humans have 18 Results: We identified 1253 co-expression modules across genes encoding for members of the ALDH enzyme super- 37 tissues, on average ∼33 modules per tissue. The aver- family. Three of these—ALDH1A1, ALDH1B1, and ALDH2—are age prediction performance, measured by the correlation most relevant to acetaldehyde oxidation. The three ALDH between predicted and observed values averaged across all enzymes encoded by these genes share more than 68 per- ten folds, was 0.74 (SD = 0.15). This is significantly higher cent amino acid sequence identity; all three enzymes func- compared to predicting individual genes using PrediXcan, tion in the cell as homotetramers. The ALDH1A1 enzyme is where the average prediction performance was close to found in the cytosol, whereas both ALDH1B1 and ALDH2 are zero. We imputed module associations for 18 neuropsychi- produced in the nucleus but have leader sequences that di- atric traits. The highest enrichment was observed for edu- rect them to cell components called mitochondria, where cational attainment (112 significant modules). In addition, they exert their functions in the mitochondrial interior. Of we identified significant associations for anorexia (n = 1), the three isoenzymes, ALDH2 seems to carry out most of ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 16 Abstracts the oxidation of ethanol-derived acetaldehyde, as demon- ADH1B, and ADH1C genes1 produce closely related proteins strated by the effects of its inhibition by activated forms that function as homo- and heterodimers; their kinetic prop- of the medication disulfiram and by the effects of a func- erties, tissue localization, and developmental expression all tional polymorphism commonly found in East Asian popula- support major roles in oxidative ethanol metabolism in the tions (ALDH2 ∗2), in which a critical glutamate is substituted liver. The ADH4 gene is expressed almost exclusively in the by a lysine residue at position 504 of the precursor protein liver, where it contributes significantly to ethanol oxidation (487 of the mature protein). at higher levels of consumption. The product of the ubiqui- Methods: The evolutionary history was inferred by using tously expressed ADH5 gene is the glutathione-dependent the Maximum Likelihood method based on the Tamura-Nei formaldehyde dehydrogenase. The main functions of this model (Tamura et al., 1993). The sequences were taken enzyme are to oxidize formaldehyde to formic acid and to from KEGG GENES Database ( https://www.genome.jp ). terminate nitric oxide signaling. The human ADH5 enzyme Evolutionary analyses were conducted in MEGA5 (Tamura et was originally thought to contribute little to ethanol oxida- al., 2011). tion. Although the ADH6 gene has been identified, there are Results: The order of duplication of human ALDH encod- as yet no physiological data on the functions of the ADH6 ing gene is analyzed by Maximum Likelihood method. The enzyme. The ADH7 gene has a limited expression pattern tree with the highest log likelihood (-19135.3636) is shown. and mainly is found in endothelial cells, as well as dur- The percentage of trees in which the associated taxa clus- ing embryonic development when it may contribute to the tered together is shown next to the branches. Initial tree(s) metabolism of retinol, a form of vitamin A (Hurley et al. for the heuristic search were obtained automatically by ap- 2002). In adults, ADH7 has been implicated in the first-pass plying Neighbor-Join and BioNJ algorithms to a matrix of metabolism of ethanol taking place in the gastroesophageal pairwise distances estimated using the Maximum Composite tissues, before the ethanol is delivered to the liver via the Likelihood (MCL) approach, and then selecting the topol- portal vein (Hurley et al. 2002). ogy with superior log likelihood value. The tree is drawn to Methods: The evolutionary history was inferred by using scale, with branch lengths measured in the number of sub- the Maximum Likelihood method based on the Tamura-Nei stitutions per site. model (Tamura et al., 1993). Discussion: Three different ALDHs and their paralogs that Analyses were conducted using the Maximum Composite metabolize ethanol have been identified. The bioinformat- Likelihood model (Tamura et al., 2004). Evolutionary analy- ics analysis involved 19 nucleotide sequences. Codon posi- ses were conducted in MEGA5 (Tamura et al., 2011). tions included were 1st + 2nd + 3rd + Noncoding. All positions Results: The order of duplication of human ADH encoding containing gaps and missing data were eliminated. There gene was calculated. The tree with the highest log like- was a total of 961 positions in the final dataset. The prod- lihood (-5711.0071) is shown. The percentage of trees in ucts of these genes assemble into dimers in different com- which the associated taxa clustered together is shown next binations and participate in metabolism of alcohol. to the branches. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ Disclosure: Nothing to disclose. algorithms to a matrix of pairwise distances estimated using the Maximum Composite Likelihood (MCL) approach, doi: 10.1016/j.euroneuro.2018.08.249 and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths mea- SA28 sured in the number of substitutions per site.

PARALOGS OF HUMAN ALCOHOL DEHYDROGENASE Discussion: The estimation of divergence between se-

ENCODING GENE THAT MAY INFLUENCE ALCOHOL quences of human ADH encoding gene has been accom- plished and shows the number of base substitutions per DEPENDENCE site from between sequences. The analysis of divergence between sequences of human ADH encoding gene involved Olga Kolesnyk 1, Andrii Venger 2 7 nucleotide sequences. Codon positions included were + + + 1st 2nd 3rd Noncoding. All positions containing gaps and 1 National Center of Seed and Cultivars Investigations missing data were eliminated. There were a total of 1085

Odessa positions in the ﬁnal dataset. 2 Odessa National Medical University Thus, seven different ADHs that metabolize ethanol have been identiﬁed. The products of these genes assemble into

Background: The executed research is devoted to estima- dimers in different combinations. ADHs may differentially tion of divergence between sequences of human alcohol de- influence risk for the development of alcohol dependence hydrogenase (ADH) encoding gene. Humans have seven ADHs across various ethnic groups. that can carry out the first step in alcohol metabolism. The genes encoding these enzymes all are localized on chro- Disclosure: Nothing to disclose. mosome 4 in a head-to-tail array about 370 kb long. The enzymes produced from these genes all differ slightly in doi: 10.1016/j.euroneuro.2018.08.250 their activities. There are seven paralogs of ADH; the first ADH1 enzyme has got three subunits A, B and C. The ADH1A, ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 17

SA29 contribute to the genomic precision health and medicine THE GENETIC RELATIONSHIP BETWEEN REPRODUCTIVE (monitoring individual health and early intervention based BEHAVIOUR TRAITS AND SIX PSYCHIATRIC DISORDERS on his or her actual genotypes). For example, the ADHD risk in offspring can be more precisely predicted by modelling Guiyan Ni, Sang Hong Lee information of the reproductive behaviours and genetic factors in addition to psychosocial factors. On the other hand, University of South Australia the knowledge of the shared genetic architecture can contribute to promoting for women reproductive health associ-

Background: Female reproductive traits have an important ated with mental disorder liability. implication in reproductive health and evolutionary fitness. Disclosure: Nothing to disclose. In epidemiological research, there are evidences to suggest that reproductive traits are phenotypically associated with doi: 10.1016/j.euroneuro.2018.08.251 increased risk of psychiatric disorders in offspring. Beyond the evidence of phenotypic association, studies have found the shared genetic architecture between reproductive traits SA30 and psychiatric disorders. For example, age at first birth VARIANCE COMPONENT TEST FOR CROSS-DISORDER (AFB) is genetically associated with risk of schizophrenia PATHWAY ANALYSIS (SCZ). However, for other psychiatric disorders and reproductive traits, the latent shared genetic architecture is Jin Szatkiewicz 1, Rachel Marceau 2, Zeynep Yilmaz 1, largely unknown. Here, we investigate the association of Cynthia Bulik 1, James Crowley 1, Manuel Mattheisen 3, five reproductive traits and six psychiatric disorders, which Patrick Sullivan 1, Wenbin Lu 2, Arnab Maity 2, can contribute to promoting for women reproductive health Jung-Ying Tzeng 2, PGC-ED Working Group, PGC-OCD and the best child outcomes by preventing the risk of psy- Working Group, The Swedish Schizophrenia Study chiatric disorders. Collaboration Methods: We used the second wave of UK Biobank data = (N 220,685) to evaluate the association between five re- 1 University of North Carolina at Chapel Hill productive traits and polygenetic risk scores (PRS) projected 2 North Carolina State University from genome-wide association study summary statistics of 3 University of Wuerzburg six psychiatric disorders. The projection was conducted using MTG2. The five reproductive traits are AFB, age at

ﬁrst sexual intercourse (AFS), age at menarche (AMC), age Background: Genetic correlations and comorbidities among at menopause (AMP) and number of live births (NLB) and psychiatric disorders are common. Large-scale cross- six psychiatric disorders are attention-deﬁcit/hyperactivity disorder studies are on-going aiming to identify unique and disorder (ADHD), autism spectrum disorder (ASD), eating shared genetic risk factors in a manner that transcends di- disorder (ED), bipolar disorder (BIP), major depressive dis- agnostic boundaries. Advanced analytic methods that lever- order (MDD), and SCZ. Using a linear model, we assessed if age co-heritability and comorbidities among psychiatric dis-

PRS of the disorders signiﬁcantly predict the phenotypes of orders are urgently needed as existing methods have critical the reproductive traits. We also estimated the genetic cor- limitations. When exploring genetic associations, traditional relation (rg) among all pairs of traits and PRS via LDSC. analyses follow a “bottom-up" approach, examining one

Results: In the liner model analyses, the PRS of the six gene (or variant) and one disorder at a time, using meta- psychiatric disorders were signiﬁcantly associated with at analysis to combine results for multiple genes/disorders. least one of the ﬁve reproductive traits. In particular, the These approaches may be underpowered due to failure to

PRS of ADHD were a substantially signiﬁcant predictor of address comorbidities of disorders, coheritability of variants

AFB (R2 = 1.1E-02, P = 1.2E-303), AFS (P = 3.3E-253), NLB and due to high multiple testing burden.

(P = 9.7E-43) and AMP (P = 3.2E-31). There were also robust Methods: We propose a variance component test under the associations between the PRS of ASD and AMC (P = 5.3E- framework of multivariate generalized linear mixed model

06), ED and AFB (P = 6.5E-14) and ED and AFS (P = 4.7E- (MV-GLMM) to simultaneously analyze the effects of mul-

08). The associations were also evidenced by genetic cor- tiple genes along a pathway on multiple diseases, where relation analyses. AFB was inversely genetically correlated the disease information is collected from non-overlapping with ADHD (-0.68 ± 0.03), MDD (-0.27 ± 0.07) and positively subjects. The proposed MV-GLMM accommodates both bi- genetically correlated with ASD (0.16 ± 0.06), BIP (0.12 ± nary and continuous traits, accounts for the multi-trait cor-

0.05) and ED (0.35 ± 0.06). The genetic effects of AFS were relation from non-overlapping subjects, uses random ef- inversely correlated with those of ADHD (-0.56 ± 0.03), MDD fects to model the joint effect of high dimensional genes,

(-0.27 ± 0.07) and SCZ (-0.10 ± 0.03). For AMC and AMP, and assesses pathway-level associations by testing for the there was no signiﬁcant rg with any of the six psychiatric corresponding variance component. Compared to single- disorders except that rg between AMP and ADHD was signiﬁ- disorder pathway analysis, the cross-disorder analysis based cantly different from zero (-0.27 ± 0.04). NLB had a positive on MV-GLMM explicitly incorporates cross-disorder similar- rg with ADHD (0.36 ± 0.04). ity, thereby increasing information content and yielding in-

Discussion: We revealed the complex bio-social genetic risk creased power to detect both unique and shared genetic architecture underpinning the association between repro- effects. ductive traits and six psychiatric disorders, which ultimately Results: First, we demonstrate the utility and performance of our method over single-disorder pathway analysis via ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 18 Abstracts simulation studies. Then we conduct a proof of concept for shrinkage of effect estimates in any multiple-testing study using published GWAS data from PGC-ED, PGC-OCD, scenario. and The Swedish Schizophrenia Study. SNP data were available for all 3 disorders (AN, OCD, and SCZ), all imputed Disclosure: Nothing to disclose. and prepared using the PGC Ricopili pipeline. CNV data are doi: 10.1016/j.euroneuro.2018.08.253 only available for SCZ. The results suggest that our method demonstrates improved performance to detect associations that are unique to one disorder or shared among multiple SA32 disorders. FAMILIAL RISK FOR BIPOLAR DISORDER IS ASSOCIATED Discussion: Future work will further extend our method to include non-coding regions. WITH DECREASED NEUROCOGNITIVE PERFORMANCE IN UNAFFECTED RELATIVES: A PRELIMINARY REPORT Disclosure: Nothing to disclose. FROM THE AMISH-MENNONITE BIPOLAR GENETICS (AMBIGEN) PROJECT doi: 10.1016/j.euroneuro.2018.08.252

Emily Besancon 1, Fabiana Lopes 1, Lexie Wille 2,

Mariana Mallmann 3, Layla Kassem 1, Francis McMahon 2

SA31 1 National Institute of Mental Health

“PERMUTATION SHRINKAGE” APPLIED TO GWAS RE- 2 NIH/NIMH

SULTS INCREASES EXPLANATORY POWER OF POLY- 3 Universidade Católica Dom Bosco (UCDB) GENIC RISK SCORES BY 35% Background: Psychiatric nosology based only on symptom 1 1 1 Paul O’Reilly , Yunfeng Ruan , Shing Wan Choi , measures has proven to lack strong correspondence to un- 2 Loes Olde Loohuis derlying genetic risk factors, leading to renewed interest in performance-based assessments, such as neurocognitive

1 King’s College London tests. However, performance deﬁcits may be a consequence

2 University of California, Los Angeles of psychiatric illness or its treatment. Family-based designs provide one approach to this confound, since unaffected Background: A major challenge in statistical inference is relatives share genetic (and other) risk factors with their estimating population effect sizes from finite samples. The affected kin that may manifest as performance deficits in problem is particularly pertinent in big data settings where the absence of psychiatric symptoms. Here we report pre- the effects of numerous factors are estimated, with many liminary findings on neurocognitive performance assessed having a substantial contribution from stochastic variation within large families ascertained from Amish and Mennon- (“Winner’s Curse”). Several shrinkage techniques have been ite founder populations introduced to address this –e.g. Lasso, Ridge and Least An- Methods: A neurocognitive battery including six assess- gle Regression. ments covering general intelligence, working memory, ex- Methods: Here we introduce a novel method - Permutation ecutive functioning, and emotion recognition was adminis- Shrinkage - that is simple, highly intuitive, fast and requires tered to an initial sample of 85 probands diagnosed with no parameter optimisation. The kth largest effect estimate bipolar disorder or related conditions (BD) and 238 of their is adjusted by subtracting the kth largest effect estimate unaffected relatives. All probands were assessed with the expected under the null, estimated by re-analysing the data Diagnostic Interview for Genetic Studies (v 4); relatives under permutations of the outcome. Permutation allows the were screened for psychopathology with self-report mea- null effect sizes to be estimated while preserving sample sures. Neurocognitive performance was compared between characteristics and the correlation structure between pre- cases and unaffected individuals, and among unaffected rel- dictors. atives grouped by relatedness to the proband (105 first-, Results: We demonstrate via simulation that Permutation 25 second-, and 108 third-degree relatives). Age, sex, and Shrinkage has remarkably similar performance to Lasso re- education were included as covariates, where appropriate. gression in many settings, despite involving no parameter Data points lying more than 3 SD from the mean were ex- optimisation, while it outperforms the Lasso when effect cluded. All data were analyzed using SPSS Version 22. Heri- sizes are homogenous. We then apply Permutation Shrink- tability of the neurocognitive parameters was analyzed us- age to genome-wide association studies (GWAS) on a range ing SOLAR v 8.3.2. of traits across the UK Biobank and show that the effect size Results: As expected, probands scored more poorly than un- estimates after adjustment are systematically closer to out- affected individuals on several measures, including digit- of-sample estimates. Finally, we show that the explanatory symbol (p = 0.009), DANVA errors (p = 0.007), and Trails power (R2) of polygenic risk scores (PRS) based on GWAS A (p < 0.001). Among unaffected relatives, degree of re- adjusted by Permutation Shrinkage is increased by 20%-70% latedness to the proband was also significantly associ- (mean 36%). ated with decreased performance on the digit-symbol Discussion: While Permutation Shrinkage will not offer uni- (p < 0.0001), DANVA (p = 0.007), and Trails A (p = 0.027) versal improvement over alternatives, we have demon- tests. All tests were significantly heritable, especially BD strated its benefits in the GWAS setting and believe that it (H2r = 0.49, p < 0.001), DANVA (H2r = 0.3, p = 0.001), and provides an interesting new option in the statistical toolkit Trails A (H2r = 0.3, p = 0.03). ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 19

Discussion: These data suggest that decreased neurocogni- R2 = 0.8%). However, ADHD-PT did not differentiate the UK tive performance may be a heritable marker of familial risk BP cases from controls. for BD. Further research is needed to address the genetic 2. Both in the total RO and UK BP samples ADHD-PRS and neural underpinnings of these deficits and any relation- PT significantly predicted the linear Wender score with P- ships with specific risk alleles. values from 0.042 to 0.008 (R2 = 0.9% to 1.5%). 3. In the RO sample the ADHD-PRS differentiated the BP Disclosure: Nothing to disclose. cases with cADHD (N = 203) from controls at all PT with best P-values for PT-0.1 to 0.5 (P = 0.007, R2 = 2%). No ADHD-PT doi: 10.1016/j.euroneuro.2018.08.254 differentiated the cases with cADHD (N = 162) from controls in the UK sample, although a trend (P = 0.06) was observed for PT_0.4 and PT_0.5.

SA33 4. No ADHD-PRS PT differentiated between cases with ADHD POLYGENIC RISK SCORES IN ROMANIAN AND cADHD (N = 203) and cases with no cADHD (N = 267) in the UK BIPOLAR PATIENTS WITH CHILDHOOD ADHD RO sample, but in the UK sample four PRS-PT distinguished between cases with cADHD (N = 162) and cases with no 1 2 Maria Grigoroiu-Serbanescu , Giovani Giaroli , cADHD (N = 310) (best P Pt_0.01 = 0.015; R2 = 1.8%). 2 2 3 Johan Thygesen , Oris Shenyan , Tim Bigdeli , 5. Both in the RO and the UK BP sample all ADHD-PRS PT 2 4 5 Nicholas Bass , Carmen C. Diaconu , Andreas J. Forstner , signiﬁcantly predicted the Wender score when sex was used 6 2 Markus M. Nöthen , Andrew McQuillin as a covariate (P = 0.01 to 0.004). 6. There was a strong inﬂuence of the covariate AO on

1 Alexandru Obregia Clinical Psychiatric Hospital, Medical ADHD–PRS loading in the total BP RO and UK samples (PAO University, Bucharest < 0.000) with a negative correlation between BP-AO and

2 University College London ADHD-PRS loading. Comparing the early onset (EO) cases

3 SUNY Downstate Medical Center (AO ≤ 21) with the late onset cases (AO > 22) the ADHD-

4 Stefan S. Nicolau Institute of Virology PRS predicted the linear Wender score only in EO cases in

5 Institute of Human Genetics, University of Bonn, School of both samples, although at different PT. Medicine & University Hospital Bonn, University of Basel Discussion: We are the ﬁrst investigators to use polygenic

6 Institute of Human Genetics, University of Bonn, School of risk score analysis to investigate ADHD as a trait in bipo- Medicine, University Hospital Bonn lar disorder. The results demonstrated increased ADHD PRS in bipolar subjects with ADHD symptomatology in childhood Background: The comorbidity between bipolar disorder and these findings were influenced by the age of onset of BP (BP) and ADHD has been observed in family studies which and by gender. These results extend the findings of overlap- suggests a shared genetic basis for the disorders. Faraone ping genetic aetiology between BP and ADHD. et al (2012) reported in a meta-analysis an ADHD prevalence of 27% in the offspring of BP-I parents and 16.5% in BP-I par- Disclosure: Nothing to disclose. ≤ ents compared to 5.29% in the general population aged 18 doi: 10.1016/j.euroneuro.2018.08.255 years (Polanczyk et al, 2007) and 2.5% in adults (Simon et al, 2009). A meta-analysis of PGC ADHD GWAS data (Neale et al, 2010) and PGC BP GWAS data (Sklar et al, 2011) identified two genome-wide significant common loci for BP and ADHD and an additional locus for early onset BP ( ≤21 y) and ADHD (Van Hulzen et al, 2017). SA34 The objective of our study was to investigate the shared STUDY OF RARE AND COMMON GENETIC VARIATIONS IN genetic basis of childhood onset ADHD (cADHD) and BP using NINE MULTIPLEX FAMILIES WITH BIPOLAR DISORDER polygenic risk scores (PRS) derived from the latest GWAS of ADHD (Demontis et al, bioRxiv, 2017) for predicting the Elisa Courtois 1, Annabelle Henrion 1, Caroline Barau 2, presence of cADHD in BP patients and their association with Bruno Etain 3, Philippe Lecorvoisier 4, Marion Leboyer 5,

BP age-of-onset (AO) and proband sex in our target samples. Stephane Jamain 6, FACE-BD Fondamental Advanced

Methods: cADHD was retrospectively rated using the Wen- Centers of Expertise in Bipolar Disorders 7 der Utah Rating Scale (Ward M et al, 1993) with a cut-off of 46 for diagnosing cADHD in 470 BP-I Romanian (RO) pa- 1 INSERM U955, Psychiatrie Translationnelle, Université tients and 472 BP UK patients. GWAS genotype data were Paris Est generated using the Omni Express array for the RO sample 2 AP-HP, Hôpital H. Mondor –A. Chenevier and from the PsychChip for the UK samples. GWAS data was 3 AP-HP, Hôpital Lariboisiere Fernand Widal, INSERM U 705 available for all patients and 329 RO and 1287 UK controls. CNRS UMR 8206, Paris Diderot University

Ten ADHD-PRS P-thresholds (PT) ranging from PT_0.01 to 4 INSERM, Centre d’Investigation Clinique 1430 and APHP

PT_0.5 were computed in the RO and UK samples. The sta- 5 INSERM U955, Psychiatrie Translationnelle, Université tistical analysis was performed with R. All reported P-values Paris Est, AP-HP, Hôpital H. Mondor –A. Chenevier, Pôle are nominal with no correction for multiple testing. de Psychiatrie

Results: 1. ADHD-PRS signiﬁcantly discriminated between 6 INSERM U955, Psychiatrie Translationnelle, Université cases and controls in the RO sample. The best discrimination Paris Est, Fondation FondaMental, Créteil was found for PT-0.1 to PT-0.5 (P-values = 0.034 to 0.028; 7 Fondation FondaMental, Créteil ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 20 Abstracts

Background: Bipolar disorder (BD) is a complex psychiatric Background: Bipolar disorder (BD) is associated with pre- disease with a heterogeneous genetic model, combining mature mortality and higher incidence of age-related disor- common variants with a small effect and rare variants of ders compared to the general populations. Several studies higher penetrance. During the past decade, many genome reported premature cell senescence in BD, as shown by re- wide association studies used common polymorphisms to duced telomere length in affected subjects. Recent findings unravel the genetic architecture of BD but were able to have also shown that antidepressants and lithium (Li) may explain only 25% of the genetic variance. In contrast, few have a protective effect against telomere shortening. In our family studies with a high density of illness have been con- previous work (Squassina et al., 2016, PMID: 27084304) we ducted, whereas they provide a relevant support to identify showed that duration of Li treatment is inversely correlated rare high penetrant variants, which might explain this miss- with leukocyte telomere length (LTL) in BD patients. In the ing heritability. current study, we compared LTL between BD patients and Methods: To demonstrate the contribution of common and non-psychiatric controls and tested if Li treatment may af- rare variants in BD, we combined both a whole exome se- fect LTL in BD in a larger sample compared to our previous quencing (WES) and a genotyping of more than 900,000 poly- work. morphisms in 9 multiplex families with BD (42 subjects, of Methods: The sample comprised 313 BD patients and 316 whom 28 were affected). We compared the contribution of non-psychiatric controls of Sardinian ancestry. Diagnosis of common variations in families with a population of 452 pa- BD was done according to DSM-IV and SADS-L criteria. Pa- tients with BD and 1,636 controls. We also looked at the tients were characterized for Li response using the “Retro- distribution of rare variants discovered in families in a co- spective Criteria of Long-Term Treatment Response in Re- hort of 284 WES of patients with BD and the ExAC cohort search Subjects with Bipolar Disorder” (Alda scale). Cor- with non-psychiatric individuals. relation between LTL and age at onset, number of manic Results: In our families, we did not observe a signifi- and depressive episodes, years of illness before start of Li cant contribution of a polygenic accumulation of common treatment and duration of Li treatment was also assessed. variants previously identified in the Psychiatric Genomics DNA was extracted from leukocytes and relative LTL mea- Consortium genome-wide association study. However, we sured using SYBR Green real-time PCR as previously de- showed an accumulation of rare damaging variants in con- scribed. Correlation between LTL and age was assessed us- strained genes. A cellular component analysis of mutated ing nonparametric Spearman’s correlation test. Correlation genes highlighted an enrichment in different parts of neu- between LTL and quantitative variables was determined us- rons, suggesting that neuronal genes were more frequently ing the partial correlation and linear regression tests con- mutated in families with aggregation of BD. Mutation rates trolled for age. Differences in LTL between cases and con- for these genes were thus compared in a larger population trols and between BD patients stratified for Li-exposure and of patients with BD and unaffected controls. controls were tested using Man-Whitney test and linear re- Discussion: Our results suggest that the common polygenic gression models. variants have a minor effect on the clinical manifestation of Results: LTL correlated negatively with age (P < 0.001, BD in multiplex families. In contrast, rare variations in con- Spearman’s rho = −0.16) and was independent of sex (p > strained genes expressed in neurons seem to play a signifi- 0.05). Partial correlation test corrected for age confirmed cant role in BD vulnerability. Although these rare variations the positive correlation between LTL and Li treatment du- may explain a part of the missing heritability, we did not ration in patients with at least 24 months of treatment also show differences between affected and unaffected subjects in the extended sample (n = 173, beta = 0.17, p = 0.03), in our families, suggesting a significant role of environmen- while there was no effect of the other variables tested. tal factors on the disease onset. BD patients had longer LTL compared to healthy controls (beta = -0.16, p = 0.00002). To test if Li treatment influ- Disclosure: Nothing to disclose. enced the observed difference in LTL between affected and non-affected individuals, we divided the BD sample into two doi: 10.1016/j.euroneuro.2018.08.256 groups according to Li exposure. BD patients treated with Li for at least one year (n = 234) had longer LTL compared to patients never exposed to Li (n = 62; p = 1.5 × 10-8). The latter group showed reduced LTL compared to controls (mean LTL 1.11 vs 1.37 respectively), though this was not

SA35 statistically signiﬁcant (p > 0.05). DIFFERENCES IN LEUKOCYTE TELOMERE LENGTH Discussion: Our data show that BD patients have longer BETWEEN BIPOLAR DISORDER PATIENTS AND NON- LTL compared to controls, a ﬁnding that is apparently in PSYCHIATRIC CONTROLS ARE INFLUENCED BY LITHIUM contrast with the hypothesis of accelerated aging and cell TREATMENT senescence in BD. However, this difference was exclusively driven by Li treatment, as BD patients exposed to Li had

Alessio Squassina 1, Claudia Pisanu 1, Donatella Congiu 1, longer LTL compared to both never-exposed patients and

Carla Melis 1, Eleni Merkouri Papadima 1, Paola Caria 1, healthy controls, while BD subjects never exposed to Li had

Tinuccia Dettori 1, Giovanni Severino 1, Alberto Bocchetta 2, shorter though not signiﬁcant telomeres compared to con-

Roberta Vanni 1, Maria Del Zompo 1, Caterina Chillotti 2 trols. Our data farther support previous ﬁndings showing that long-term Li treatment has a protective effect against

1 University of Cagliari telomere shortening in BD. Further analyses are ongoing to

2 University Hospital of Cagliari ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 21 validate our ﬁndings in independent samples and to account stable temperament in BD-I patients and their non-BD-I rel- for the effect of variables associated with aging. atives. In addition, we show evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes. Disclosure: Nothing to disclose. These results underscore the importance of regulated sleep and activity, in particular for individuals with BD-I and those doi: 10.1016/j.euroneuro.2018.08.257 at risk.

Disclosure: Nothing to disclose. SA36 GENETIC ANALYSIS OF ACTIVITY, BRAIN AND BE- doi: 10.1016/j.euroneuro.2018.08.258 HAVIORAL ASSOCIATIONS IN EXTENDED FAMILIES WITH HEAVY GENETIC LOADING FOR BIPOLAR DISORDER SA37

Annabel Vreeker 1, Scott Fears 2, Susan Service 2, HERITABILITY OF ALZHEIMER’S DISEASE –COMPAR-

Lucia Pagani 3, Costa Rica-Colombia Bipolar Consortium, ISON OF TWIN AND POLYGENIC METHODS

Nelson Freimer 4, Carrie Bearden 2

Ida Karlsson 1, Chandra A. Reynolds 2,

1 UMC Utrecht Valentina Escott-Price 3, John Hardy 4, Margaret Gatz 5,

2 UCLA Nancy L. Pedersen 6

3 University of Texas Southwestern Medical Center

4 Semel Institute for Neuroscience and Human Behavior 1 Institute of Gerontology, School of Health and Welfare, Jönköping University

Background: Disturbed sleep and activity are prominent 2 University of California-Riverside features of bipolar disorder type I (BD-I). However, the rela- 3 MRC Centre for Neuropsychiatric Genetics & Genomics, tionship of sleep and activity characteristics to brain struc- Cardiff University ture and behavior in euthymic BD-I patients and their non- 4 Institute of Neurology UCL

BD-I relatives is unknown. In addition, underlying genetic 5 University of Southern California relationships between these traits have not been investi- 6 Karolinska Institutet gated. Methods: Here, we investigated multi-generational pedi- Background: Genetic factors explain a substantial propor- grees including at least 1 member with known BD-I from the tion of the variance in Alzheimer’s disease (AD). Tw i n stud- genetically related populations of Antioquia, Colombia and ies have estimated the heritability of AD at 60-80%, while the Central Valley of Costa Rica. We analyzed the relation- Genome-wide Complex Trait Analysis (GCTA), a method uti- ships between 12 sleep and activity phenotypes assessed lizing all available SNPs across the genome to assess her- using actigraphy to structural neuroimaging, cognitive and itability, estimated the heritability at 53%. Differences in temperament phenotypes that we found to be associated heritability estimates from the two methods largely stem with BD-I in our previous studies. In addition, we assessed from the fact that they capture different aspects of heri- the genetic correlation between actigraphy-brain and tability. While twin studies capture all additive and nonaddi- actigraphy-behavior associations and carried out bivariate tive genetic variance shared among twins, the GCTA method linkage analysis on trait pairs that showed evidence of captures only additive, common genetic variants tagged by shared genetic influences. the genotyping array. However, heritability estimates from Results: Thirty-four actigraphy-brain traits were signifi- both methods may be influenced by validity of the outcome cantly associated, following multiple comparison correc- measure, age and representativeness of the study population. More specifically, higher activity levels (as reflected tion, and similar factors, and a direct comparison is thereby either more physical activity or reduced sleep) were as- fore difficult. In this study, we therefore performed a twin sociated with larger brain volumes and cortical thickness model alongside GCTA using the same sample. and smaller ventricular volume. In addition, there were 41 Methods: The study sample consisted of 11,677 individuals significant actigraphy-behavior traits associations, showing from the Swedish Tw i n Registry, including 831 AD cases and that higher activity levels were related to better long-term 10,846 controls. All had genotype data imputed against 1000 memory, (verbal) working memory, processing speed and ex- Genomes Project phase 1 version 3 data, as well as informa- ecutive function. Higher activity levels were also related to tion about age at end of follow-up and sex. Principal com- lower impulsivity, lower psychosis proneness and a more sta- ponents (PCs) were created using GCTA. First, a biometri- ble mood. The associations did not differ between BD-I pa- cal ACE twin model was fitted, adjusting for age and sex. tients and their non-BD-I relatives. Of the significant asso- The method compares the phenotypic correlation between ciations, we found genetic correlations for 9 activity-brain monozygotic and dizygotic twin pairs to tease out propor- or activity-behavior pairs. Of these pairs, we identified a tions of variance attributed to additive genetic effects (A), quantitative trait locus on chromosome 7 for mean of wake shared environmental effects (C), and non-shared environ- duration and verbal working memory. mental effects (E). Secondly, GCTA was performed, setting Discussion: Our results show that higher activity, as re- disease prevalence to 10% and adjusting for age, sex, and 5 flected by more adequate sleep and more physical activ- PCs. ity, is related to larger brain volumes and thickness, smaller Results: The sample included 4,544 complete twin pairs, ventricular volume, better cognitive function and a more all of which were included in the twin model. The resulting ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 22 Abstracts heritability was estimated at 63% (standard error [se] 18%, amount of independent regions (P < 0.0025). The variation p < 0.001), with non-shared environmental factors explain- of CD2AP known to be associated with AD (rs10948363) was ing the remaining 37% (se 6%, p < 0.001). After excluding part of an associated LD region but failed significant associ- related individuals with kinship coefficient > 0.025, while ation on its own. preferentially keeping cases over controls, 6,284 individu- Discussion: Results of this study indicate an influence of als remained for the GCTA analysis. The resulting heritabil- LOAD associated variations on cognitive performance in ity was estimated at 42% (se 13%, p < 0.001). healthy controls. Additionally, 3 index SNPs of an allocated Discussion: Based on the same study sample, we demon- gene, CD2AP, which acts as a major intracellular signaling strated a twin-based heritability of 63% and a SNP-based molecule coordinating axon-sprouting and structural plas- heritability of 42%. This indicates that while a substantial ticity in humans showed significant associations. These find- proportion of the genetic variance of AD is in fact due to ad- ings could help to improve the knowledge of the pathophys- ditive effects of multiple common SNPs, additional genetic iology and genetics of cognitive decline. However, further factors may also play an important role. research is needed to validate these associations and detect the functional relevance of the affected genes and varia- Disclosure: Nothing to disclose. tions. doi: 10.1016/j.euroneuro.2018.08.259 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.260 SA38 ASSOCIATION OF SNPS IMPLICATED IN ALZHEIMER’S DISEASE WITH COGNITIVE PHENOTYPES SA39 SEARCHING FOR THE CAUSAL EFFECTS OF GENETIC Annette Hartmann, Bettina Konte, Lisa Endlich, VARIANTS FOR ALZHEIMER’S DISEASE IN UK BIOBANK Marius Krause, Ina Giegling, Dan Rujescu USING PHENOME-WIDE ANALYSIS

Martin Luther University Halle-Wittenberg Roxanna Korologou-Linden, Louise Millard, Wes Spiller, George Davey Smith, Laura Howe, Emma L. Anderson, Background: Late onset Alzheimer’s disease (LOAD) is a Evie Stergiakouli chronic and progressive neurodegenerative disorder affecting the elderly and is accompanied by severe cognitive de- MRC Integrative Epidemiology at the University of Bristol cline. Genetics is supposed to be one of the key factors for the susceptibility to the disease. Several loci have been as- Background: Observational studies for Alzheimer’s disease sociated with an increased risk of developing Alzheimer’s have reported conflicting evidence for most potential modi- disease in genome-wide association studies (GWAS). The aim fiable risk factors. This may be due to bias from confounding of this study was to investigate whether 9 previously con- and reverse causation that can be problematic in observa- firmed AD associated SNPs affect cognition in a population tional studies. Furthermore, the hypothesis-driven nature of of healthy subjects. In addition, we selected one of the al- previous work has introduced further bias into our knowl- located genes, CD2-asscociated protein (CD2AP), for a de- edge of risk factors for Alzheimer’s disease. Alzheimer’s tailed analysis. disease is highly heritable with estimates as high as 79%. Methods: Therefore, 2147 unrelated healthy subjects of Genetic studies have identified 21 single nucleotide poly- German descent as part of the PAGES sample were selected. morphisms associated with late-onset Alzheimer’s disease, Psychiatric disorders were excluded using the Structured all exerting low to modest effects (except for those in the Clinical Interview for DSM-IV (SCID 1 and SCID 2). Family apolipoprotein E gene). We perform a phenome-wide asso- history was recorded to exclude a positive family history ciation analysis to investigate the causal effects of a poly- for psychiatric disorders. The Mini Mental Status Examina- genic risk score (PRS) for Alzheimer’s disease on a large and tion (MMSE) was conducted for every subject older than 60 diverse array of phenotypes, without a prior and without the years, to exclude possible cognitive impairments. Cognitive biases present in most observational studies. performance was assessed via the German version of the Methods: We used a sample of 334,968 participants from UK Wechsler Adult Intelligence Scale, Revision 1991 (WAIS-R). Biobank, and generated a PRS calculated as the weighted Genotype data was obtained using chip technology and im- sum of the risk-increasing alleles identified in a genome- putation. Nine variations previously implicated in AD were wide association study of Alzheimer’s disease (Lambert et selected for analysis. In addition, 385 SNPs located in the al. 2013). We performed a phenome-wide association anal- CD2AP gene clumped into 20 LD-independent loci were an- ysis of this PRS on 21,868 traits, using the PHEnome Scan alyzed. Analysis was calculated using an additive linear re- Analysis tool (PHESANT) (Millard et al. 2017). We also exam- gression model. ined whether findings varied by age. Results: In the first analysis screening for an influence of AD Results: We identified associations of the PRS for associated SNPs on cognition one SNP (rs983392) showed sig- Alzheimer’s disease with family history of dementia, own nificant association (P = 1.92 × 10-4) with the subtest verbal diagnosis of dementia, death from dementia, and brain information after correction for the amount of SNPs tested. related-measures (e.g. lower mean intra-cellular volume in For the CD2AP based analysis 3 index SNPs were significantly parahippocampal part of cingulum, lower cognitive func- associated with different subtests after correction for the tion). Other factors associated with the PRS included ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 23 lifestyle (e.g. more days of moderate/vigorous activity), bi- association between depression and an increasing level of ological measures (e.g. lower monocyte percentage), higher intensity in the exercise practiced. risk of diseases (e.g. atherosclerotic disease, delirium), and Results: Out of the 4,507 individuals that participated in physical measures (e.g. lower body mass index). The associ- the study, 295 (6.5%) had depression and the rest 4.212 ations observed for the entire sample appear to be driven by (93.45%) were controls. To sum up, 2.214 were men (49.1%) data at mean age 58 years and above. For the youngest sam- and 2.293 were women (50.9%) with a mean age of 42.8 ple with mean age 47 years (39-53), we only identified as- years (SD = 15.22). After doing a frequency analysis, we sociations with biological measures, hypercholesterolemia found a statistical significant association between the prac- and family history of dementia. tice of exercise and a lower rate of depression ( χ2 = 18.6; Discussion: The novel factors identified by our phenome- p < 0.0001), showing a decrease of 40% in the frequency of scan may either lie on the causal pathway from genetic pre- depression in participants who practice exercise (OR: 0.597; disposition to Alzheimer’s disease or may be a consequence 95%IC = 0.4-0.7). We also found a lineal significant associa- of a higher genetic risk for Alzheimer’s disease. These novel tion showing the greatest intensity of exercise and the low- associations should be replicated in independent cohorts. est probability of depression ( χ2 = 3.8; p = 0.049). Discussion: This study confirms the results from previous Disclosure: Nothing to disclose. studies and provides additional support for a protective effect of physical exercise against depression. Besides it doi: 10.1016/j.euroneuro.2018.08.261 shows the importance of exercise intensity, so that at higher intensity, less presence of depression. This study also highlights the importance of including physical exercise in the

SA40 treatment of depression, either alone or combined with an-

PHYSICAL EXERCISE DECREASES THE RISK OF DE- tidepressant drugs / psychotherapy. This could decrease de- PRESSION IN THE GENERAL POPULATION: EVIDENCE pressive symptoms and improves the quality of life of pa- FROM THE SPANISH PISMA-EP STUDY tients with depression.

Margarita Rivera, Alejandro Porras-Segovia, Disclosure: Nothing to disclose. David Lopez-Chavez, Esther Molina, Blanca Gutierrez, doi: 10.1016/j.euroneuro.2018.08.262 Jorge Cervilla

University of Granada SA41

Background: In the first century AC, roman poet Juvenal de- GENOME-WIDE GENE-ENVIRONMENT ANALYSES OF clared the importance of a right balance between mind and DEPRESSION AND REPORTED LIFETIME TRAUMATIC body with his famous quote ‘Mens sana in Corpore Sano’. EXPERIENCES IN UK BIOBANK Among the many mental health disorders that have been 1 2 1 associated with physical exercise, major depression stands Jonathan Coleman , Thalia Eley , Gerome Breen out for the strength of such association as well as for the impact that this condition has in our society. In the past 1 King’s College London few decades, a number of studies have addressed this is- 2 Institute of Psychiatry, Psychology & Neuroscience, King’s sue. Several epidemiological studies have found a significant College London association between physical exercise and depression. This association has often been found to be bidirectional. In a re- Background: Depression and reported trauma exposure cent meta-analysis of 24 observational studies (n = 193,166), have a complex relationship, such that individuals with de- sedentarism was confirmed as a risk factor for major depression are more likely to report previous exposure to pression. Additionally, physical exercise has been found to trauma and to experience later traumatic events. In addi- be an effective preventive strategy. The aim of this study is tion to this, both depression and reported trauma exposure to investigate if there is an association between practicing are heritable traits, implying genetic influences. Genetic exercise and depression, as well as to explore the possible research into the relationship of depression and reported influence that its intensity may have on depression. trauma exposure has been inhibited by small sample sizes Methods: The PISMA-ep is a cross-sectional epidemiological and differing methods of measurement, and the conclusions study of mental disorders based on a sample of 4,507 from previous high-quality studies have been contradictory. individuals representative of the general adult population Methods: In 92,957 individuals from the UK Biobank, we ex- of Andalusia, Spain. A DSM-IV diagnosis of major depression amined genetic influences on depression (as defined from was ascertained using the MINI interview. The information questions asked as part of the mental health follow-up ques- on physical exercise was briefly assessed with 3 questions tionnaire derived from the Composite International Diagnos- which cover the type of exercise the person practices, the tic Interview) in individuals with or without reported trauma number of hours per week and the intensity of the exercise. exposure (defined as reporting two or more categories of The association between depression and physical exercise traumatic experience across the lifespan). Specifically, we was tested in two ways: 1) Using χ2 tests to compare performed genome-wide association studies of depression the frequency of physical exercise between individuals stratified by reported trauma exposure, and assessed SNP- with depression and controls, and; 2) Using the variant heritability, genetic correlations (in LDScore) and polygenic of Mantel-Haenszel of the χ2 to test if there was a linear risk score analyses (using PRSice). ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 24 Abstracts

Results: Depression was heritable in participants reporting decreased appetite and/or weight, and all current MDD pa- trauma exposure (16-23%) and in unexposed individuals (8- tients) were checked for enrichment of 162 inflammatory 14%, both liability scale), and the genetic correlation be- pathways with a Wilcoxon rank-sum test. tween the groups was substantial (0.77) and not significantly Results: Analyses indicated that 32 inflammatory path- different from 1 (p = 0.11). Genetic correlations with pub- ways were significantly (FDR < 0.1) enriched in MDD with lished traits indicate strong genetic correlations of depres- increased appetite and/or weight. Among the 32 enriched sion with other psychiatric traits, which were common to inflammatory pathways in MDD with increased appetite exposed and unexposed individuals. However, significant ge- and/or weight were inflammasome and cytokine signaling netic correlations of depression with BMI (and related traits) pathways, namely IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-12, and and with educational attainment were observed only in in- IL-22. Of these, 20 pathways were uniquely enriched in this dividuals reporting trauma exposure, and the magnitude of group and were not found in the total current MDD group. these correlations was significantly greater than those seen Only two pathways (adaptive immune system and IL8- and in unexposed individuals (p range: 0.0002-0.001). CXCR2-mediated signaling) were enriched in MDD with de- Discussion: Although there is considerable genetic similar- creased appetite and/or weight, which were also enriched ity between depression in individuals reporting trauma ex- in the total current MDD group and the group with increased posure (16-23%) and in unexposed individuals, there are in- appetite and/or weight. trinsic differences. Specifically, genetic correlations with Discussion: The results show that, at the gene expression depression observed only in individuals reporting trauma ex- level, several dysregulated inflammatory pathways play a posure suggest genetic influences in this group partially re- larger role in MDD patients with increased appetite and/or flect environmental exposures, which is reminiscent of ear- weight during an active episode. We confirm the importance lier ideas of reactive and endogenous depression. of inflammation in MDD pathology, especially for those who display symptoms of increased appetite and/or weight. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.263 doi: 10.1016/j.euroneuro.2018.08.264

SA42 PATHWAY ENRICHMENT REVEALS A STRONG INVOLVE- SA43 MENT OF INFLAMMATORY CYTOKINE PATHWAYS IN ANALYSIS OF GENETIC AND ENVIRONMENTAL CON- DEPRESSED PATIENTS WITH SYMPTOMS OF INCREASED TRIBUTION TO ALTERED GENE EXPRESSION PROFILES APPETITE AND WEIGHT OBSERVED IN MAJOR DEPRESSIVE DISORDER

Hilde de Kluiver 1, Rick Jansen 2, Yuri Milaneschi 1, Edoardo Giacopuzzi 1, Chiara Sacco 1, Alessandra Minelli 2,

Brenda Penninx 1 Massimo Gennarelli 1, Chiara Magri 2

1 VU Medical Center 1 IRCCS San Giovanni di Dio Fatabenefratelli

2 Vrije Universiteit 2 University of Brescia

Background: The pathology of Major Depressive Disorder Background: Major Depressive Disorder (MDD) is a com- (MDD) is highly heterogeneous. Previous evidence shows plex disabling psychiatric condition among the top five that the role of inflammation, as measured with CRP or IL-6 leading causes of disability throughout the world. Recent protein level, in MDD pathology is stronger in MDD patients genetic studies identified some reproducible risk loci for characterized by increased vegetative symptoms (i.e., ap- MDD, but the extent of the contribution from genetic ar- petite and weight) during an active episode. Which exact in- chitecture and environmental factors in altering disease- flammation gene pathways can differentiate MDD subgroups related biological mechanisms remains to be investigated. in terms of gene expression is unknown. This study aims to The aim of this study is to investigate the contribution of identify inflammatory pathways enriched in gene expression the genetic background and of environmental factors on profiles of subgroups of current MDD cases stratified accord- altered expression profiles observed in MDD by dissecting ing to symptoms of change in appetite and/or weight. observed gene expression levels in their two major compo- Methods: Whole-blood gene expression profiles, measured nents: an expression component regulated uniquely by ge- with Affymetrix U219 arrays, were analyzed from a total netic polymorphisms (GReX) and a component influenced by 881 current MDD cases (with a DSM-IV based diagnoses in the environmental/disease-related factors (EDeX). prior six months) and 331 controls (without psychiatric diag- Methods: We analyzed genotype and blood expression data nosis in lifetime) from the Netherlands Study of Depression from the Levinson’s dataset (NIMH Study 88), that includes and Anxiety (NESDA). The MDD patients were stratified ac- 463 MDD patients and 459 controls of European-ancestry. cording to appetite and/or weight increase/decrease during PrediXcan tool was used to estimate GReX. EDeX was com- a depressive episode, resulting in 246 cases with increased puted from the residuals of a linear regression model that and 341 cases with decreased appetite and/or weight. The correlated the observed gene expression levels with the pre- results of differential gene expression analyses between dicted GReX levels. The contributions of EDeX and GReX controls and the three MDD (sub)groups (i.e., MDD patients components were studied for the innate immune response with increased appetite and/or weight, MDD patients with and interferon signaling, the biological mechanism found ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 25 altered in the original study. To get further insights on bi- tion in depressed individuals, others have described oppo- ological mechanisms altered by genetic background in MDD, site patterns. The aim of our study was to determine the GReX component was estimated in ten brain tissues. methylation pattern of 15 CpG regions within the promoter Results: Using PrediXcan we predicted the GReX compo- IV in a clinical sample diagnosed with depression compared nent in blood for 5,359 autosomal genes. Analysis of EDeX to controls. We also wanted to determine if there was a pos- and GReX gene expression levels in MDD and controls re- sible mediation of stress on those methylation levels. vealed some differentially regulated genes for both compo- Methods: We examined blood samples from patients diag- nents, but none survived multiple test correction. Gene-set nosed with depression (n = 47) and controls (n = 43). All par- enrichment analysis for EDeX component revealed signifi- ticipants signed informed consent and completed a series of cant enrichment (DAVID enrichment score > 1.30) for clus- psychological tests (Mini-International Neuropsychiatric In- ter involved in innate immune response and interferon sig- terview, State-Trait Depression Inventory, State-Trait Anx- naling, proteins of intracellular organelles, Golgi apparatus iety Inventory, Life Events Questionnaire). Early and late and protein for transport and localization. The same anal- stressful events and history of childhood abuse was also ysis performed on the GReX component revealed no signif- evaluated, as well as the value given to certain life events icant enrichment on the innate immune system, while sig- (positive/negative, controllable/no controllable). We mea- nificant enrichments emerged for cell adhesion and cell-cell sured the global methylation level of BDNF promoter IV and interaction. Genes with low p-values in the analysis of GReX the methylation levels of 15 CpG positions through direct or EDeX were significantly over-represented among genes sequencing of bisulfite-treated DNA (BSP) from leukocytes. with an observed differential expression between MDD and The DNA methylation analysis was performed using the ESME controls. software. Data analysis included T-test, linear regressions Finally, the analysis of GReX components in the ten brain and analysis of variance. tissues revealed, in the nucleus accumbens (basal ganglia), Results: We found that the overall methylation of the BDNF a significant enrichment of genes involved in the function of promoter IV and the specific methylation levels in three cilium/primary cilium. out of 15 CpG sites were significantly different between pa- Discussion: The results of the EDeX and GReX analyses sug- tients and controls (p < 0.001 each). In all these cases the gest a small contribution of the genetic background on the methylation was higher in controls compared to depressed differences in gene expression levels observed in MDD pa- subjects. A model including the methylation level at two of tients, especially for the interferon signaling pathway. Our those three CpG sites (BDNF IV CpG 1: NG_011794.1: 25369 data suggest that the dysregulation reported in MDD could and CpG 9: NG_011794.1: 25469) can explain in 34,6% the be triggered by the genetic background, but a strong con- categorization as control or depressive patient (p < 0.001). tribution of environmental factors is needed to exhibit a Regarding stress variables, we found that 45% of the pa- biological effect on the individuals. Finally, the analysis of tients had a history of abuse, while in controls this value GReX in blood and in brain tissues suggested new biological was 19%, varying significantly (p = 0.008). Being exposed to pathways potentially related with MDD, but further studies abuse during childhood seems to reduce the methylation will be required to unravel their no obvious biological mean- level at two CpG sites (BDNF IV CpG 5: NG_011794.1: 25416 ings. and CpG 9) within the promoter. Those same regions ap- peared to be hypomethylated in subjects exposed to psy- Disclosure: Nothing to disclose. chological stress and in those that tend to evaluate in a negative way certain life events or who claim to have no control doi: 10.1016/j.euroneuro.2018.08.265 over them. Those two CpG regions contain binding sites for genes as glucocorticoid receptors (GR- Alpha 1) and GATA- 1, which have been involved in depressive behavior since it

SA44 represses synapse-related genes under stressed conditions.

WHAT CPGS CAN TELL: AN APPROACH TO THE METHY- Discussion: Our study shows overall and speciﬁc hy- LATION PATTERN OF BDNF PROMOTER IV IN MAJOR pomethylation patterns within certain CpG sites in the BDNF DEPRESSION DISORDER AND ITS RELATION TO STRESS promoter IV in patients, suggesting that these epigenetic marks could be useful in the diagnosis of this psychiatric 1 1 María Marcela Velásquez Toledo , Yvonne Gómez Maquet , disorder. Also, it points out that the stress history and indi- 2 3 1 Eugenio Ferro , Álvaro Arenas , Catalina Uribe , vidual responses to life events could be playing an impor- 1 1 Ileana Manzanilla , Claudia Lattig tant role in the epigenetic regulation of the promoter. The question remains whether stress response affects epigenetic

1 Universidad de los Andes marks, or if the epigenetic marks affect stress responses.

2 Instituto Colombiano del Sistema Nervioso Further research is needed to conﬁrm these results and to

3 Hermanas Hospitalarias del Sagrado Corazón de Jesús clarify which gene networks may be altered by the methylation changes in the promoter. Background: The epigenetic mechanisms involved in Ma- jor Depressive Disorder are not well understood. Among the Disclosure: Nothing to disclose. genes that have been widely investigated regarding its po- doi: 10.1016/j.euroneuro.2018.08.266 tential role in depression is the brain-derived neurotrophic factor (BDNF) speciﬁcally its promoter IV, whose regulation is activity dependent and mediated by epigenetic mechanisms. While some studies have reported hypermethyla- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 26 Abstracts

SA45 Background: In the last decade the microbiome has gained APPLYING GENETIC RISK SCORES TO AN ETHNICALLY more interest in psychiatric research in the context of the DIVERSE SAMPLE OF POSTPARTUM WOMEN gut-brain-axis which is an extensive bidirectional communication network between the gastrointestinal tract and Jerry Guintivano, Patrick Sullivan, Samantha Meltzer-Brody, the central nervous system. Treatment with probiotics in- David Rubinow ﬂuences the gut microbiome and may also improve depressive symptoms. Recent studies have shown that genetic and University of North Carolina at Chapel Hill epigenetic factors play an important role in the development and maintenance of depressive disorders. There is

Background: Postpartum depression (PPD) is a perinatal also evidence that antidepressants e.g. serotonin reuptake form of major depressive disorder (MDD) and affects ap- inhibitors increase the gene expression of “antidepressive proximately 1 in 7 women (prevalence 10-15%). The genetic genes” such as the well investigated BDNF gene. Treatment contribution to PPD etiology is not well understood, partic- with probiotics may lead to similar changes in gene expres- ularly how genetic predisposition to other psychiatric disor- sion like treatment with conventional antidepressants and ders contributes to risk for PPD. improve depressive symptoms by increasing serotonin avail-

Methods: A total of 1,464 women (535 cases and 929 con- ability and/or decreasing levels of inﬂammatory markers. trols) were recruited at six weeks postpartum from obstet- Furthermore, BDNF and the val66met polymorphism were rical clinics in North Carolina. PPD status was determined associated with altered cognitive function. The aim of this using the MINI-plus (v6). Psychiatric history was extracted study is therefore to analyze the global gene expression pat- from medical records. Biological samples were also taken tern and cognitive function in major depression prior and for genotyping using Illumina Multi-Ethnic Genotyping Array. post probiotic treatment.

We used summary statistics from the Psychiatric Genomics Methods: The study is conducted as a placebo-controlled,

Consortium (PGC) to create genetic risk scores in our co- randomized, double-blind, prospective, monocentric clini- hort to estimate the relationship between risk for various cal study, with a two-arm parallel group design including psychiatric disorders (e.g. MDD, bipolar disorder, anxiety, 80 individuals receiving inpatient care at the Department schizophrenia) and PPD. of Psychiatry in Graz, Austria. After giving written informed

Results: This population is racially diverse (68% Black, 13% consent a clinical diagnostic interview takes place and fast-

Latina, 18% European), which requires special considera- ing blood and stool samples are collected. A speciﬁc cogni- tions when using summary statistics generated on individ- tive test-battery is performed to measure different param- uals of mostly European ancestry. Analyses are currently eters of cognitive functions (verbal learning and memory, underway. We will present our approach to estimating ge- information processing speed, cognitive ﬂexibility, working netic risk scores in our diverse population of women and the memory) at the time of admission and after four weeks. ability of genetic risk scores to predict various symptom do- Additionally, to standard care individuals in the interven- mains of PPD. tion group receive the multispecies probiotics “Omnibiotics

Discussion: These results may provide empirical genetic ev- Stress Repair” in addition to biotin, while the control group idence for important shared genetic etiology between PPD receives placebo with biotin for four weeks. Gene expres- and other psychiatric disorders. Only by understanding of sion arrays are performed in peripheral blood taken at the the interplay between genetic and other risk factors for PPD time of admission and at the end. Changes in the cognitive can we develop diagnostic categories informed by biology, domains under probiotic treatment will be associated with identify individuals at risk before the illness emerges, and gene expression of “antidepressive acting” genes (ARNTL, offer effective and individualize treatment options. BDNF). Results: At the time of submission 75 patients have already Disclosure: Nothing to disclose. been included in the study. In summer we/our collaborators are going to perform RNA isolation from collected, frozen doi: 10.1016/j.euroneuro.2018.08.267 PAX blood tubes, gene expression analysis and after quality control of the raw gene expression data we are going to do the statistical analysis. The ﬁrst results will be presented at SA46 the WCPG 2018. THE EFFECTS OF PROBIOTICS ON GENE EXPRESSION Discussion: The potential of probiotics to be used as a novel AND COGNITIVE FUNCTION IN DEPRESSIVE PATIENTS therapeutic agent is especially promising for those not ben- eﬁtting from conventional antidepressant treatments or pa-

Alexandra Rieger 1, Susanne Bengesser 1, Martina Platzer 1, tients who are suffering from side effects. As innovative

Frederike Fellendorf 1, Robert Queissner 1, Armin Birner 1, treatment approach, probiotics may broaden the therapeu-

Nina Dalkner 1, Lilli Mendel 1, Matthias Seidl 1, Tanja Färber 1, tic opportunities dramatically by affecting biological path-

Lisa Wetzlmair 1, Martina Heigl 2, ways such as gene expression.

Anna Maria Birkl-Toeglhofer 3, Thomas Schwarzbraun 4, The study has been approved by the local ethics commit-

Eva Reininghaus 1 tee (EK 29-235 ex 16/17). ClinicalTrials.gov Identiﬁer: NCT03300440

1 Medical University of Graz

2 Therapy Center Justuspark, Bad Hall Disclosure: Nothing to disclose.

3 Institute of Human Pathology, Medical University of Graz doi: 10.1016/j.euroneuro.2018.08.268 4 Institute of Human Genetics, Medical University of Graz ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 27

SA47 OH-D) and major depressive disorder (MDD) exploiting data GENETIC PREDISPOSITION TO VITAMIN B12 AND and tools from genomics. FOLATE DEFICIENCY LEADS TO THE DEVELOPMENT Methods: Analyses were based on > 2,000 participants from OF DEPRESSION IN POSTPARTUM PERIOD BY HYPO- the Netherlands Study of Depression and Anxiety, with mea- METHYLATION OF SEROTONIN TRANSPORTER AND sures of genotype, circulating 25-OH-D and DSM-IV life- MONOAMINE OXIDASE-A GENE LOCI time diagnoses of MDD. A polygenic risk scores (PRS) for increased 25-OH-D was built using genome-wide signiﬁ-

Pooja Dhiman, Soundravally Rajendiran, Balaji Bharadwaj cant SNPs identified by previous GWAS. Associations of the PRS with 25-OH-D concentrations and lifetime MDD diagnosis were estimated. Tw o - s a m p l e Mendelian Randomization JIPMER, Pondicherry analyses were performed testing the causal role of vitamin D on MDD, using data from the Psychiatric Genomics Consor- Background: Postpartum depression (PPD), which is defined tium as an episode of major depression with onset within the 1-12 Results: The 25-OH-D PRS was strongly associated (p = 1.4e- months after delivery, has unfavorable effect on both ma- 20, ∼4% variance explained) with 25-OH-D level. No associa- ternal and child health. PPD poses a significant public health tion was found with MDD. The genetic instrument for 25-OH- issue because of its impact not only on the lives of the D was not causally related to MDD risk (p = 0.50). The results women themselves, but also on their children’s growth and will be complemented with full bi-directional PRS and MR development (cognitive, social and behavioral). The cause analyses. for PPD is a poorly understood area. There are a number of Discussion: Preliminary results leveraging on genomics tools social and biological factors are known to be associated with showed that a direct impact of circulating 25-OH-D concen- an increased risk for developing PPD. Vitamin B12 and fo- trations on MDD is unlikely. The potential role of vitamin D late are water soluble micronutrients, which are critical for in depression pathophysiology should be reconsidered. nucleic acid biosynthesis, methylation reactions involved in the biosynthesis of monoamine neurotransmitters and epi- Disclosure: Nothing to disclose. genetic regulation by DNA and histone methylation. Methods: We searched three database-Pubmed, Embase doi: 10.1016/j.euroneuro.2018.08.270 and Google Scholar using search terms- “postpartum depression”, “folate”, “Vitamin B12”, and “genetics” from Jan- uary 1996 to May 2017. SA49 Results: We identified 207 articles of which 31articles sug- THE EFFECT OF CHILDHOOD TRAUMA ON BLOOD gest the role of folate on development of postpartum de- EXPRESSION OF MED22 IN PATIENTS WITH MAJOR pression. DEPRESSIVE DISORDER IS MEDIATED BY CIS-ACTING Discussion: Based on the present literature, we hypothe- SNPS size that women who develop depression in postpartum period, are genetically predisposed to develop folate and vi- Edoardo Giacopuzzi 1, Alessandra Minelli 2, Chiara Sacco 2, tamin B12 deficiency, because of the presence of functional Massimo Gennarelli 2, Chiara Magri 2 polymorphisms in the metabolizing enzymes, and this leads to hypomethylation of monoamine oxidase-A enzyme and 1 IRCCS Centro S. Giovanni di Dio Fatebenefratelli serotonin transporter, leading to decreased bioavailability 2 University of Brescia of serotonin, and hence development of depression. This concept hence provides nutritional intervention as a means Background: There is evidence that childhood trauma (CT) to prevent postpartum depression. increase the risk of developing severe mental illnesses, such

Disclosure: Nothing to disclose. as major depressive disorder (MDD), during adulthood. How- ever, the biological mechanisms underlying this relation- doi: 10.1016/j.euroneuro.2018.08.269 ship remain largely undetermined. It is unclear, how the physiological and psychological consequences of early life stress are inﬂuenced by an inherited vulnerability to stressful events. To clarify these issues, we carried out a reanal- ysis of genotype and blood expression data from a large

SA48 mRNA sequencing dataset of MDD patients (368 patients) for

EXAMINING THE ROLE OF VITAMIN D IN MAJOR DE- whom information about CT was available. PRESSION USING GENOMICS Methods: We studied differences in gene expression profiles among MDD patients that have or not experienced different Yuri Milaneschi, Brenda Penninx type of CT. For differentially expressed genes, the genetically regulated component of gene expression (GReX) and VU Medical Center the environmental component (EReX) were calculated (applying PrediXcan method) and correlated with CT. Background: Based on observational and preclinical data it Results: Expression analysis of single genes revealed a has been hypothesized that vitamin D may have a role in significant association between neglect CT and MED22 gene depression pathophysiology. We aimed to examine the na- (p value = 1.11 × 10-6; FDR = 0.016). Furthermore, analyses ture of the association between 25-hydroxyvitamin D (25- of the principal components of expression data support a ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 28 Abstracts dysregulation of cytokine system pathways in association grounds in implementing genetic counselling sessions for with emotional abuse. disorders such as schizophrenia, bipolar disorder and de- The dissection of MED22 expression profiles in GreX and pression. The aim of a psychiatric genetic counselling ses- EReX components revealed a positive association of neglect sion is to better understand an individual’s condition and/or both with EReX (p-value: 6 × 10-3) and with GReX (p-value: risk to other family members, facilitate empowerment and 2.6 × 10-4). Intriguingly, GreX component of MED22, but not decision making, whilst reducing stigma, shame and guilt EReX, resulted significantly associated also to sexual and surrounding mental illness and dispel myths held within emotional abuses (p-values = 2.1 × 10-3 and 2.2 × 10-5, re- families. spectively). Participants were asked to fill out a pre- and post- Finally, in an independent cohort of 177 controls, we ob- workshop questionnaire. Responses were anonymous and served a significant association between cis-acting SNPs of collated using an online survey. MED22 (SNPs responsible for changes in gene expression) Results: 81 participants attended the two-day course. Par- and neuroticism (best p-value = 0.00848). Literature data ticipants comprised of three clinical geneticists, one clini- indicates that people with high score on neuroticism di- cal scientist, 64 genetics counsellors, one genetic ethicist, mension exhibit a decreased amount of resilience to stress one mental health policy lead, six psychiatrists, four psy- events. chologists and one statistical geneticist. They represented Discussion: In conclusion, our results corroborate the hy- 17 countries. pothesis that specific types of CT affect distinct molecular The response rate to the questionnaires pre-course was pathways, and in particular, emotional abuse and neglect 82.7% and 66.7% follow-up. Following the course, both exert the strongest impact on gene expression in MDD. In knowledge [t(66) = 33.18, p < 0.001] and self-efficacy sig- addition, our data provide insights suggesting that the bi- nificantly increased [t(66) = 27.1, p < 0.001] suggesting that ological and psychological consequences of CT depend also health professionals felt they knew more and felt empow- on the effect of genetic background that could induce vul- ered to apply psychiatric genetic counselling in their clinics. nerability/resilient to stressful events by shaping people’s Discussion: To our knowledge this is one of the very few em- personality traits and trauma memories. pirical studies supporting the need for an expansion of training in psychiatric genetic counselling. The evidence shows Disclosure: Nothing to disclose. that healthcare professionals benefited from this training in terms of knowledge and self-efficacy. The mix of countries doi: 10.1016/j.euroneuro.2018.08.271 and healthcare backgrounds represented at these courses reinforces that there is a global demand for psychiatric genetic counselling training and that a collaborative effort is

SA50 needed in order to develop further training, research and PSYCHIATRIC GENETIC COUNSELLING TRAINING IN services. Future developments will be discussed. THE UK OVER THE LAST THREE YEARS Disclosure: Nothing to disclose.

Kevin McGhee 1, Angela Inglis 2, Emily Morris 2, doi: 10.1016/j.euroneuro.2018.08.272 Jehannine Austin 2

1 Bournemouth University

2 University of British Columbia SA51 THE LIMITS OF POLYGENIC EMBRYO SELECTION FOR Background: Genetic counselling encompasses a process of COGNITIVE ABILITY helping people understand and adapt to the to the medi- 1 2 3 4 cal, psychological and familial implications of the genetic Todd Lencz , Ehud Karavani , Max Lam , Nir Barzilai , 5 5 4 contributions to disease. It was shown to be effective in Nikolaos Stefanis , Alexandros Hatzimanolis , Gil Atzmon , 2 monogenic, chromosomal and multi-factorial disorders, Shai Carmi including serious mental illnesses. Although genetic testing is currently limited in its clinical usefulness for psychiatric 1 Hofstra Northwell School of Medicine disorders, interest in genetic counselling for psychiatric 2 Hebrew University of Jerusalem disorders has a relatively long history and many positive 3 Institute of Mental Health outcomes have been posited. Yet, empirical studies of 4 Albert Einstein College of Medicine psychiatric genetic counselling training are lacking. 5 University of Athens Medical School The aim of the current study was to analyze whether psychiatric genetic counselling training had a positive im- Background: Given recent developments in genome-wide pact on trainees’ knowledge and self-efficacy towards im- association studies (GWAS), researchers have increasingly plementing genetic counselling specifically for individuals utilized polygenic scores (PGS) as a tool for genetic pre- and families with psychiatric illness. diction of complex traits and diseases. While progress in Methods: Four training courses ran between February 2015 cognitive genomics had lagged behind studies of other an- and February 2018 for genetic counsellors, psychiatrists, thropometric traits such as height, very recent large-scale clinical psychologists and clinical geneticists. The courses GWAS for general cognitive ability have finally permitted were built to facilitate knowledge and skills on how health- the application of PGS approaches to cognition. This has care professionals could use their experience and back- led to an increasing ethical concern, also documented in ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 29 the popular media, that cognitive PGS could be used to SA52 select embryos generated by in vitro fertilization (IVF) RETURNING SECONDARY PSYCHIATRIC GENETIC FIND- for eugenic purposes. Our study quantifies the limits of INGS TO PATIENTS AND THEIR RELATIVES: LEGAL AND such applications, based on both present and projected ETHICAL ISSUES IN THE UNITED STATES developments in cognitive genomics. Methods: Using genotype and phenotype data of individ- Teneille Brown uals (parents) and offspring across multiple cohorts, we calculated the average difference between: 1) the maxi- University of Utah mum predicted phenotypic value (based on PGS) and the mean predicted value (the average of the parental values); Background: Not infrequently, whole-exome (WES) or and 2) the maximum and minimum predicted values (i.e., whole-genome sequencing (WGS) that is conducted for twice the value of the max-mean difference). We simulated one purpose reveals information about other features of genotypes of embryos (offspring) under simplified assump- the genome that may be of clinical significance. In 2013, tions: 10 testable embryos per IVF cycle and no assortative the American College of Medical Genetics (ACMG) recom- mating. [Note that these assumptions were deliberately se- mended that clinical laboratories inform people if their ge- lected in order to simulate optimal conditions, and thereby netic analyses indicate that they have certain secondary determine the upper limits of prediction; more realistic as- mutations (SFs). These mutations were selected because sumptions of fewer viable/testable embryos and positive as- they probably cause a serious disease, which is treatable, sortative mating would tend to reduce the available vari- and may go undetected. The ACMG’s recommendations gal- ance for selection.] We utilized available PGS from large- vanized critical responses by the genetics and ethics com- scale GWAS for general cognitive ability, which currently munity. One of the most important open questions concerns have a maximum predictive R ^ 2 of ∼4-5%. We also exam- the scope of negligence liability for clinical laboratories if ined PGS for height, which are based on larger GWAS and they failed to provide any of these SFs to patients who never have considerably greater predictive R ^ 2, in order to esti- requested them. The author recently published a law re- mate the future potential of selection. view article that argues that while there might be an ethical Results: For general cognitive ability, the average differ- or professional obligation to share knowledge about these ence in predicted cognitive ability between the embryo with specific genetic mutations, clinicians and labs should not maximal PGS and the mean embryo was ∼0.115 standard be subject to tort liability for failure to share secondary deviations (SD), or roughly 1.75 IQ points. The average dif- findings directly with patients. The problem with the preference between embryos with the maximal and minimal vious paper is that it focused on SFs in the abstract. In or- cognitive PGS was ∼0.23 SD (3.5 IQ points). For height, the der to provide case-specific answers, this project analyzes max-mean difference was 1.5cm ( ∼0.2 SD) and the max-min the ethical and legal obligations of health care providers difference was 3cm ( ∼0.4 SD). More broadly, theory shows and laboratories in the context of predicting genetic risk of that if the variance explained by the PGS is R ^ 2, then the schizophrenia, depression, and substance abuse. gain in PGS (max-mean) is proportional to R. Moreover, if Methods: I employed traditional legal reasoning, using the we have n embryos, the gain in PGS (max-mean) grows ap- common law precedent in the United States. Specifically, I proximately as a function of (log(n)). Thus, a more realis- scrutinized the tort of negligence and the imposition of af- tic scenario of ∼5 viable and testable embryos would result firmative duties to warn, applying these principles to the in values that are reduced by a factor of 0.84, and a future disclosure of risk of developing psychiatric genetic disor- IVF technology permitting 100 viable and testable embryos ders. I also briefly discuss how these cases might come out would increase utility only by a factor of ∼1.4. differently in other common law jurisdictions (Australia and Discussion: Our results reassuringly demonstrate that the the U.K.). prospects for eugenic application of PGS are relatively lim- Results: My analysis argues against imposing a duty on labs ited for the foreseeable future. Given that the upper limit to warn patients of their secondary psychiatric genetic find- on SNP heritability for cognitive ability is ∼0.3 (at most), ings. To do so would be engaging in the tempting imposition and that sample sizes in the hundreds of thousands have of tort obligations where harms are conceivable ex ante, but yielded out-of-sample prediction R2 < 5%, it is unlikely that hardly reasonably foreseeable. However, it may be reason- attainable sample sizes in the foreseeable future will yield able to impose a duty on clinicians in some cases, where the PGS that permit average predicted gains of more than a few mutation or group of mutations are highly penetrant, pre- IQ points at best. dictably expressed, insurance covers the follow-up testing, and the resulting disorder has a significantly better progno- Disclosure: Genomind, Inc. - Consultant, Self sis with early intervention. doi: 10.1016/j.euroneuro.2018.08.273 Discussion: Whether there is a legal duty to warn will depend on the mutations being tested, the available treatment interventions, and the risk/benefit profile. Because we currently have limited information on the likelihood that even a monogenic mutation will develop into psychiatric disease, and the information we do have likely inflates this value for people who are currently symptom-free, having a genetic mutation for many disorders does not present the kind of foreseeable, imminent, and serious risk that ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 30 Abstracts creates a common law duty to warn in the US. Applying dication for 134/300 patients (45%). After counselling about U.S. case law, I provide a framework for addressing when etiology and risk-reducing strategies, 116 (39%) opted to re- imposing a tort duty to warn would be appropriate, con- ceive recurrence numbers. When numbers were given, most sidering relevant factors such as the ethics and morality (n = 64 55%) perceived the number to be lower than ex- of non-disclosure, risk of harm, insurance coverage and pected. GCOS scores increased significantly from T1-T2 for reimbursement, the need to validate SFs through addi- all patients. However, there was no difference in T2 GCOS tional testing, and to determine whether mutations are scores between those who: a) received recurrence numbers spontaneous or inherited. vs. those who did not, or b) perceived the number to be lower than expected vs. those with other perceptions. How- Disclosure: Nothing to disclose. ever, a subset of patients (who did not receive recurrence numbers after changing their minds about their interest dur- doi: 10.1016/j.euroneuro.2018.08.274 ing the session) had larger increases in GCOS scores. Discussion: Our data demonstrate that optimal increases in patient empowerment after psychiatric genetic counseling SA53 are not contingent on receipt of recurrence numbers and RISK COMMUNICATION IN PSYCHIATRIC GENETIC COUN- challenge the notion that recurrence numbers should be

SELLING: HOW OFTEN DO PATIENTS WANT TO DISCUSS routinely provided in genetic counseling – especially when

SPECIFIC CHANCES FOR ILLNESS, HOW ARE THESE they are unrelated to the availability of/eligibility for treat- CHANCES PERCEIVED, AND HOW DO THEY IMPACT ments/interventions. Our data also demonstrate the impor- PATIENT OUTCOMES? tance of an informed, autonomous decision-making process for patients around the types of information that they want: Kennedy Borle, Emily Morris, Angela Inglis, Jehannine Austin a substantial minority of patients who initially indicated interest in receiving recurrence numbers but changed their University of British Columbia mind during the process of genetic counseling had the greatest increases in empowerment scores. Background: The psychiatric genetics community is working towards clinical implementation of polygenic risk scores. Disclosure: Nothing to disclose.

There is an implicit assumption that individuals with psychi- doi: 10.1016/j.euroneuro.2018.08.275 atric disorders and their families will want and benefit more substantively from genetic counseling when it incorporates the more accurate risk assessment that may be afforded SA54 by genetic testing data. However, knowledge gaps exist regarding how often patients want to discuss specific chances ARE INTERNALIZING DISORDERS GENETICALLY DIS- for developing illness, how are these chances perceived, TINCT? LESSONS LEARNED FROM ITEM-LEVEL ANALY- and how they impact patient outcomes. To address these SES gaps, in a specialized psychiatric genetics clinic, we aimed 1 2 1 to explore patient interest in discussing empirically derived Jeanne Savage , Mats Nagel , Kyoko Watanabe , 1 1 chances for illness recurrence (recurrence numbers), per- Danielle Posthuma , Sophie van der Sluis ception of recurrence numbers, and their impact on patient outcomes. We hypothesized that greater increases in em- 1 Vrije Universiteit Amsterdam powerment, as measured by the Genetic Counselling Out- 2 VU Medical Centre comes Scale (GCOS) would be seen among patients who: a) received recurrence numbers (vs. those who did not) and b) Background: Psychiatric disorders, especially internalizing perceived numbers that they received to be lower than an- disorders (depression and anxiety), have remained among ticipated (vs. individuals who had other perceptions of the the most challenging phenotypes in genetic research de- number they received). spite the growing successes of gene identification strategies Methods: We conducted a retrospective chart review at a for other complex traits. Pervasive pleiotropy, correlated psychiatric genetic counseling clinic where patients rou- genetic liabilities, and symptom overlap between disorders tinely complete the GCOS pre (T1)/post (T2)-appointment. contributes to this difficulty. Bottom-up approaches to re- In this clinic, demographic variables, reason for referral, fine phenotypes based on empirical clusters of symptoms and patient perception of numbers received are routinely or traits, rather than top-down syndromic disorder classi- recorded. We used descriptive statistics for frequencies of fications, may better reflect the underlying genetic archi- interest, and ANCOVA to test our hypotheses about patient tecture of psychopathology. Here we apply item-level fac- outcomes. Specifically, we tested the effect on T2 GCOS tor analysis of internalizing-related phenotypes to 1) iden- score of: a) receiving recurrence numbers, and b) patient tify genetically homogenous symptom clusters to improve perception of recurrence numbers whilst controlling for T1 power for gene identification and 2) compare the clustering GCOS score. patterns of symptoms at the genetic and phenotypic levels. Results: Most patients (81%) had a personal history of men- Methods: Self-report survey data was collected from tal illness, with the remainder having a family history – diag- 386,078 individuals from the population-based UK Biobank noses included: depression, anxiety, bipolar disorder, addic- sample. Genome-wide association analysis was conducted tion, PTSD, schizophrenia/ schizoaffective disorder, eating on each of 34 measures of internalizing symptoms (recent disorders, and OCD. Recurrence numbers were a primary in- and prolonged anxiety and depression) and related traits ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 31

(neuroticism, irritability). We conducted exploratory fac- Methods: WES was performed using the SureSelectXT Hu- tor analysis on the genetic and phenotypic correlations be- man All Exon V6 + UTR kit (Agilent) on an Illumina HiSeq 2500 tween these items. We then created new target phenotypes machine (paired-end reads, 101bp per read). After align- based on the clusters of similar items indicated by factor ment (BWA) and de-dupping (Picard), further preprocessing analysis and conducted GWAS and functional annotation of was done with GATK. We used XHMM to detect copy num- these empirically-informed symptom clusters. We validated ber variations using depth-of-coverage information. Work- these symptom cluster phenotypes through the use of poly- ing memory was initially tested in 2’711 healthy young in- genic score prediction in an independent sample and ex- dividuals with a European background with an n-back task. amining their patterns of genetic correlations with external After matching for sex, age, smoking behavior and genetic phenotypes. background, 139 pairs (i.e. 139 high and 139 low perform- Results: Results of these analyses indicated a difference in ers) were sequenced. To focus on rare events, we restricted factor structure between phenotypic and genetic item cor- our analyses on CNVs that were unique in either high or low relations, with phenotypic factors mapping closely to the performers. structure of measurements in the survey (i.e. separate anx- Results: A global burden test of unique deletions and du- iety, depression, and neuroticism scales) and genetic factors plications revealed a higher proportion of CNVs in high per- demonstrating substantial overlap between anxiety, depres- formers compared to low performers in both all CNVs and sion, and neuroticism items. Distinct item clusters had mod- genic CNVs (i.e. CNVs intersecting at least one hg19 RefSeq erate to high genetic correlations but also showed evidence gene, ±20kb). We next performed a segment-based analysis of unique genetic association signals. of the unique CNVs, i.e. CNVs that only occur in low or high Discussion: We highlight implications of the discordance be- performers, respectively. This analysis revealed significant tween phenotypic and genetic factor structures for the ap- associations for chr19: In high performers, we observed one plication of gene-identification efforts using disorder-level deletion and four duplications compared to no such variant phenotypes and compare the advantages and disadvantages in low performers (pcorrected = 0.03). Gene-based analysis of an empirically-based item-level approach. Our results identified the following four genes mapping to this region: support the emerging evidence from twin and molecular ZNF765-ZNF76, TPM3P9, ZNF761 and ZNF813. studies that diagnostic definitions of psychiatric disorders Discussion: Our data provide first preliminary evidence that do not always accurately represent their underlying genetic rare structural variants play a role in working memory per- etiology. A brute force approach of amassing huge samples formance. may not be enough to overcome the challenge of statistical power this implies. More studies focusing on phenotypic Disclosure: Nothing to disclose. refinement are needed to assess whether this may be a vi- doi: 10.1016/j.euroneuro.2018.08.277 able parallel approach to improve gene identification and thereby improve the nosology, understanding, and treatment of internalizing disorders.

Disclosure: Nothing to disclose. SA56 INTERFERENCE CONTROL AND SOCIAL AWARENESS doi: 10.1016/j.euroneuro.2018.08.276 AS A CANDIDATE INTERMEDIATE PHENOTYPE FOR ADHD

SA55 Seung-Hyun Shon 1, Hyo-Won Kim 2, Keejeong Park 2 GENOME-WIDE ASSOCIATION OF COPY NUMBER

VARIANTS FROM WHOLE-EXOME SEQUENCING DATA 1 University of Ulsan College of Medicine, Seoul

REVEALS AN ASSOCIATION BETWEEN EXTREMES IN 2 University of Ulsan Asan Medical Center, Seoul WORKING MEMORY PERFORMANCE AND RARE CNVS Background: Attention-deficit/hyperactivity disorder Angela Heck, Annette Milnik, Vanja Vukojevic, (ADHD) is a highly heritable neurodevelopmental disorder. Jana Petrovska, Virginie Freytag, Dominique J.-F. de Because ADHD has a heterogeneous clinical manifestation Quervain, Andreas Papassotiropoulos with a complex syndromic clinical definition, it has been suggested that quantitative phenotypes, that is, intermedi- University of Basel ate phenotypes, could be useful for dissecting the genetic basis of ADHD. The aim of the current study is to identify Background: Working memory (WM) refers to the ability the intermediate phenotype by comparing clinical and to temporarily store and manipulate information. It is a neuropsychological profiles of children who presumed to physiological cognitive capacity that is dysregulated in such have different genetic predisposition. neuropsychiatric disorders as schizophrenia, depression and Methods: We compared the following three groups; chil- attention-deficit/hyperactivity disorder. WM performance is dren with ADHD (n = 307), their unaffected sibling (n = 63), a heritable and well measurable complex phenotype. Be- and typically developing children (n = 112). The children sides common genetic variation larger structural variants completed the Continuous Performance (CPT), Stroop, are thought to play a role in WM. In the present study we Children’s Trail Making, and Rey-Kim Memory tests. The aim at the identification of unique variants using an extreme parents of these subjects underwent the Attention- phenotyping approach. Deficit/Hyperactivity Disorder Rating Scale (ARS), 10-item ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 32 Abstracts

Parent General Behavior Inventory (P-GBI), and the Social netic contributions account for a modest fraction of the ob- Responsiveness Scale (SRS). served phenotypic variance. Results: The Social Awareness scale of the SRS was highest in typically developing children, followed by unaf- Disclosure: Nothing to disclose. fected siblings, and ADHD children (Bonferroni adjusted doi: 10.1016/j.euroneuro.2018.08.279 p < 0.001). ADHD and their unaffected sibling showed sig- niﬁcantly lower scores on Color-Word scores of the Stroop test than typically developing children (Bonferroni adjusted p < 0.001). SA58 Discussion: Our results suggest that interference control, ASSOCIATION OF CLOCK AND PER2 POLYMORPHISMS measured by the Stroop test, and social awareness of the WITH DIURNAL PREFERENCE AND AFFECTIVE TEMPER-

SRS could be a potential intermediate phenotype of ADHD. AMENTAL TRAITS IN HEALTHY YOUNG ADULTS

Disclosure: Nothing to disclose. Seung Jun Kim 1, Jee In Kang 2, Se Joo Kim 2 doi: 10.1016/j.euroneuro.2018.08.278

1 Konyang University College of Medicine, Daejeon

2 Yonsei University College of Medicine

SA57 Background: Various clock genes, which are involved in GENETIC CORRELATION BETWEEN VISUO-SPATIAL generating the circadian rhythms, have been reported to MEMORY AND WORKING MEMORY IN HEALTHY YOUNG make an inﬂuence on diurnal preference. Given that diur- ADULTS nal preference is related to affective temperament traits, clock genes can be associated with individual affective tem- Virginie Freytag, Nathalie Schicktanz, Jana Petrovska, perament as well as diurnal preference. In this study, we Dominique J.-F. de Quervain, Andreas Papassotiropoulos aimed to evaluate association of CLOCK and PER2 polymorphisms with diurnal preference and affective temperamen-

University of Basel tal traits. Methods: A total of 578 Korean undergraduate students participated in the final analyses. The assessments of diurnal Background: Recently published large-scale GWAS results preference and affective temperament were made by self- from the UK Biobank study suggest that common genetic reported questionnaires. Genotyping of CLOCK (rs1801260) variation accounts for a modest albeit significant fraction and PER2 (rs2304672) single nucleotide polymorphisms was of heritability of visuo-spatial memory (h2 = 0.05). In this conducted. study, we investigated the genetic relationship between Results: In male subjects, CLOCK non-C allele carriers visuo-spatial memory performance as reported in the UK showed a higher proportion of morning type than C allele Biobank and specific memory components, namely episodic carriers. On the other hand, female subjects with CLOCK and working memory. C allele carrier status showed significantly higher Compos- Methods: At total of N = 1,499 healthy young adults (mean ite Scale of Morning-type and anxious temperament scores age in years: 22) underwent genotyping assessment and than those with CLOCK non-C allele carrier status. a set of cognitive tasks targeting specifically episodic and Discussion: These findings show the clock genes-related as- working memory function. Exploratory factor analyses were sociation between affective temperament as well as diurnal conducted on these behavioral measures and yielded dis- preference. tinct factors related to working and episodic memory processes, respectively. A genome-wide polygenic score was Disclosure: Nothing to disclose. derived using UK Biobank GWAS summary statistics for the memory ’pairs-matching test’ (N = 336,881), with a greater doi: 10.1016/j.euroneuro.2018.08.280 genetic score indicating lower performance in the task. This genetic profile was subsequently tested for association with the extracted factor scores in our sample. Results: This analysis revealed a significant association be- SA59 tween the visuo-spatial memory genetic score and the work- POLYGENIC RISK SCORE INCREASES SCHIZOPHRENIA ing memory related component (p = 3e-05) while no as- LIABILITY THROUGH COGNITION-RELEVANT PATHWAYS sociation was observed with the episodic memory related factor. Considering individual tasks, the strongest correla- Timothea Toulopoulou 1, Xiaowei Zhang 2, Stacey Cherny 2, tion was observed for N-back working memory performance Dwight Dickinson 3, Karen F. Berman 4, Richard Straub 5,

(r = -0.08; p = 1.1e-03). This association was replicated in Pak Sham 2, Daniel Weinberger 5 a second independent sample comprising N = 1,130 healthy young adults, who performed a similar N-back task (r = 1 Bilkent University

−0.1; p = 9.8e-04). 2 University of Hong Kong

Discussion: These results suggest that the performance in 3 NIH the pairs matching test is genetically related to working 4 National Institute of Mental Health memory performance, even though the derived common ge- 5 Lieber Institute for Brain Development ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 33

Background: Cognitive deficit is thought to represent at Servei de Salut Mental, Psiquiatria i Addiccions, Hospital least in part genetic mechanisms of risk for schizophrenia, Universitari de Santa Maria, Institut de Recerca Biomèdica, with prior evidence suggesting causality from the former to Lleida the latter. However, earlier evidence was based on infer- 3 Institute of Neurosciences, Hospital Clínic, Barcelona ences from twin data. 4 Institute of Neurosciences, Hospital Clínic, Barcelona, Investigació en Biomedicina August Pi׳ Methods: We included direct measurements of genetic risk CIBERSAM, Institut d (e.g. schizophrenia polygenic risk scores) in causal mod- i Sunyer, IDIBAPS els to assess the extent to which cognitive deficit medi- 5 University of Athens ates the effect of polygenic risk scores (L-PRS) on the dis- 6 University of Barcelona, CIBERSAM (Biomedical Research order. Causal models of cross sectional family data tested Network in Mental Health; Instituto de Salud Carlos III) relationships among key variables and allowed parsing of 7 Hospital Universitari Germans Trias i Pujol, Barcelona, genetic variance components. Polygenic risk scores (PRS) Catalunya were calculated from summary statistics from the current 8 IdiSNa (Instituto de Investigación Sanitaria de Navarra), largest genome-wide association study of schizophrenia and Pamplona, Servicio Navarro de Salud, Pamplona was represented as latent trait (L-PRS). Cognition was also 9 University of Barcelona modelled as latent trait (L-COG). Participants were 1,313 10 FIDMAG Research Foundation / University of Barcelona members of 1,078 families: 416 schizophrenia patients, 290 unaffected siblings, and 607 controls. Background: The study of the genetic basis of psychiatric Results: L-PRS explained 8.07% (CI 5.45 ∼10.74%) of disorders has a serious limitation in the high clinical and schizophrenia liability in our sample. 2.71% (2.41 ∼3.85%) biological heterogeneity associated with these diagnoses. of the L-PRS influence was mediated indirectly through Therefore, the reduction of the phenotypic complexity has cognition paths, exceeding the direct influence of L-PRS become an essential step for the understanding of the neu- on schizophrenia liability (1.43%, 0.46 ∼3.08%). The 3.93% robiology of psychiatric disorders and their etiological and (2.37 ∼4.48%) remainder of the L-PRS influence was cor- pathophysiological underpinnings. The use of nuclear fami- related, reflecting reciprocal causation. Analysis of ge- lies as the unit of study emerges as a valuable strategy to netic variance components of L-SZ indicated that 26.87% guide the stratification of families in order to reduce het- (21.45 ∼32.57%) was associated with L-COG related path- erogeneity and to facilitate the identification of genetically ways not captured by L-PRS. The remaining variance in more homogeneous forms of a disorder (Ferentinos et al, schizophrenia was through pathways other than L-COG and 2015; Peralta et al, 2015). L-PRS. Methods: Data from families with at least one patient with Discussion: Although our results are not absolute proof a psychiatric disorder might allow the examination of the of causality, we found that cognition mediated a signifi- familial aggregation or familiality of a phenotype. Besides cant part of the influence of cumulative genetic risk on the estimation of a global parameter of familiality in a sam- schizophrenia. At the same time, analysis of genetic vari- ple, we were also interested in identifying specific families ance components suggested that other cognition pathways, in which the members were concordant for a specific phe- not captured by current polygenic risk score, relate to an notype. Then, we developed a method to calculate the de- even greater portion of schizophrenia risk. We estimate gree of similarity among family members on a trait a (intra- from our model that 33.51% (CI 27.34 ∼43.82%) of overall ge- family resemblance score, IRS). The IRS is a quantitative netic risk is mediated through influences on cognition, but score calculated for each family that allows the classifica- this requires further studies and analyses as the genetics of tion of a set of families according to their members’ resem- schizophrenia becomes better characterized. blance on a phenotype. It can differentiate families in which members share similar scores (higher IRS) from those fami- Disclosure: Nothing to disclose. lies in which members show discordant scores (lower IRS). doi: 10.1016/j.euroneuro.2018.08.281 Results: In a sample of 30 patients with psychosis and their 82 healthy first-degree relatives we described that schizotypy is a familial marker of vulnerability for psychotic disorders (p < 0.001) and we could identify a subgroup of families SA60 in which at least two members showed higher schizotypy

THE STUDY OF FAMILIALITY AS A STRATEGY TO REDUCE scores (according to the IRS). In addition, we also found

HETEROGENEITY AND TO FACILITATE THE IDENTIFICA- that the schizotypy familial aggregation pattern was asso- TION OF GENETICALLY MORE HOMOGENEOUS FORMS ciated with the presence of neurodevelopmental risk mark- OF A DISORDER ers such as dermatoglyphic abnormalities (p < 0.001) (Soler et al, 2017). Also, by the use of the same approach, in a 1 2 3 Jordi Soler Garcia , Salvador Miret Fallada , Sara Lera , sample of 26 patients with early-onset bipolar disorder and 4 5 6 Luisa Lázaro , Panagiotis Ferentinos , Claudia Prats , their 73 ﬁrst-degree relatives we have shown that attention 7 8 9 Maria Giralt , Peralta Victor , Lourdes Fañanás , and working memory dimension might represent a valuable 10 Mar Fatjó-Vilas endophenotypic marker for familial liability of early-onset bipolar disorders (ICC = 0.37 p < 0.001).

1 Universitat de Barcelona, Institut de Biomedicina de la Discussion: According to our results, the study of the fa- Universitat de Barcelona (IBUB) miliality of a trait represents a valuable strategy to identify

2 Instituto De Salud Carlos III, Centro De Investigación familial vulnerability markers for a disorder. Therefore, this Biomédica En Red De Salud Mental (CIBERSAM), Madrid, ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 34 Abstracts method putatively allows the identification of families with our analysis, for the 934 blood samples (First episode Psy- a higher genetic loading, which might ultimately facilitate chosis cases = 413; Controls = 521) that passed the stringent the identification of associated specific genetic risk factors. QC pipeline checks (i.e. signal intensity, duplicates, sex, Acknowledgements: i) ERA-NET-NEURON-PIM2010ERN, ii) bisulphite conversion, genotypes). Linear model was used ISCIII through de project PI15/01420 (co-funded by Euro- to compare across the genome the DNA methylomic profil- pean Regional Development Fund/European Social Fund) ing of regular cannabis users ( > than once a week) and users "Investing in your future"), iii) SAF 2015-71526-REDT, iv) of high potency types of cannabis with never users, control- 2014SGR1636, v) APIF-UB JS and CD16/00264 to MF-V. ling for the named confounders, and entering cases-control status as a covariate. Disclosure: Nothing to disclose. Results: Our preliminary analyses revealed regular cannabis use-associated dysregulation of DNA methylation at multi- doi: 10.1016/j.euroneuro.2018.08.282 ple loci across the epigenome that also include CpGs previously associated with Schizophrenia. Downstream pathway analysis revealed enrichment of genomic regions that are SA61 highly disease relevant.

CAN DNA METHYLATION PROFILING SHED LIGHT cannabis associated psychosis.

ON THE BIOLOGY OF CANNABIS ASSOCIATED PSY- Discussion: This epigenome-wide study of ﬁrst episode psy- CHOSIS? PRELIMINARY DATA ON THE EWAS CANNABIS chosis patients and healthy controls represents the largest USE SIGNATURE IN THE EUGEI CASE-CONTROL STUDY and most comprehensive study of methylomic variation in regular cannabis users compared to never users performed 1 2 3 Marta Di Forti , Emma Dempster , Diego Quattrone , to date. Findings from this study point to a cannabis EWAS 4 2 2 Eilis Hannon , Joe Burrage , Georgina Mansell , signature, which might contribute to understand the biolog- 5 6 7 Bart Rutten , Jim van Os , Michael O’Donovan , ical mechanism underlying

Alexander Richards 7, Craig Morgan 1, Robin Murray 1,

Chloe Chung Yi Wong 1, Jonathan Mill 2 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.283 1 Institute of Psychiatry, Psychology & Neuroscience, King’s College London

2 University of Exeter

3 MRC Social, Genetic & Developmental Psychiatry Centre, SA62 Institute of Psychiatry, Psychology & Neuroscience, King’s IDENTIFICATION OF MOLECULAR MECHANISMS FOL- College London LOWING CANNABIS EXPOSURE IN PATIENTS WITH

4 University of Exeter Medical School PSYCHOSIS

5 School for Mental Health and Neuroscience, Maastricht

University Anne-Kristin Stavrum 1, Tatiana Polushina 1, Ingrid Melle 2,

6 University of Utrecht Trine V. Lagerberg 3, Petter Andreas Ringen 3,

7 Cardiff University Srdjan Djurovic 3, Ole Andreassen 3, Per Hoffmann 4,

Markus Nöthen 5, Stephanie Le Hellard 1 Background: Epigenetic mechanisms are emerging as potential important players that underlie the interactions be- 1 University of Bergen tween genetic and environmental risk factors in the aeti- 2 Institute of Clinical Medicine, University of Oslo ology of psychiatric disorders. Cannabis is the most widely 3 Oslo University Hospital used recreational drug and its use, with a dose relationship 4 University of Basel pattern, has consistently been associated with an increased 5 University of Bonn risk to develop Psychotic Disorders. Consistent with animal data, it has been shown that regular cannabis users show Background: Cannabis is the strongest environmental risk higher levels of CB1 mRNA expression and promoter methy- factor for psychosis. Psychotic disorders are arguably the lation status in peripheral blood cells than non-users. We most serious of mental illnesses, the best-known being are the first to investigate if cannabis use leaves a distinct schizophrenia (SCZ), but psychosis can also be observed in DNA methylation signature across the genome and if this patients suffering from bipolar disorder (BPD), drug addic- overlaps with biological pathways already associated with tion and post-traumatic stress disorder. Although a large Psychotic Disorders. part of the etiology of these disorders is attributable to ge- Methods: We performed genome-wide DNA methylomic pro- netic factors, environmental factors, such as cannabis, are filing in human peripheral blood tissue from 1022 blood considerable risk factors. Environmental factors modulate samples using the Illumina EPIC microarray (Illumina In- gene expression through epigenetic modifications. Despite finium HumanMethylation850). Samples were randomized the relatively easy access and frequent use and abuse of with respect to phenotypic status, age, sex and centre cannabis, data on epigenetic effects of this drug is sparse. to avoid batch effects throughout all experimental proce- The aim of our study is therefore to identify epigenetic dures. All data pre-processing and downstream statistical changes due to cannabis exposure. analyses were performed using R statistical packages. We Methods: We have carried out a whole genome DNA methy- calculated the tobacco smoking score, the epigenetic age lation study on 1000 blood samples from patients with and the cell type proportions, all potential confounders to schizophrenia, bipolar disorder and non-psychiatric persons ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 35 and compared the methylation profiles of those who are us- symptoms replicates known and suggests novel genes, which ing cannabis to those who do not. may play a crucial role in alcohol withdrawal. Results: Functional analysis of genes related to the sites that are differentially methylated show a significant enrich- Disclosure: Nothing to disclose. ment for genes related to cell junction, synapse and postsy- doi: 10.1016/j.euroneuro.2018.08.285 naptic cell membrane. Some of these genes are also previously considered to be associated with schizophrenia. Com- paring the methylation profiles of current and never users of cannabis to former users show some methylation sites that SA64 are closer in methylation level to that of current cannabis DIFFERENTIAL DNA METHYLATION OF GDAP1 AND users, while other sites are closer to never users. HECW2 IN POST MORTEM BRAIN SAMPLES AND IN A RAT Discussion: These results show that cannabis introduces MODEL FOR ALCOHOL DEPENDENCE epigenetic changes in DNA positions that may be important 1 1 for psychosis Ariane Wiegand , Vanessa Gräf Olmos ,

Wolfgang H. Sommer 2, Anita C. Hansson 2,

Disclosure: Nothing to disclose. Vanessa Nieratschker 1 doi: 10.1016/j.euroneuro.2018.08.284 1 University of Tuebingen

2 Institute of Psychopharmacology, Central Institute of Men- tal Health, Heidelberg University

Background: Alcohol dependence (AD) is a severe disorder

SA63 accompanied by mental and physical health problems. The

METHYLATION PROFILES DURING ACUTE ALCOHOL complex pathogenesis includes environmental and genetic WITHDRAWAL IN A CLINICAL SAMPLE factors. Evidence is emerging that epigenetic mechanisms might contribute to a gene environment interaction which 1 1 1 Stephanie Witt , Josef Frank , Jens Treutlein , seems to play a major role in the manifestation of addiction. 1 1 1 Fabian Streit , Ulrich Frischknecht , Jerome Foo , In previous studies, we already identiﬁed several genes, 2 3 2 Franziska Degenhardt , Kristina Adorjan , Markus Nöthen , amongst others GDAP1 and HECW2, as being differentially 1 1 1 Rainer Spanagel , Falk Kiefer , Marcella Rietschel methylated in patients compared to healthy controls. Inter- estingly, these two genes are both involved in the cellular

1 Central Institute of Mental Health stress response and in neurodevelopment.

2 University of Bonn One of the biggest challenges in psychiatric epigenetics

3 IPPG is the inaccessibility of living brain tissue. Therefore, in this study we tried to replicate our previous hits, which had been Background: Withdrawal is a serious and sometimes life- identified in human blood, in human post mortem brain sam- threatening event in alcohol-dependent individuals. It has ples as well as in blood and brain samples derived from a rat been suggested that epigenetic processes may play a role model for AD. in this context. Identification of genes involved in such pro- Methods: We investigated post mortem human brain sam- cesses may hint to relevant mechanisms underlying with- ples originating from Brodman area 9 either from AD pa- drawal. tients (n = 13) or healthy controls (n = 10). In addition, brain Methods: In the present study we sought to longitudinally and blood samples from a rat model for AD were investi- investigate epigenome-wide methylation patterns in 100 gated. To induce AD, rats had been exposed to daily in- severely alcohol-dependent patients during alcohol with- termittent cycles of alcohol vapor intoxication and withdrawal and after 2 weeks of recovery, and also in 100 drawal. Rats were weight-matched and assigned to two matched controls. More than 850,000 methylation sites groups which were either exposed to ethanol vapor (n = 8) were assessed using Illumina EPIC bead chips. Reflecting the or normal air (n = 8). Samples from blood and from four dif- high quality of our methylation data, we found – consis- ferent brain regions of the same animal (orbitofrontal cor- tent with earlier reports – that correlation of methylation tex (OFC), infralimbic cortex (ILC), prelimbic cortex (PrLC), age with biological age of assessed individuals was very high cingulate cortex (CgC)) were obtained one day after alcohol (r = 0.9). abstinence. Results: We found pronounced genome-wide significant dif- DNA methylation levels in the promoter region of GDAP1 ferences between patients in withdrawal and after 2 weeks, and an intragenic region of HECW2 previously found to be among them in genes which have been reported to play associated with AD were assessed by pyrosequencing. a role in withdrawal symptomatology in previous studies Results: Interestingly, for the human brain samples GDAP1 (SLC29A1, FYN). as well as HECW2 showed differential DNA methylation As expected, methylation between patients and controls when comparing patients with healthy controls. However, differed considerably, also in genes implicated in with- for both genes the changes in methylation were in opposite drawal (FKBP5, BDNF, EFNA5). direction to our previous results comparing human whole Discussion: This epigenome-wide longitudinal methylation blood samples. In the rat model, we found increased study conducted in the so far largest sample of severely DNA methylation levels for GDAP1 in the PrLC which are alcohol-dependent individuals suffering from withdrawal in line with our findings from the human brain samples. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 36 Abstracts

Furthermore, we found trends for differential methylation ings as these studies relied on adult retrospective reports of in HECW2 in the PrLC and ILC, however, the direction of stress or trauma, unusual clinical groups (suicide victims, in- change was different for the two investigated regions. While stitutionalized children), and relatively small samples. The the PrLC indicated a trend for decreased methylation levels current study proposes a powerful and sensitive design to for AD, which is in line with the results for human whole ascertain a ‘purer’ impact of psychosocial stress on the blood, the ILC showed a trend for increasing methylation epigenome by combining the unique discordant MZ twin de- levels in line with the human samples from BA9. sign with a longitudinal approach allowing us to control for Discussion: Our results further facilitate the potential role potential confounders such as genetic variation, age, sex of the two investigated candidate genes in AD. Interestingly, and shared environmental exposures. GDAP1 and HECW2 both play a role in the cellular stress Methods: We generated genome-wide DNA methylation pro- response as well as in neurodevelopment. However, more files for 118 MZ twin pairs from the E-Risk longitudinal research is needed to examine on a cellular level how the study (62 pairs concordant for no severe stress during child- regulation of these two genes might be involved in AD. hood but discordant for stress during adolescence, 28 pairs Furthermore, of the four different brain regions investi- concordant for no severe stress during childhood but con- gated only the PrLC and ILC indicated differential methyla- cordant for exposure to stress during adolescence, and 28 tion patterns. Both brain regions are thought to be involved pairs with no exposure to stress during childhood or ado- in drug-seeking behavior, but, in line with our results, their lescence) using buccal DNA collected at ages 5,10 and 18 roles might oppose each other. and the Illumina Infinium EPIC array. Methylation profiles Our results further emphasize the tissue and cell type from age-18 blood derived DNA were also generated and specificity of epigenetic changes. Although we can some- compared to those of age-18 buccal derived DNA to inter- times assume a correlation of DNA methylation changes be- rogate the tissue-specific nature of the DNA methylome and tween different cell types, further studies are needed to the impact of psychosocial stress on multiple tissue sources. identify which genes do correlate between certain tissue All data pre-processing and downstream statistical analy- and cell types and which seem to be regulated indepen- ses were performed using R statistical packages. The lon- dently. gitudinal epigenetic trajectories associated with exposure to adolescent psychosocial stress were interrogated using Disclosure: Nothing to disclose. linear regression with cluster-robust standard errors. Addi- tionally, the interaction between time and exposure on the doi: 10.1016/j.euroneuro.2018.08.286 DNA methylomic profile of twins discordant for stress at different time points and twins concordant for no exposure to SA65 stress was explored using the interaction model.

DNA METHYLOME MARKS OF EXPOSURE TO PSY- Results: Preliminary data analysis of the repeated mea-

CHOSOCIAL STRESS DURING ADOLESCENCE: ANALYSIS sures buccal samples revealed site-specific differential DNA methylation associated with exposure to adolescence OF A NOVEL LONGITUDINAL MZ DISCORDANT TWIN psychosocial stress at multiple CpG sites located across STUDY the epigenome including genes involved in the stress response pathway and inflammation. Tissue specific differen- Radhika Kandaswamy 1, Eilis Hannon 2, Georgina Mansell 3, tial methylation at CpG loci associated with stress expo- Ben Williams 4, Joe Burrage 3, Susanna Roberts 1, sure was also evident in our blood and buccal epigenome Andrea Danese 1, Jonathan Mill 3, Louise Arseneault 1, analysis. Downstream pathway analysis is underway and will Helen Fisher 5, Chloe Chung Yi Wong 5 help reveal the involvement of genomic regions enriched for

stress/inflammation related pathways. 1 King’s College London Discussion: The current longitudinal epigenome-wide study 2 University of Exeter Medical School of MZ twins discordant for psychosocial stress exposure dur- 3 University of Exeter ing adolescence represents a novel approach in elucidating 4 Duke University how stress gets under the skin to leave lasting biological 5 King’s College London, Institute of Psychiatry, Psychology imprints. Findings from this study point towards a stress- and Neuroscience related EWAS signature which is also tissue specific, thereby, contributing to the understanding of the biological mech- Background: Prolonged activation of the stress response anisms underlying psychosocial stress exposure during key system during key developmental periods such as early stages of development. childhood development and puberty are strongly linked with a range of stress-related diseases and cognitive impairments Disclosure: Nothing to disclose. that persist well into adulthood. An emerging body of evidence has shown that individuals exposed to psychosocial doi: 10.1016/j.euroneuro.2018.08.287 stressors have different epigenetic fingerprints compared to individuals exposed to no/minimal stressful events. Lim- ited conclusions, however, can be drawn from previous find- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 37

SA66 responses. They may also provide biomarkers of successful EPIGENOME-WIDE ASSOCIATION STUDY OF ANTIDE- and unsuccessful antidepressant prescription. PRESSANT USE Disclosure: Nothing to disclose. 1 1 1 Jonathan Hafferty , Mark Adams , David Howard , doi: 10.1016/j.euroneuro.2018.08.288

Toni Clarke 1, Stewart W. Morris 2, Mairead Bermingham 1,

Rosie Walker 1, Riccardo Marioni 1, Archie Campbell 1,

Kristin Nicodemus 1, David Porteous 1, Kathryn Evans 2,

Andrew McIntosh 1 SA67

1 University of Edinburgh PERIPHERAL METHYLOME ANALYSIS IN COCAINE USE

2 Institute of Genetics and Molecular Medicine, University DISORDER PATIENTS SUGGESTS BRAIN-RELEVANT of Edinburgh ALTERATIONS IN THE INNATE IMMUNE SYSTEM: (EPI)GENETICS OF COCCAINE USE DISORDER: COL- Background: DNA methylation (DNAm) acts as an archive LABORATIVE CASE-CONTROL INITIATIVE IN COCAINE of many environmental exposures and may mediate al- ADDICTION terations in gene expression and cellular protein production associated with psychological disorders and their treat- Consuelo Walss-Bass 1, Gabriel Fries 1, Thiago Viola 2, ment. Epigenome-wide association studies (EWAS) of an- Breno Sanvicente-Vieira 2, Diego Rovaris 3, Claiton Bau 3, tidepressants therefore offer an opportunity to better un- Joy Schmitz 1, Rodrigo Grassi-Oliveira 2 derstand antidepressant action and reveal biomarkers associated with antidepressant dosing, absorption, metabolism 1 University of Texas Health Science Center at Houston and response. There is, however, a shortage of published 2 Brain Institute of Rio Grande do Sul (InsCer), Pontiﬁcal EWAS studies. Catholic University of Rio Grande do Sul (PUCRS)

Methods: DNA was extracted from whole blood sam- 3 Universidade Federal do Rio Grande do Sul (UFRGS) ples in 5000 participants from the Generation Scot- land:Scottish Family Health Study. DNA methylation was Background: Recent studies have implicated a role for measured genome-wide using the Illumina HumanMethyla- DNA methylation in modulating addictive behavior. How- tionEPIC BeadChip 850k array. Antidepressant use was as- ever, previous reports have failed to identify robust brain- certained using self-report and record-linkage to prescribe relevant alterations in periphery, which has limited func- data. DNAm was compared between 589 individuals pre- tional studies with genes of interest. In this study, we aimed scribed antidepressants and 3823 non-antidepressant us- to investigate blood methylome alterations in patients with ing controls. Further sensitivity analysis was performed on cocaine use disorder (CUD), compared to controls, and ex- cases using antidepressant medication in the absence of plore their relevance to brain tissue. = other psychiatric medicines(n 359). The EWAS was con- Methods: Genome-wide methylation was assessed in blood trolled for age, sex, smoking history and use, and population from 99 patients with CUD and 90 controls matched by age, stratification. Confounding by presence of major depressive sex, and ethnicity. Assessments were made using the In- disorder was addressed through a separate EWAS. finium MethylationEPIC BeadChip (Illumina) and analyzed by Results: One locus met criteria for genome wide signifi- the RnBeads package. Comparisons between groups were cance in the main analysis, located within the Myosin 1E made for CpGs and region levels controlling for age, sex, = = × gene on chromosome 15 (M value 8.50, p 1.78 10-8). BeadChip, batch, and blood cell type composition, with ad- The sensitivity analyses showed partial attenuation of this justment for false discovery rate (FDR). signal in the group using antidepressants and no other psy- Results: Groups showed a significant FDR-corrected = = × chiatric mediation (M value 2.73 p 8.9 10-6). Several (p < 0.05) difference in methylation of 34 genes. Of these other genes previously associated with depression and/or genes, S100A8 was found by gene set enrichment analyses = < antidepressant action were identified at thresholds (p to be involved in several pathways related to the innate im- × 1 10-5) suggestive of association. mune system. Discussion: Here we present one of the largest EWAS studies Discussion: S100A8, a toll-like receptor 4 (TLR4) agonist, yet undertaken on the epigenetic effects of antidepressant was identified as one of the primary differentially expressed use. Myosin 1e is a non-muscular actin-based motor protein genes in the PFC and striatum of rats treated with stim- thought to play a role in cellular adhesion and migration ulants amphetamine and methamphetamine. TLR4 antago- and is significantly expressed in both blood and neural cells. nists are currently being used in treatment of alcohol and Its potential role in antidepressant action is unknown, al- opioid dependence. We are in the process of analyzing ad- though there have been previous reports of altered mus- ditional peripheral samples from our cohort, together with cular myosin (myosin II) phosphorylation resulting from an- postmortem brain tissue. Our current findings support a role tidepressant use. Despite caution about using methylation of the TLR4 and innate immune system pathways in cocaine of blood cells to investigate antidepressant action, EWAS addiction and may be helpful in future development of novel studies of this kind may in future enable better understand- treatments for addiction. ing of antidepressant action, adverse effects and individual Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.289 ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 38 Abstracts

SA68 Respectively, 3 and 8 DMRs have been identiﬁed in the SUICIDE-ASSOCIATED DNA METHYLATION CHANGES PFC and CER. Top-ranked in the PFC, the WRB-associated IN POST-MORTEM BRAIN SAMPLES: A META-ANALYSIS DMR was found consistently hypomethylated across all 5 CpGs sites in suicide cases compared with controls, in all

Stefania Policicchio 1, Joana Viana 2, Artemis Iatrou 3, 4 independent studies. Located at a maternally-methylated

Eilis Hannon 2, Joe Burrage 1, Gustavo Turecki 4, DMR, the function of this gene is currently unclear. In con-

Zachary Kaminsky 5, Jonathan Mill 1, Emma Dempster 1, trast, the top-ranked DMR in the CER was found hyperme-

Therese Murphy 1 thylated in suicide cases relative to controls across the 3 independent suicide brain cohorts. This DMR is in theCECR2

1 University of Exeter gene which is involved in chromatin remodeling and DNA

2 University of Exeter Medical School damage response.

3 Maastricht University Discussion: In summary, a meta-analysis of genome-wide

4 McGill University DNA methylation studies in two brain regions has iden-

5 Johns Hopkins University tiﬁed a number of candidate DMRs of potential relevance to the pathogenesis of suicide. Future work in-

Background: Suicide is the second leading cause of death cludes applying a system-level approaches (i.e. WGCNA) globally among young people and the tenth leading cause of to identify co-methylated modules associated with suicidal death across all ages. Despite its social and economic bur- behaviour. den, the molecular pathology of suicidality remains poorly Disclosure: Nothing to disclose. understood. The risk for suicidal acts is multifactorial, including a range of biological, psychiatric, psychosocial and doi: 10.1016/j.euroneuro.2018.08.290 cultural risk factors. Epigenetic processes, including DNA methylation, have recently been implicated in suicidal behaviour. The objective of this study was to identify suicide- SA69 associated DNA methylation changes in post-mortem brain GENETIC AND EPIGENETIC SIGNATURES OF AGGRESSION samples. IN THREE DISTINCT RODENT MODELS Methods: DNA methylation profiles were available for 2 brain regions ((Prefrontal cortex (PFC) and Cerebellum Joana Viana 1, Georgina Mansell 1, Amanda Jager 2, (CER)) from post-mortem brain samples of suicide com- Floriana Mogavero 2, Sophie Walker 3, Damien Huzard 3, pleters and non-psychiatric, sudden-death controls and Francesca Zoratto 4, Simone Macrì 4, Eilis Hannon 1, meta-analyzed across 7 suicide cohorts (PFC: n = 211; CER Giovanni Laviola 4, Carmen Sandi 3, Jeffrey Glennon 2, n = 114)). For each cohort, quality-control processing of Jonathan Mill 1 raw DNA methylation data was performed using the pre- processing pipeline WateRmelon for Illumina 450K and EPIC 1 University of Exeter DNA methylation data. 2 Radboud University Medical Center, Nijmegen 28 probes on the X- and Y-chromosomes were used to con- 3 Brain Mind Institute, EPFL firm sample sex. Non-specific probes and probes on the X- 4 Centre for Behavioural Sciences and Mental Health, Isti- and Y-chromosomes were also removed. Statistical analyses tuto Superiore di Sanità were performed using R statistical package (version 3.2.1). A fixed-effect meta-analysis was performed separately for each brain region using the ‘metagen’ function. Regres- Background: Aggressive behavior is a common feature of sion coefficient and standard error (SE) from each individual several child and adolescent psychiatric disorders includ- cohort were used to calculate weighted pooled estimates ing attention-deficit/hyperactivity disorder (ADHD), con- and to test for significance. duct disorder (CD) and oppositional defiant disorder (ODD).

To identify suicide-associated differentially methylated These disorders, like most psychiatric disorders, have a regions (DMRs) in our data, we used the Python module complex etiology, where hundreds or thousands of common

Comb-p to group spatially correlated DMPs (seed P-value < genetic variants are thought to each contribute modestly

1 × 10 −3, minimum of three probes) at a maximum distance to disease risk. Epidemiological research suggests that pre- of 500 bp in each brain tissue. DMR P-values were corrected natal environmental insults or stressful events during child- for multiple testing using Šidák correction. hood could also be important. These observations have led

Results: In the PFC, one DMP (cg00963169) reached to a growing interest in the role of developmentally regu- experiment-wide signiﬁcance (P < 1 × 10-7) This site is lo- lated epigenetic variation in the molecular etiology of these cated in the body of ELAVL4 gene well known to have a role disorders and of their underlying characteristics, such as ag- in neuron-speciﬁc RNA processing and previously implicated gression. In this study we aimed to identify both genetic in paraneoplastic neurologic disorders. Whereas, in the CER and epigenetic variation underlying aggressive behavior us-

6 DMPs passed the experiment-wide signiﬁcance threshold. ing well-characterized rodent models.

The top-ranked DMP (cg14392966, P = 3.06 × 10-11) in the Methods: We examined genetic and epigenetic differ-

CER is located in the promoter region of the ZIC1 gene which ences between the BALB/cJ mouse model of aggression is a gene with transcription factor activity and has been re- compared to BALB/cByJ controls using whole genome ported as a crucial player in the human CER differentiation. sequencing (WGS) to identify DNA sequence variants and reduced representation bisulfite sequencing (RRBS) to profile methylomic variation across multiple brain regions. We ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 39 subsequently explored differences in two other rodent mod- nal articles to check the inclusion and exclusion details. Any els of aggression to identify consistent genomic signatures discrepancies were resolved by a discussion with the third using RRBS using tissue from multiple regions of the brain. reviewer. Full texts of eligible articles were retrieved and These additional models of excessive aggressive behaviours reviewed by two reviewers and assessed further for eligi- have been characterized for specific changes in brain bility; any discrepancies will be discussed or subsequently structure and function. They include early-corticosterone solved by a third reviewer. One reviewer extracted the data treated BALB/cJ mice and three rat lines genetically se- from all articles included, with the third reviewer again re- lected for differential corticosterone responses to stress viewing 20% of extracted data to ensure consistency. (extreme low, extreme high and intermediate). Results: Data extracted from articles include: Author, Year, Results: WGS analysis identified a number of DNA sequence Population, DNA methylation measures, trauma/hardship differences between the BALB/cJ and BALB/cByJ mice, in- measures, mental health outcomes and methylation type. cluding changes in a number of genes previously implicated A number of existing review articles were excluded from in human ADHD, CD and ODD such as Rbfox, Mecom, Avpr1a, inclusion in the data We will present the findings with DNA Dcc, Igf1, Git1, Gad1, Shank2, and Gad2. We also identi- methylation by "type" of exposure (e.g. childhood maltreat- fied differences in DNA methylation in several loci in the ment and/or trauma, socio-economic status, childhood three rodent models of aggression using tissue dissected exposure to war and war-related trauma). Inconsistent from brain regions implicated in aggression. findings in the literature can be attributed in part to Discussion: We identified genetic and epigenetic differ- different exposures, evaluation of different regions of the ences in three different independent rodent models of ag- epigenome, and use of different technologies. This will be gression. Our results nominate novel candidates for a role described in detail. in several child and adolescent psychiatric phenotypes that Discussion: The findings presented are significant, as there have aggression as a common characteristic. have been no epigenomic systematic reviews on this frequently discussed topic in the scientific literature. Our con- Disclosure: Nothing to disclose. clusions can be used to identify and guide future research questions doi: 10.1016/j.euroneuro.2018.08.291

Disclosure: Nothing to disclose.

SA70 doi: 10.1016/j.euroneuro.2018.08.292 DNA METHYLATION AND CHILDHOOD ADVERSITY: A SYSTEMATIC REVIEW

Natasha Wood, Thomas Trebilco, Sarah Cohen-Woods SA71 ALTERNATIVE SPLICING AND ISOFOROM DIVERSITY Flinders University IN THE DEVELOPING BRAIN: RELEVANCE FOR NEU- ROPSYCHIATRIC DISEASE Background: It is well established that adverse childhood 1 2 3 events such as abuse, maltreatment, or trauma are asso- Aaron Jeffries , Nick Bray , Paul O’Neill , 4 1 3 ciated with adverse mental health and psychological out- Jeremie Poschmann , Eilis Hannon , Jonathan Mill comes. There is a growing literature that presents evidence that adverse childhood events have potential to facilitate 1 University of Exeter Medical School epigenetic changes, however findings are not completely 2 Cardiff University School of Medicine consistent. Despite there being many (positive) reviews 3 University of Exeter on this topic, no systematic review has been published to 4 Université de Nantes date. Here we present a systematic review investigating evidence in the literature that global DNA methylation, or site- Background: Alternative splicing and the differential ex- specific DNA methylation, is associated with exposure to pression of RNA isoforms dramatically increase the protein- childhood adversity. This systematic review also aims to give coding potential of the human genome during development. an overview of the potential link between mental health There is evidence for alternative splicing at the majority of outcomes, DNA methylation, and childhood adversity. human genes, and it plays a particularly prevalent role in Methods: Three electronic databases were searched (Sco- the central nervous system where it impacts upon neurode- pus, Web of Science, and PubMed), using keywords that velopment and neuronal function. Traditional short-read aimed to capture any DNA methylation study related to RNA-seq approaches cannot span full-length transcripts, childhood stressor exposure or experience. Exclusion crite- making it difficult to accurately characterize the diverse ria were any non- human articles and theoretical papers and landscape of isoforms. In this study we used Pacific Bio- review articles. To be included articles had to be original re- sciences long-read isoform sequencing (iso-seq) to generate search articles on humans, with at least one analysis of DNA full-length cDNA sequences from human brain samples span- methylation data in relation to a change in the child’s social ning different stages of development. environment. Titles and abstracts obtained from the above Methods: We used Pacific Biosciences iso-seq to catalogue search strategy were screened independently by 2 reviewers isoform diversity in multiple brain regions (cortex, striatum through Covidence to ensure that they meet the inclusion and hippocampus) dissected from both fetal and adult hu- criteria. The third reviewer also reviewed 20% of the origi- man brain. Sequence data was processed using the Iso-Seq2 ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 40 Abstracts pipeline followed by downstream analysis using other pub- variant deletions in cases. We found that GWAS findings licly available resources and customized scripts. for cognitive ability were more associated with fetal brain Results: We identified significant isoform diversity in the hu- FIREs, and TAD boundary regions were associated with genes man brain, with many novel transcripts not previously an- containing rare variation implicated in intellectual disabil- notated in existing genomic databases. Of note, we report ity. We combined chromatin interaction, epigenetic, and both known and new isoforms of several genes previously eQTL data to interpret the genetic loci implicated in the implicated in neuropsychiatric phenotypes including TCF4, largest schizophrenia GWAS to date. HSPD1, GPM6A, and KLC1. Of interest, high levels of intronic Discussion: Our results suggest that interpretation of GWAS reads were detected in fetal brain that were not observed for complex traits can be aided by the incorporation of 3D in adult brain samples. interactome data from relevant tissues. Discussion: We present evidence for widespread isoform diversity in the developing human brain, with potential rele- Disclosure: Nothing to disclose. vance to neuropsychiatric disease. Our dataset represents a doi: 10.1016/j.euroneuro.2018.08.294 valuable resource to the community, identifying novel isoforms of genes implicated in neuropsychiatric disease.

Disclosure: Nothing to disclose. SA73 doi: 10.1016/j.euroneuro.2018.08.293 SITES OF ACTIVE GENE REGULATION IN THE DE- VELOPING HUMAN BRAIN AND THEIR ROLE IN NEU- ROPSYCHIATRIC DISORDERS SA72

A HIGH-RESOLUTION MAP OF CHROMATIN INTER- Manuela Kouakou 1, Jonathan Mill 2, Matthew Hill 3,

ACTIONS IN ADULT AND FETAL CORTEX Nick Bray 1

Paola Giusti-Rodriguez 1, Leina Lu 2, Yuchen Yang 1, 1 Cardiff University School of Medicine

Cheynna Crowley 1, Xiaoxiao Liu 2, Julien Bryois 3, 2 University of Exeter

Ivan Juric 4, Philip Jansen 5, Antonio Pardiñas 6, 3 Cardiff University

Michael O’Donovan 6, Danielle Posthuma 5, Fulai Jin 2, 4 1 1 Ming Hu , Yun Li , Patrick Sullivan Background: Neuropsychiatric conditions such as schizophrenia, autism and attention deﬁcit hyperactiv-

1 University of North Carolina at Chapel Hill ity disorder are complex disorders with a hypothesized

2 Case Western Reserve University early neurodevelopmental component. Most common risk

3 Karolinska Institutet loci for these disorders are located in non-coding regions

4 Lerner Research Institute, Cleveland Clinic Foundation of the genome and are therefore likely to index functional

5 VU Amsterdam variants that alter gene regulation rather than protein

6 Cardiff University structure. Identifying regulatory genomic regions active in the developing human brain will therefore be important Background: Findings from genome-wide association stud- for elucidating genetic mechanisms underpinning these ies have been extremely successful and we now have an conditions. embarrassment of riches of potential disease loci for psychi- Methods: I sought to identify sites of open chromatin, atric disorders such as schizophrenia. Interpretation of most indicative of active regulatory regions, in frontal lobe GWAS findings is complicated by the presence of many sig- from three samples from the 2nd trimester of gestation nificant and highly correlated associations in non-coding re- using the Assay for Transposase-Accessible Chromatin with gions. Chromatin conformation capture methods shed light high throughput sequencing (ATAC-seq). Nuclei from fresh on the three-dimensional organization of chromatin. brain tissue (frontal lobe) were isolated and ATAC-seq Methods: We have generated the most detailed 3D chro- performed according to the protocol of Buenrostro et al matin interactome of adult brain cortex and fetal cerebra to (2013). Libraries were sequenced on a HiSeq4000 to a depth date using easy Hi-C (eHi-C), a variation of Hi-C that yields of over 200 million reads per sample. Sequencing reads high quality libraries using a much lower input. We also were aligned to the human genome and open chromatin generated additional omic data at these two developmen- sites identified using MACS2 peak caller. LD score regres- tal time points, including RNA-seq, ATAC-seq, and ChIP-seq sion analysis was used to test for potential enrichment of (CTCF, H3K27ac, and H3K4me3). We used in-house pipelines polygenic risk signal for neuropsychiatric disorders (derived for the analysis of compartment A/B, to call frequently in- from large-scale genome-wide association studies) within teracting regions (FIREs), and to identify topologically asso- these sites. ciated domain (TAD) boundaries and chromatin interactions. Results: A total of 232,477 high confidence (FDR < 0.01) Results: Our Hi-C readouts agreed with external datasets open chromatin sites were identified in the prenatal hu- and captured key biological processes of adult and fetal man frontal cortex. LD score regression indicated that these brain. FIREs from adult brain showed pronounced asso- open chromatin regions were highly enriched for genetic ciations to schizophrenia common-variant GWAS findings. risk variants associated with schizophrenia (7.9-fold enrich- Boundaries of TADs were not enriched for schizophrenia ment, P = 2.4 × 10-3) and attention deficit hyperactivity dis- GWAS findings or for greater burden of rare copy number order (13.5-fold enrichment, P = 1.6 × 10-2). ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 41

Discussion: These data advance our understanding of gene Discussion: Collectively, our data show that the neurobiol- regulation in the developing human brain and strongly impli- ogy of BRD1 is sex-biased and implicates dysregulation of cate early neurodevelopmental gene regulatory processes in nuclear receptor signaling in sex differences in neuropsy- the pathogenesis of schizophrenia and attention deﬁcit hy- chiatric pathology. peractivity disorder. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.296 doi: 10.1016/j.euroneuro.2018.08.295

SA74 THE NEUROBIOLOGY OF BRD1 IS SEX-BIASED AND SA75 IMPLICATES DYSREGULATION OF NUCLEAR RECEPTOR LARGE-SCALE TRANSCRIPTOME-WIDE CHARACTER- SIGNALING IN PSYCHIATRIC DISORDERS IZATION OF ASD, SCHIZOPHRENIA, AND BIPOLAR DISORDER

Per Qvist 1, Anto Praveen Rajkumar Rajamani 2, 1 1 Sanne Hage Larsen , Jonatan Pallesen , Michael Gandal 1, Pan Zhang 2, Rebecca Walker 1, 3 1 4 4 Veerle Paternoster , Tue Fryland , Kim Fejgin , Arne Mørk , Hyejung Won 1, Evi Hadjimichael 3, Harm van Bakel 3, 1 4 1 Mette Nyegaard , Michael Didriksen , Jens Nyengaard , Jillian Haney 1, Andrew Jaffe 4, PsychENCODE Consortium, 1 5 1 Gregers Wegener , Ole Mors , Jane H. Christensen , Kevin White 5, Mette Peters 6, Mark Gerstein 7, Chunyu Liu 8, 1 Anders Børglum Lilia Iakoucheva 2, Dalila Pinto 3, Daniel Geschwind 9

1 Aarhus University 1 UCLA 2 King’s College London 2 University of California, San Diego 3 Aarhus University and Ipsych 3 Icahn School of Medicine at Mount Sinai 4 H. Lundbeck A/S 4 Lieber Institute for Brain Development 5 Aarhus University Hospital, Risskov 5 University of Chicago

6 Sage Bionetworks

Background: The schizophrenia and bipolar disorder asso- 7 Yale University ciated gene, BRD1, encodes an epigenetic regulator which 8 SUNY Upstate Medical University chromatin interactome is enriched with genes implicated in 9 UCLA School of Medicine mental health. Preclinical data from genetically modified male mice (Brd1 + /- mice) supports a role for BRD1 in psy- Background: Non-coding regions harbor psychiatric disease- chopathology, however, its neurobiology remains poorly un- associated genetic variation, implicating pathogenic dysreg- derstood. ulation of gene expression. Methods: In this study we assess sex-differential changes in Methods: For the psychENCODE project, we examined over Brd1 + /- mice and we examine the molecular mechanisms 2000 brain samples from 1695 subjects with Autism Spec- by which BRD1 exerts its effects. This involves behavioral-, trum Disorder, Schizophrenia and Bipolar Disorder and con- neurostructural-, pharmacological-, and neurochemical trols, integrating genotype and RNA-Seq data. characterizations along with cerebral gene expression pro- Results: Over 25% of the transcriptome exhibits differential filing and integrative genomic analyses. splicing or expression in at least one disorder, including Results: We report common and sex-specific behavioral 944 non-coding RNAs. Using gene and isoform co-expression phenotypes in Brd1 + /- mice accompanied by changes in networks, we isolate cellular and molecular processes associated monoaminergic systems and brain morphometry. altered in disease as well as enrichment for causal ge- Psychotomimetic drug super-sensitivity was only displayed netic factors. We identify disease-specific alterations in by male Brd1 + /- mice whereas changes in affective be- microglial, astrocyte, interferon-response, and NFkB mod- haviors were exclusively observed in female Brd1 + /- ules, defining trajectories of neural-immune mechanisms. mice and could be reversed by clinically effective antide- A transcriptome-wide association study prioritizes disease pressants. Correspondingly, regional brain transcriptomic loci likely mediated by cis-effects on brain expression. changes were enriched with major depressive disorder Discussion: These results provide the largest characteriza- and schizophrenia risk in female and male Brd1 + /- mice, tion of the transcriptome across major psychiatric disor- respectively, and they clustered in functional pathways ders, providing an unparalleled resource for mechanistic in- associated with psychiatric disorders - including G-protein sight and therapeutic development. coupled receptor-, calcium-, and nuclear receptor signaling pathways. We provide in vitro evidence that BRD1 Disclosure: Nothing to disclose. modulates the transcriptional drive of a subset of nuclear doi: 10.1016/j.euroneuro.2018.08.297 receptors (e.g. the vitamin D and glucocorticoid receptors). Finally, we show that nuclear receptor target genes are overall enriched with psychiatric disorder risk and that expression of nuclear receptors is sex-biased in the adult mouse-, and in the developing human brain. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 42 Abstracts

SA76 5 National Centre for Register-based Research

SLEEP DISTURBANCES AND THE VNTR POLYMOR- 6 Aarhus Institute of Advanced Studies PHISM OF CANDIDATE GENES DRD4 AND DAT IN MALE POPULATION 25-64 YEARS IN RUSSIA/SIBERIA: WHO Background: Tw i n studies which used surveys in US popu- PROGRAM MONICA-PSYCHOSOCIAL lations have estimated that genetics explains between half and approximately two thirds of the variation in electoral

Valery Gafarov 1, Elena Gromova 2, Dmitriy Panov 2, participation. Past research in political science has impli-

Almira Gafarova 2, Igor Gagulin 2, Mikhail Voevoda 2, cated highly heritable traits such as education and IQ as key

Vladimir Maximov 2 mediators for political participation. Mechanisms linking genetics to electoral turnout have not been studied previously.

1 Collaborative Laboratory of Cardiovascular Diseases Epi- Methods: Using validated voter turnout information and demiology SB RAMS comprehensively-genotyped data on individuals with diag-

2 NIITP- branch Institute of Cytology and Genetics nosed mental disorders, as well as a representative population cohort across three different elections in Denmark,

Background: We aimed to study genetic features of sleep we estimate the SNP heritability for voting turnout. We in- disorders in the open male population aged 45-64 years in vestigate the amount of variance in electoral turnout ex-

Russia/Siberia. plained by genetic risk scores for IQ, educational attainment

Methods: Random representative sample of male inhab- and ﬁve major personality traits. Using publicly available itants one of Novosibirsk district 45-69 years (n = 657) summary statistics from genome wide association studies, was examined as part of WHO epidemiological program we calculate genetic correlations between electoral turnout

MONICA-psychosocial. Assessment of sleep was based on and educational attainment, childhood IQ, health habits and self-estimation of sleep quality. personality traits.

Results: There were 48.3% in the male population aged 25- Results: We observe that voter turnout is a heritable trait

64 with sleep disorders: assessment of sleep "fair" - 39.6%, across all elections in a cohort of individuals with psychiatric

"bad" - 7.6%, "very bad" - 1.1%. “Good” esteem was in 46.2%, illness. The estimates of heritability are reduced as the so-

«very good» in 5.6%. The most common VNTR polymorphism cial salience of elections increase in a representative popu-

DRD4 gene was genotype 4/4 -57.9% in studied population; lation cohort. Electoral turnout shows positive correlations genotype 2/2 was in 6.1%, genotype 2/4 in 12.5% and geno- with IQ and educational attainment, negative correlations type 3/4 –5,6%; less frequency for genotype 4/6 –4.2%. The with smoking behavior, gastrointestinal illnesses, insomnia population was dominated by a homozygous genotype 10/10 and psychiatric illness.

VNTR polymorphism DAT gene -54.8%, less frequency geno- Discussion: Our population-based study utilizing complex type 9/10 -36.6% and genotype 9/9- 3.7%. Genotype 4/6 trait analyses establishes a genetic overlap between re-

DRD4 gene ( χ2 = 26.941; df = 1 p < 0.001) and genotype 9/9 sources for political participation and voter turnout. The

DAT ( χ2 = 6.459 df = 1 p = 0.011) associated with sleep disor- effects are more pronounced in a population of individuals ders. with mental disorders, which could suggest that psychiatric

Discussion: There was signiﬁcant association of genotype illness adds additional burden on the democratic process. 4/6 DRD4 gene and genotype 9/9 DAT gene with sleep disor- Disclosure: Nothing to disclose. ders. doi: 10.1016/j.euroneuro.2018.08.299 Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.298 SA78 GENETIC RISK FOR LONELINESS APPLIED TO THE EHR REVEALS ADVERSE PHENOTYPIC ASSOCIATIONS SA77

GENES, RESOURCES AND VOTER TURNOUT: A STUDY Julia Sealock 1, Abdel Abdellaoui 2, Sandra Sanchez-Roige 3,

INVESTIGATING GENETIC VARIATION UNDERLYING John T. Cacioppo 4, Dorret Boomsma 2, Abraham A. Palmer 3,

ELECTORAL PARTICIPATION WITHIN A COHORT OF Lea Davis 5 PSYCHIATRIC PATIENTS AND A REPRESENTATIVE POPU-

LATION 1 Vanderbilt University

2 Vrije Universiteit

Lene Aarøe 1, Vivek Appadurai 2, Kasper Møller Hansen 3, 3 University of California, San Diego

Andrew Schork 2, Wesley Thompson 2, Alfonso Buil 2, 4 University of Chicago iPSYCH-Broad Working Group 4, Esben Agerbo 5, 5 Vanderbilt University Medical Center

Michael Bang Petersen 6 Background: Chronic loneliness is strongly correlated with

1 Aarhus University serious health problems; indeed, loneliness is a greater risk

2 Research Institute of Biological Psychiatry factor for mortality than either obesity or cigarette smok-

3 University of Copenhagen ing. Loneliness is deﬁned as distress due to a discrepancy

4 iPSYCH between perceived and desired social connections. While epidemiological studies show that loneliness is associated ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 43 with chronic health conditions, the nature of this relation- SA79 ship remains unclear. Uncovering the genetics of loneliness, GENETIC ANALYSES ON INTERMEDIATE PHENOTYPES with heritability estimates between 14-27%, could help un- OF POST-TRAUMATIC STRESS DISORDER IN A DUTCH ravel connections between loneliness and disease. MILITARY COHORT Methods: GWASs of self-reported loneliness performed in seven independent cohorts totaling 475,661 subjects of Eu- Dick Schijven 1, Sara Pulit 1, Marie Malgaz 2, ropean descent were meta-analyzed by The Loneliness Con- Christiaan Vinkers 2, Marco Boks 3, Jan Veldink 1, sortium (TLC) to produce the largest GWAS of loneliness to Elbert Geuze 2, Eric Vermetten 4, Jurjen Luykx 1 date. Polygenic scores of loneliness were constructed for

18,498 individuals from Vanderbilt University Medical Cen- 1 Brain Center Rudolf Magnus, UMC Utrecht ter’s biobank (BioVU) using the sum of individual alleles 2 University Medical Centre Utrecht weighted by their estimated effect sizes from the meta- 3 Brain Center Rudolf Magnus analyzed GWAS. We then ran analyses to test the associa- 4 Research Centre Military Mental Healthcare tion between the polygenic scores and 897 disease phenotypes using a phenome-wide association analysis (PheWAS) Background: Military personnel are at increased risk of approach. We examined the moderating effect of sex on mental health symptoms and psychiatric disorders follow- the associations between genetic risk for loneliness and the ing their deployment. Post-traumatic stress disorder (PTSD) phenome, after adjusting for possible confounders including lifetime prevalence among combat-exposed individuals is body mass index (BMI) and diagnosis of major depressive dis- estimated at 13%, which is over two times higher compared order (MDD). Genetic correlations between loneliness and to the general population. PTSD involves multiple biolog- 59 traits computed using LD-score regression. ical systems and psychological domains, which leads to a Results: A PheWAS of the standardized genetic risk scores large variation in symptoms. Therefore, we conducted a for loneliness revealed associations with neuropsychiatric, multiple-phenotype GWAS on intermediate phenotypes re- cardiovascular, and metabolic phenotypes, including mood lated to PTSD in a longitudinal cohort of Dutch military per- disorders (OR = 1.11, p = 1.83e-7), ischemic heart disease sonnel. (OR = 1.10, p = 2.42e-7), and type 2 diabetes (OR = 1.08, Methods: Questionnaire data on mental health (SRIP, Self- p = 3.66e-5). We observed an enrichment of depression as- rating inventory for PTSD; SCL-90-R, Dutch revised symp- sociations in females and cardiovascular disease associa- tom checklist; CIS, Checklist of Individual Strength) as tions in males. Addition of BMI and MDD diagnosis to the well as hormone levels in blood plasma (DHEA, dehy- model attenuated the association between genetically pre- droepiandrosterone; cortisol; GABA, gamma-aminobutyric dicted loneliness, cardiovascular disease and depression. acid; NPY, neuropeptide Y; SHBG, Sex Hormone-Binding Interestingly, males with high genetic risk for loneliness Globulin; testosterone) were collected for 560 male in- were at significantly greater risk for myocardial infarction dividuals one month prior to deployment and one month (OR = 1.21, p = 7.47e-5) even after adjusting for both BMI after return. Genome-wide data was obtained through and MDD diagnosis. Furthermore, genetic correlation anal- SNP-array genotyping and imputation of additional ge- ysis of loneliness with 59 traits exhibited highly significant netic markers. Using Software for Correlated Phenotype signals with depressive symptoms, neuroticism, and coro- Analysis (SCOPA), we performed a multiple-phenotype nary artery disease consistent with previous loneliness ge- GWAS using post-deployment measurements corrected for netic studies. pre-deployment measurements and Bayesian information Discussion: We have found associations between genetic criterion (BIC) for optimal model selection per tested risk for loneliness and cardiovascular disease, depression, SNP. and metabolic disease, supporting previous epidemiological Results: We identified one genome-wide significant locus research. Research examining the temporal relationship be- (top variant rs10100651, p = 9.9 × 10-9) inferred from a re- tween loneliness and cardiovascular disease suggests that gression model including DHEA, GABA, NPY, SHBG, SRIP and loneliness is causally linked to chronic health conditions. SCL-90-R. This locus survived permutation by label swapping However, causality may be difficult to determine in epi- (permutation p = 2.0 × 10-8) and various sensitivity analy- demiological studies due to the slow development of car- ses. In addition, the top variant reached nominal signifi- diovascular and metabolic disease. It remains possible that cance in the UK Biobank case-control GWAS on self-reported these correlations are due to pleiotropic effects of genes PTSD (p = 0.02). Furthermore, this locus is a significant ex- that predispose people to both increased feelings of loneli- pression quantitative trait locus (eQTL) for four surround- ness and cardiovascular disease. We are currently conduct- ing genes (INTS8, CCNE2, TP53INP1, NDUFAF6) in multiple ing conditional joint and Mendelian randomization analy- tissues included in the Genotype-Tissue Expression (GTEx) ses to further parse these associations. As loneliness in- database. creases in prevalence and social awareness, understanding Discussion: Using a combination of quantifiable phenotypes the health risks loneliness poses may help to prevent chronic in a regression analysis with BIC for optimal model se- health conditions through early intervention. lection per SNP, we identified a credible locus associated with change in intermediate PTSD phenotypes over a pe- Disclosure: Nothing to disclose. riod of combat-related stress during deployment. This lo- doi: 10.1016/j.euroneuro.2018.08.300 cus was nominally significant in an independent GWAS on self-reported PTSD. Because the top variant of this locus is associated with expression of surrounding genes, we are ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 44 Abstracts currently assessing its role on the expression of these genes and IL-8 ( ρg = 0.48, p = 3.52 × 10-03); sex-specific analysis in physiologically stressed human fibroblasts. In conclusion, showed that the genetic correlation was significant in fe- we show that a multiple-phenotype approach can be a pow- males ( ρg = 0.57, se = 0.17, p = 6.49 × 10-03) but not males erful approach in genetic studies of heterogeneous diseases ( ρg = 0.26, se = 0.49, p = 0.61). The correlation between IL-6 like PTSD and might open opportunities for functional ex- and suicide attempt was significant only if BMI was removed periments. as a covariate ( ρg = 0.54, se = 0.19, p = 6.12 × 10-03). Discussion: The previous literature on inflammation and sui- Disclosure: Nothing to disclose. cide has placed greater focus on IL-6 than IL-8 as a marker of risk; but the present results demonstrate that IL-8 (but doi: 10.1016/j.euroneuro.2018.08.301 not IL-6) have shared genetic influences with risk for suicide attempt and that this effect is sex specific. Further- more, the present findings suggest that the association be-

SA80 tween suicidality and IL-6 documented in previous studies

INTERLEUKIN-8 (BUT NOT INTERLEUKIN-6) SHARES might have been confounded by BMI. The present study GENETIC OVERLAP WITH RISK FOR SUICIDE ATTEMPTS highlights the importance of accounting for factors influenc- IN WOMEN (BUT NOT IN MEN) ing inflammation levels such as sex and BMI when evaluating peripheral biomarkers for psychiatric illness. Going further, 1 2 1 Emma Knowles , Joanne Curran , Samuel Mathias , the findings of the present study generate a tentative but 2 3 2 Harald Goring , Rene Olvera , Ana Leandro , testable hypothesis, which is that the well-characterized IL- 2 4 2 Ravi Duggirala , Laura Almasy , John Blangero , 8 chemokine signaling pathway holds potential risk markers 5 David Glahn and/or preventative targets for suicide.

1 Yale University Disclosure: Nothing to disclose.

2 University of Texas of the Rio Grande Valley School of doi: 10.1016/j.euroneuro.2018.08.302 Medicine

3 University of Texas Health Science Center San Antonio

4 Children’s Hospital of Philadelphia

5 Yale University, Olin Neuropsychiatric Research Center SA81 ASSOCIATION OF WHOLE-GENOME AND NETRIN1 Background: Suicide is major public health concern. In the

United States alone the rate of suicide attempts has risen by SIGNALING PATHWAY-DERIVED POLYGENIC RISK SCORES

30% since 1999 and those attempts are not always preceded FOR MAJOR DEPRESSIVE DISORDER AND WHITE MATTER by a known mental health condition. Suicide may be pre- MICROSTRUCTURE IN UK BIOBANK ventable if risk can be identified and appropriate interven- 1 1 1 1 tions provided promptly. To this end it is imperative to iden- Miruna Barbu , Yanni Zeng , Xueyi Shen , Simon Cox , 1 1 1 tify robust and reliable indicators, or biomarkers, of suicide Toni-Kim Clarke , Jude Gibson , Mark Adams , 1 1 1 risk that transcend traditional diagnostic boundaries. Pre- Mandy Johnstone , Chris S. Haley , Stephen Lawrie , 1 1 vious work has revealed a relationship between increased Ian J. Deary , Major Depressive Disorder Working Group , 1 inflammation levels (for example, IL-6) and risk for suicidal 23andMe, Inc. Research Team, Andrew McIntosh , 1 behavior, but it is not clear the extent to which these al- Heather Whalley terations are genetically linked. We present the first study to directly address whether the shared etiology is due to 1 University of Edinburgh genetic factors. Methods: Genetic analyses were conducted in SOLAR in Background: Major Depressive Disorder (MDD) is a herita- a sample of 1898 Mexican-American individuals from ex- ble and clinically heterogenous psychiatric disorder with tended pedigrees. Genetic correlations were calculated be- a polygenic architecture. Genome-wide association studies tween the interleukins IL-6 and IL-8 measured in serum (Mil- have identified a mounting number of risk-associated vari- lipore catalog #HADK2MAG-61K) and lifetime risk for suicide ants across the genome, and growing evidence of NETRIN1 attempt and current suicidal ideation, as assessed by struc- pathway involvement. Genetic variation within the NETRIN1 tured clinical interview. The effects of age, age ^ 2, sex and pathway, which is crucial for axonal guidance, may provide BMI were considered on each trait. an important tool for the identification of disease mecha- Results: One hundred and fifty-nine individuals endorsed nisms by focusing on a specific process excluding heteroge- having attempted suicide in their lifetime (h2 = 0.46, nous risk-associated variation in other pathways. Here, we p = 2.79 × 10-04) and there were significantly more female sought to investigate the association between MDD risk- than male cases (p = 0.01). Both IL-6 (h2 = 0.18, p = 2.50 × 10- associated variants in (a) the NETRIN1 signaling pathway and 05) and IL-8 (h2 = 0.25, p = 2.51 × 10-08) were significantly variants in (b) the rest of the genome and white matter mi- heritable, age was a significant covariate of both inter- crostructure. leukins (p = 3.62 × 10-08 and p = 7.23 × 10-21), sex was a Methods: We derived polygenic risk scores from single nu- significant covariate of IL-8 (p = 9.91 × 10-06) and BMI was a cleotide polymorphisms (SNPs) within the NETRIN1 pathway significant covariate of IL-6 (p = 9.85 × 10-29). Genetic cor- and SNPs outside of the pathway and tested their associ- relation analysis (including relevant covariates) revealed ation with white matter microstructure. We used two dif- a significant correlation between risk for suicide attempt fusion tensor imaging measures, fractional anisotropy (FA) ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 45 and mean diffusivity (MD), within the UK Biobank study (N ing the initiation codon. Thus, eIFs function as rate limit- FA = 6,401; N MD = 6,390). ing step for post-transcriptional gene regulation. The role Results: FA: Lower FA in the superior longitudinal fas- of eIFs in psychiatric disorders and in particular in major de- ciculus was significantly associated with NETRIN1-PRS pressive episode is not fully understood. It has been shown ( β = -0.036, p-corrected = 0.030). Genomic-PRS was as- that intake of probiotics influences the expression of vari- sociated with lower FA in the uncinate fasciculus ous proteins including eIFs. Here, we investigate the effect ( β = -0.032, p-corrected = 0.043), forceps major ( β = - of probiotic administration on eIF gene expression in whole 0.032, p-corrected = 0.043), forceps minor ( β = -0.032, p- blood of patients suffering from major depressive episodes corrected = 0.043) and generally in global FA ( β = -0.033, under standard care. p-corrected = 0.011) and projection fibres ( β = -0.029, p- Methods: Inpatients of the Department of Psychiatry and corrected = 0.021). Psychotherapeutic Medicine in Graz, Austria, with a ma- MD: Higher MD was significantly associated with NETRIN1 jor depressive episode according to the DSM-IV criteria PRS in the inferior longitudinal fasciculus ( β = 0.029, were included in the double-blind, randomized, prospec- p-corrected = 0.043), superior longitudinal fasciculus tive, monocentric clinical study (ClinicalTrials.gov Identi- ( β = 0.034, p-corrected = 0.039), anterior thalamic radia- fier: NCT03300440). The study was approved by the local tions ( β = 0.025, p-corrected = 0.047), superior thalamic ra- ethics committee (EK 29-235 ex 16/17). All individuals gave diations ( β = 0.027, p-corrected = 0.043) and the thalamic written informed consent. To assess cognitive function in- radiations tract category ( β = 0.030, p-corrected = 0.021). cluding verbal learning and memory, information process- With regards to genomic-PRS, significantly higher MD was ing speed, cognitive flexibility and working memory, a spe- found in the cingulate gyrus part of cingulum ( β = 0.035, p- cific test-battery was applied prior to the first admission corrected = 0.014), the parahippocampal part of cingulum and after 28 days. The intervention group (n = 30) received ( β = 0.033, p-corrected = 0.014), the uncinate fasciculus “Omnibiotics Stress Repair”, a multispecies probiotic, and ( β = 0.029, p-corrected = 0.019), and within association vitamin B7 for 28 days, whereas the control group (n = 30) ( β = 0.042, p-corrected = 0.001), and projection fibres received placebo and vitamin B7. All individuals received ( β = 0.029, p-corrected = 0.023). antidepressant treatment. For gene expression analyses, Discussion: Here, we were able to find specific structural whole blood is collected prior to the first administration and connectivity markers associated both with variants in the after 28 days. Intracellular RNA is isolated, and reverse tran- NETRIN1 signalling pathway and variants outside of it. This scribed from both timepoints. Quantitative real-time PCR is indicates that these brain structures may be involved in the performed for several eIFs. manifestation of genetic risk of MDD and ultimately the ae- Results: RNA isolation and gene expression analyses of the tiology of the disorder. Lastly, our finding regarding an MD intervention and control group are still in progress at the increase in thalamic radiations links the pathway’s role in time of submission. Results on the eIF gene expression will thalamocortical axon guidance, the sets of tracts, and a po- be presented at the WCPG 2018. tential genetic predisposition to MDD. Discussion: We assume that eIF gene expression assessed in whole blood will be altered upon probiotic administration. Disclosure: Nothing to disclose. Previous studies showed an effect of probiotic administration on functional connectivity in the brain of healthy vol- doi: 10.1016/j.euroneuro.2018.08.303 unteers. Therefore, we suppose that probiotic intervention in patients will be altered compared to patients receiving placebo also in the periphery. In case of observable differ-

SA82 ences in eIFs gene expression, association studies between

GENE EXPRESSION OF EUKARYOTIC INITIATION FAC- gene expression and cognitive function will be performed. TORS UPON PROBIOTIC ADMINISTRATION IN DEPRES- This study will allow to elucidate beneﬁcial effects of pro- SIVE PATIENTS biotic administration upon the standard therapeutic treatment options in psychiatric disorders.

Anna Maria Birkl-Toeglhofer 1, Susanne Bengesser 2,

Alexandra Rieger 2, Frederike Fellendorf 2, Martina Platzer 2, Disclosure: Nothing to disclose.

Robert Queissner 2, Carlo Hamm 2, Alexander Maget 2, doi: 10.1016/j.euroneuro.2018.08.304 Sabrina Mörkl 2, Jolana Wagner-Skacel 2,

Thomas Schwarzbraun 2, Johannes Haybaeck 3,

Eva Reininghaus 2 SA83

1 Diagnostic & Research Institute of Pathology, Diagnostic & MIRROR EFFECTS OF 4 NEURODEVELOPMENTAL CNVS Research Center for Molecular BioMedicine, Medical Uni- ON GENERAL FUNCTIONAL CONNECTIVITY AND IMPLI- versity of Graz CATIONS FOR IDIOPATHIC AUTISM

2 Medical University of Graz

3 Medical University of Graz, Otto von Guericke University Clara Moreau 1, Sebastian Urchs 2, Leila Kushan 3, Amy Lin 3,

Magdeburg John D. Lewis 2, Alan C. Evans 2, Simons Variation in

Individuals Project Consortium 4, Carrie E. Bearden 3,

Background: Eukaryotic initiation factors (eIFs) are crucial Pierre Bellec 1, Sébastien Jacquemont 1 in translation initiation of protein synthesis. They are essential for recruiting the mRNA to the ribosome and locat- 1 University of Montreal ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 46 Abstracts

2 McGill University Discussion: We report global opposing changes in connectiv-

3 University of California, Los Angeles ity associated with the 16p11.2 and 22q11.2 loci. Deletions

4 Simons Foundation and reciprocal duplication at each genomic locus are associated with a mirror effect at the global and individual con- Background: Copy number variants (CNVs) at the 16p11.2 nection level. The individual connections most affected by and at the 22q11.2 locus are among the most common these 2 regions are mostly non-overlapping. Despite these psychiatric genetic risk factors with large effect size. The stark differences, the patterns of altered connectivity for 16p11.2 deletion (16pDel) has been associated with Autism these genomic regions are enriched in idiopathic autism spectrum disorder (ASD) and the reciprocal duplication compared to controls. This is consistent with strong hetero- (16pDup) with Schizophrenia (SZ) and ASD. The 22q11.2 geneity at the genetic and connectivity level in ASD. deletion (22qDel) has been associated with SZ and the reciprocal duplication (22qDup) with ASD. Several studies have Disclosure: Nothing to disclose. demonstrated a large effect size of these variants on brain doi: 10.1016/j.euroneuro.2018.08.305 structure. Almost nothing is known, however, on the alterations of functional connectivity (FC) associated with genomic variants. SA84 Our goals are: EVIDENCE OF NRN1 GENE EFFECT ON SCHIZOPHRENIA 1) to characterize and compare patterns of FC associated AGE AT ONSET AND BRAIN ACTIVITY with these 4 CNVs

2) investigate if these patterns may provide insight in the 1 2 Carmen Almodovar Paya , Maria Guardiola Ripoll , FC observed in idiopathic autism. 3 4 5 Pilar Salgado-Pineda , Carme Gallego , Claudia Prats , Methods: We used fMRI data from 20 16p11.2 and 52 5 3 3 Barbara Arias , Raymond Salvador , Edith Pomarol-Clotet , 22q11.2 deletion carriers, 21 16p11.2 and 12 22q11.2 du- Peter Mckenna 3, Mar Fatjó-Vilas 2 plication carriers and 128 controls. Data was acquired from the Simons VIP and a 22q project at UCLA. The idiopathic 1 autism group was comprised of 672 (363 controls, 309 ASD) FIDMAG Germanes Hospitalaries Research Foundation 2 individuals from ABIDE cohort. fMRI data were corrected for FIDMAG Germanes Hospitalaries Research Foundation, slice timing and subject motion and registered to MNI space University of Barcelona, CIBERSAM (Biomedical Research using the NIAK pipeline. Timepoints with excessive head- Network in Mental Health; Instituto de Salud Carlos III) 3 motion ( > 0.5mm) were removed. Subjects with low time FIDMAG Germanes Hospitalaries Research Foundation, points, poor T1/EPI coregistration were excluded. FC was CIBERSAM (Biomedical Research Network in Mental Health; estimated as the pairwise correlation between the average Instituto de Salud Carlos III) 4 time series of 64 brain regions. Molecular Biology Institute of Barcelona (IBMB-CSIC), A linear model was fitted to each connection with genetic Barcelona 5 status, subject motion, sex and site as explanatory factors. University of Barcelona, CIBERSAM (Biomedical Research The effect of the 4 genetic groups were then tested by post- Network in Mental Health; Instituto de Salud Carlos III) hoc contrasts. Each contrast was controlled for false discovery rate (FDR) across all connections at q < 5%. Background: Alterations of synaptic plasticity are currently The 16p11.2 and 22q11.2 connectivity patterns were accepted to play a critical role in schizophrenia (SZ) (Par- compared to the autism cohort using spatial correlation of diñas et al. 2018). Among genes of neuronal plasticity there the individual connectome with the CNV derived pattern of is Neuritin1 gene (NRN1), which has been associated with connectivity alterations. SZ, age at onset and differences in general cognitive per- Results: The 16pDel is associated with an overall increase formance in this disorder (Chandler et al. 2010, Fatjó-Vilas in connectivity: 258 connections were significantly altered et al. 2016). We aimed: i) to further investigate the asso- (FDR corrected) and only 3 connections show underconnec- ciation of NRN1 with schizophrenia-spectrum disorders (SZ- tivity. 4 seed regions were involved in nearly half (44 %) of SD), exploring its role in age at onset; ii) to examine the these altered connections (caudate nucleus, putamen, dor- brain activity correlates of NRN1 sequence variants through solateral somatomotor network, orbitofrontal cortex). a neuroimaging genetics approach. The 16pDup is associated with an overall underconnectiv- Methods: A family sample (FS: 159 offspring with SZ-SD ity but none of the individual connections survived FDR. The and their 383 parents/siblings) and a case-control sample 22qDel is associated with an overall decrease in connectiv- (CCS: 326 SZ patients and 148 healthy controls (HC)) were ity. 98 connections were significantly altered and of those, included in the genetic association analyses. Patients were only 3 were overconnected. The underconnectivity pattern classified as early-onset when onset was ≤ 18 (45.9% in originates mainly from regions in the Limbic network, and FS; 40% in CCS). Eleven SNPs in NRN1 were genotyped. the Frontal network. PLINK-v1.06 was used to estimate the haplotype phases The 22qDup is associated with an overall increase in con- and to calculate the genotypic or haplotypic association. nectivity but due to small sample size, only 9 individual con- A subsample of 132 SZ patients and 113 HC underwent a nections survive FDR correction. fMRI scanning session while performing a n-back task (1.5-T Preliminary results show that these connectivity pat- scanner). We studied the effect of the SNPs and haplotypes terns are significantly enriched in individuals with idiopathic (those identified in genetic association analyses) on whole autism compared to control subjects. brain activity (2-back vs. baseline) separately in SZ and ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 47

HC (ANOVA or t-test adjusted by age, sex and premorbid the strongest known risk factors for schizophrenia and also intelligence coefficient (TAP), using FSL). confers risk of other psychiatric disorders including ADHD Results: In the genetic association analyses we identi- and ASD. Preliminary evidence from functional MRI studies fied that the haplotype CG (rs645649-rs582262) was un- shows evidence of resting-state dysconnectivity in people transmitted from parents to EO SZ-SD patients (p = 0.011, with this copy number variant but to our knowledge this has OR (95%CI = 0.08[0.01-0.71]), and that the haplotype CT not been examined using magnetoencephalography (MEG), (rs582262-rs3763180) was less frequent in EO SZ cases than a technique which can be used to explore neural oscillatory in controls (p = 0.0258, OR (95%CI = 0.525[0.2371-1.1097]). activity across frequency bands. Then, these two haplotypes were associated to a protective Methods: 37 children aged between 10-17 years with effect. No association was observed in AO samples. 22q11.2DS and 26 healthy controls took part in the study. In the neuroimaging genetics analyses, patients carrying Whole-head MEG recordings were made using a CTF 275- the CC genotype (rs582262) showed a failure of deactiva- channel radial gradiometer system during a five-minute tion of medial prefrontal regions and cingulate cortex as resting-state recording. Datasets were filtered into the fol- compared to CG [peak at MNI (-16,40,14), p = 2.15e-06] and lowing bandwidths: delta (1-4 Hz), theta (4-8Hz), alpha to GG [peak at MNI (-14,38,14), p = 5.96e-08; 2810 voxels]. (8-13Hz), beta (13-30Hz), low gamma (30-50Hz) and high The mean activation values of each genotype (CC, CG, GG) gamma (50-90Hz). Amplitude-amplitude coupling between were 12.26(8.03), 1.72(11.19), -2.55(16.13); respectively. brain regions was analysed using the Automated Anatomi- In HC, carriers of the C allele showed lower deactivation in cal Labelling (AAL) atlas and two-tailed t-tests were then the same regions as compared to GG [CC/CG vs GG: -1.76 used to compare resting-state connectivity between cases (9.66) vs -10.64(11.00); peak at MNI (14,50,14), z = 3.71, and controls for each of the six frequency bands of inter- p = 0.0006]. est. Relationships between connectivity measures, IQ and Discussion: Our family and case-control analyses are consis- psychopathology were explored using linear regression. tent with evidence of a genetic association between NRN1 Results: After quality control, 60 datasets were included in gene and SZ and extend the knowledge on that NRN1 has the analyses (35 22q11.2DS, 25 controls). There were no sig- a selective impact on early onset. Our neuroimaging anal- nificant between-group differences in age, gender or hand- yses suggest that NRN1 variability is involved in the regu- edness. Mean IQ was 32.8 points lower for children with lation of the deactivation of areas involving frontal medial 22q11.2DS than controls. Children with 22q11.2DS had sig- regions (mPFC) in SZ patients during a working memory task nificantly lower alpha and delta global connectivity strength performance and, in a lesser extent, also in controls. This compared to controls. In the beta band, connection strength is in line with a recent study that has described the spe- between the right calcarine sulcus and the right lingual cific role of NRN1 modulating neurons excitability through gyrus was significantly reduced in children with 22q11.2DS. calcium channels in the medial PFC (Yao et al. 2016). This IQ did not predict global connectivity strength for any of the result is of special interest since mPFC is an area included frequency bands tested once CNV status was controlled for. in the Default Mode Network which has been highly doc- However, global connectivity strength in the alpha band was umented to be altered in SZ (Pomarol-Clotet et al. 2008, significantly associated with Social Communication Ques- Salgado-Pineda et al. 2011). tionnaire (SCQ) scores (a measure of ASD symptomatology) Acknowledgements: Fundación Alicia Koplowitz. and with total anxiety scores derived from the Child and 2017SGR1271. CD16/00264 to MF-V. Adolescent Psychiatric Assessment (CAPA). Discussion: In this MEG study of children with 22q11.2DS, Disclosure: Nothing to disclose. we find evidence of atypical resting-state connectivity across multiple frequency bands. We also find preliminary doi: 10.1016/j.euroneuro.2018.08.306 evidence for an association between alpha band connectivity, the social communication difficulties and anxiety symptoms that are frequently experienced by these children.

SA85 Further studies will be needed to replicate this ﬁnding and

RESTING-STATE BRAIN CONNECTIVITY IN 22Q11.2 to follow-up this high-risk group in order to explore po- DELETION SYNDROME: A MAGNETOENCEPHALOGRA- tential relationships between resting-state connectivity and PHY STUDY other psychiatric symptoms such as psychosis.

Jo Doherty 1, Marianne van den Bree 2, David Linden 2, Disclosure: Nothing to disclose.

Krish Singh 1, Michael Owen 3 doi: 10.1016/j.euroneuro.2018.08.307

1 Cardiff University

2 Cardiff University School of Medicine

3 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University

Background: Atypical brain connectivity has been hypoth- esised to underlie the clinical features of many psychiatric disorders including schizophrenia, attention deﬁcit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). 22q11.2 deletion syndrome (22q11.2DS) is one of ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 48 Abstracts

SA86 Temporo-parietal regions (1793 voxels, peak activation at EFFECT OF KCNH2 AND CACNA1C ON COGNITIVE MNI (-70,-44,14), z = 3.97, p = 3.8e-05). Also within patients, PERFORMANCE AND BRAIN ACTIVITY: GENETIC AS- CACNA1C AA genotype was associated with a de-activation SOCIATION STUDY IN SCHIZOPHRENIA PATIENTS AND failure compared to AG genotype in two clusters: 1) Medial HEALTHY SUBJECTS frontal cortex (912 voxels, peak activation at MNI (6,76,12), z = 3.88, p = 0.0066) and; 2) Precuneus (1132 voxels, peak ac- = = Maria Guardiola Ripoll 1, Carmen Almodóvar Payá 1, tivation at MNI (22,-34,68), z 3.83, p 0.0016).

Pilar Salgado-Pineda 2, Alba Lubeiro 3, Silvia Alonso-Lana 2, Discussion: Our ﬁndings show that KCNH2 and CACNA1C

Jordi Ortiz-Gil 4, Amalia Guerreo-Pedraza 5, Salvador Sarró 2, seem to be associated with cognitive performance, which is

Edith Pomarol-Clotet 2, Mar Fatjó-Vilas 6 in line with previous studies (Hashimoto et al. 2013, Krung et al. 2010, Zhang et al. 2012). Concerning neuroimaging

1 FIDMAG Germanes Hospitalàries Research Foundation analyses, previous studies using ROI based approaches and

2 FIDMAG Germanes Hospitalàries Research Foundation, mainly focused in HS (Huffacker et al. 2009, Paulus et al.

Barcelona, CIBERSAM (Biomedical Research Network in 2014) showed that both genes have an effect on brain ac-

Mental Health; Instituto de Salud Carlos III) tivity in prefrontal regions. Our data suggest that KCNH2

3 School of Medicine, University of Valladolid and CACNA1C modulate brain activation patterns during n-

4 Hospital General de Granollers back performance speciﬁcally in SZ patients. Furthermore,

5 Hospital Benito Menni-CASM, Sant Boi de Llobregat CACNA1C results are in line with a previous study which sug-

6 FIDMAG Germanes Hospitalàries Research Foundation, gested its relationship with altered activity of the Default

CIBERSAM (Biomedical Research Network in Mental Health; Mode Network in SZ (Meda et al. 2014).

Instituto de Salud Carlos III), University of Barcelona Acknowledgements: Spanish Ministry of Economy and Com- petitivity, ISCIII (PI15/01420 and PI15/00299), Ayuda co- financiada por el Fondo Europeo de Desarrollo Regional Background: The latest GWAS has added evidence on the (FEDER) “Una manera de hacer Europa”. 2017SGR1271. role of neuronal excitability mechanisms in the pathogene- CD16/00264 to MF-V. sis of schizophrenia (SZ) (Pardiñas et al. 2018), highlight- ing specific gene sets related to calcium ion import and Disclosure: Nothing to disclose. membrane depolarization during action potential. The al- teration of such mechanisms may be linked with the cogni- doi: 10.1016/j.euroneuro.2018.08.308 tive deficits and impaired neural function associated with SZ (Green and Harvey 2014; Dolmetsch et al. 2001). However, few is known about the role of genes involved in neuronal SA87 excitability, such as KCNH2 and CACNA1C, in cognitive per- BRAIN SCANS FROM 21,297 INDIVIDUALS REVEAL THE formance and brain activity. We aimed to study the role of GENETIC ARCHITECTURE OF HIPPOCAMPAL SUBFIELD

KCNH2 and CACNA1C on: i) cognitive performance and ii) VOLUMES brain activity during a functional magnetic resonance imaging (fMRI) protocol. Dennis van der Meer 1, Jaroslav Rokicki 1, Tobias Kaufmann 1, Methods: In a sample of 296 SZ patients and 157 Aldo Córdova-Palomera 2, Torgeir Moberget 3, Dag Alnæs 3, healthy subjects (HS) two SNPs were genotyped: rs38007789 Francesco Bettella 1, Oleksandr Frei 4, Nhat Trung Doan 3, (KCNH2) and rs1006737 (CACNA1C). The cognitive assess- Ole Andreassen 4, Lars Tjelta Westlye 5 ment included: i) premorbid IQ (Word Accentuation Test, TAP); ii) memory (Wechsler Memory Scale, WMS-III) and; iii) 1 Norwegian Centre for Mental Disorders Research, Oslo executive function (Behavioural Assessment of the Dysexec- University Hospital and University of Oslo utive Syndrome, BADS). The association between SNPs and 2 Oslo University Hospital cognition was tested with linear regressions (adjusted by sex 3 NORMENT and age; SPSS). A subsample (132SZ/89HS) participated in 4 University of Oslo a fMRI protocol (1.5-T scanner) while performing a work- 5 Norwegian Centre for Mental Disorders Research ing memory task (n-back). The effect of each SNP on whole brain activity (2-back vs baseline) was studied separately in Background: The hippocampus is a heterogeneous struc- SZ patients and HS (ANOVA adjusted by sex, age and TAP; ture, comprising histologically distinguishable subfields. FSL). These subfields are differentially involved in memory Results: In HS the A allele of KCNH2 was associated with consolidation, spatial navigation and pattern separation, better performance in memory (WMS) than CC homozygotes complex functions often impaired in individuals with brain (ß= 3.01, p = 0.01). SZ patients carrying CACNA1C A allele disorders characterized by reduced hippocampal volume, showed lower premorbid IQ (TAP) than GG homozygotes including Alzheimer’s disease (AD) and schizophrenia. (ß= -1.39, p = 0.027). Given the structural and functional heterogeneity of the In SZ patients, KCNH2 AA genotype was associated with hippocampal formation, we sought to characterize the a deactivation pattern compared to AC and CC genotypes subfields’ genetic architecture. in three clusters: 1) Caudate, insula and putamen (895 vox- Methods: T1-weighted brain scans (n = 21297, 16 cohorts) els, peak activation at MNI (18,0,22), z = 3.76, p = 0.0072); 2) were processed with the hippocampal subfields algorithm in Anterior cingulate and medial frontal cortex (1107 voxels, FreeSurfer v6.0. We ran a genome-wide association analysis peak activation at MNI (6,42,0), z = 3.37, p = 0.0019) and; 3) on each subfield, covarying for total hippocampal volume. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 49

We further calculated the single nucleotide polymorphism affective-to-psychotic continuum. Here, we give an update (SNP)-based heritability of twelve subfields, as well as their on the sample that is currently available and re-analyze de- genetic correlation with each other, with other structural pressive, manic and psychotic symptoms in clinical partici- brain features, and with AD and schizophrenia. All outcome pants. Moreover, we update our analyses in patients on poly- measures were corrected for age, sex, and intracranial vol- genic risk scores (PRS) as predictor of diagnostic group. ume. Methods: The PsyCourse study is a multicenter study of Results: We found 15 unique genome-wide significant loci 18 clinical centers in Germany and Austria. At the time of across six subfields, of which eight had not been previ- abstract submission, the sample consisted of 1,047 adult ously linked to the hippocampus. Top SNPs were mapped patients with a DSM-IV lifetime diagnosis of schizophrenia to genes associated with neuronal differentiation, locomo- (SZ), schizophreniform disorder (SZF), brief psychotic disor- tor behaviour, schizophrenia and AD. The volumes of all the der (BPD), schizoaffective disorder (SZA), bipolar disorder subfields were estimated to be heritable (h2 from .14 to (BD), or recurrent major depression (rMDD), as well as 288 .27, all p < 1 × 10-16) and clustered together based on their control participants. Study participants are assessed at four genetic correlations compared to other structural brain fea- equidistant points in time during a total study period of 18 tures. There was also evidence of genetic overlap of subic- months (assessments at baseline, + 6 months, + 12 months, ular subfield volumes with schizophrenia. and + 18 months). At each time point, an extensive phe- Discussion: We conclude that hippocampal subfields have notyping battery is completed, assembling information on partly distinct genetic determinants associated with spe- psychopathology, medication, cognitive performance, level cific biological processes and traits. Taking into account this of functioning, quality of life, and life events. Additionally, specificity may increase our understanding of hippocampal at each assessment, venous blood samples are collected in neurobiology and associated pathologies. order to extract biomaterials such as DNA, RNA, serum, and plasma. Disclosure: Nothing to disclose. So far, 825 clinical participants have been genotyped using the Illumina Infinium PsychArray. Genotypes were im- doi: 10.1016/j.euroneuro.2018.08.309 puted using the 1000 Genomes project dataset (Phase 3) as the reference panel. As a basic characterization of the sample, we compare

SA88 two diagnostic groups using linear mixed-effect regression: PSYCOURSE: A TRANSDIAGNOSTIC STUDY ON THE participants with a lifetime diagnosis of a predominantly COURSE OF SEVERE MENTAL DISORDERS psychotic disorder (i.e., SZ, SZA, SZF, BPD) and those with a lifetime diagnosis of a predominantly affective disorder 1 2 2 Monika Budde , Katrin Gade , Heike Anderson-Schmidt , (i.e., BD types I or II, rMDD). 3 1 1 Janos Kalman , Fanny Senner , Kristina Adorjan , Moreover, we use logistic regression to estimate the 1 3 1 Eva C. Schulte , Ashley L. Comes , Sergi Papiol , amount of variation of diagnostic group explained by SZ- 4 5 Till F. M . Andlauer , Marcella Rietschel , and BD-PRS, respectively. Descriptive statistics of the con- 6 7 1 Markus M. Nöthen , Peter Falkai , Thomas G. Schulze , trol group are also presented. 1 Urs Heilbronner Results: The basic descriptive information on the current sample is as follows: 47% of all clinical and control partici-

1 Institute of Psychiatric Phenomics and Genomics, Univer- pants are female. The mean age in the total sample is 41.35 sity Hospital, LMU Munich years (range: 18-78 years). 54% of the clinical participants

2 University Medical Center Goettingen have a lifetime diagnosis of a predominantly psychotic dis-

3 Institute of Psychiatric Phenomics and Genomics (IPPG), order; 46 % have a lifetime diagnosis of a predominantly af- University Hospital, LMU Munich, International Max Planck fective disorder. The mean duration of illness is 12.53 years Research School for Translational Psychiatry, Max Planck In- (range: 0-53 years). stitute of Psychiatry Results from the analyses will be presented at the meet-

4 Max Planck Institute of Psychiatry Munich ing.

5 Central Institute of Mental Health, University of Heidel- Discussion: The PsyCourse study is one of the ﬁrst trans- berg diagnostic longitudinal projects in the ﬁeld of psychiatric

6 Institute of Human Genetics, University of Bonn genetics and is therefore a great resource for future analy-

7 University Hospital, LMU Munich ses. A wealth of phenotypic and biological data has already been collected and the sample size will increase further Background: Although classiﬁed as separate categorical during the next months. While not in the public domain, entities in current diagnostic systems, affective and psy- data will be available to bona ﬁde researchers all over the chotic disorders partially share psychopathological features world based on mutually agreed memoranda of understand- and are genetically correlated. Moreover, patients suffering. ing from a disorder of either group are highly heterogeneous regarding their course of illness and functional out- Disclosure: Nothing to disclose. come. Longitudinal studies with phenotypes beyond mere doi: 10.1016/j.euroneuro.2018.08.310 diagnoses might help to biologically and clinically stratify patients. We have therefore designed the PsyCourse study ( www.psycourse.de; Budde et al., 2018, Am J Med Genet Part B), an ongoing transdiagnostic longitudinal study of the ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 50 Abstracts

SA89 horts. Results of meta-analysis (currently underway) will be A GENOME-WIDE ASSOCIATION SCREEN OF QUAN- reported. TITATIVE SPEECH, LANGUAGE AND READING TRAITS IN Discussion: Language-related phenotypes pose special chal- > 14,000 PEOPLE IN THE GENLANG CONSORTIUM lenges for genetic analysis, due to the labor-intensive nature of assessment and additional heterogeneity caused by

Else Eising 1, Beate St Pourcain 2, Clyde Francks 3, different assessment tools and languages. Therefore, they

Simon E. Fisher 3 have yet to fully beneﬁt from advances in large-scale genomic screens. These ﬁrst efforts by GenLang show that

1 Max Planck Institute for Psycholinguistics, Nijmegen a consortium approach, with particular attention to phe-

2 Max Planck Institute for Psycholinguistics, University of notype harmonization, makes it feasible to perform well-

Bristol powered GWAS for language-related traits. The results of

3 Max Planck Institute for Psycholinguistics, Nijmegen, Don- this GWAS meta-analysis will open up novel avenues for de- ders Institute for Brain, Cognition and Behaviour, Radboud ciphering the biological underpinnings of spoken and writ-

University ten language, including (but not limited to) investigating genetic overlaps with other behavioural/cognitive traits, with findings from neuroimaging genetics of language-related Background: The processing and production of complex brain regions, and with genomic signatures of human evo- spoken and written language are traits that are unique to lution. humans. Decades of family and twin studies established that inter-individual variation in these traits is highly heritable. Disclosure: Nothing to disclose. Nonetheless, like other human phenotypes, the relevant genetic architecture is complex, heterogeneous, and multifac- doi: 10.1016/j.euroneuro.2018.08.311 torial. Early linkage analyses and targeted association studies suggested a handful of candidate genes. However, replication efforts met with limited success. In recent years, genetic studies of spoken and written language have moved SA90 towards genome-wide association screens (GWAS) but very THE STABILITY OF EDUCATIONAL ACHIEVEMENT IS few significant hits have been identified, which may reflect LARGELY EXPLAINED BY GENETIC FACTORS low power due to the relatively small sizes involved. Other areas of human genetics have overcome this issue by setting Kaili Rimfeld 1, Margherita Malanchini 2, Eva Krapohl 3, up consortia to facilitate large-scale meta-analyses across Laurie J. Hannigan 3, Philip S. Dale 4, Robert Plomin 1 multiple cohorts. Methods: This work is performed in the context of GenLang, 1 King’s College London a new international consortium of researchers interested 2 University of Texas at Austin in deciphering the genetic underpinnings of spoken/written 3 Institute of Psychiatry, Psychology & Neuroscience, King’s language, not only for disorders but also variation in the nor- College London mal range. One aim of GenLang is to provide a framework 4 University of New Mexico for large-scale GWAS of speech, language, reading, and related skills via meta-analyses of existing datasets. The current study focuses on language-relevant traits that have Background: Educational achievement is important to both been assessed using continuous measures in cohorts with society and to children as individuals. Compulsory educa- available genotype data. Cohorts include twin (e.g. TEDS, tion in the UK culminates with standardized nation-wide

NTR, BATS), population-based (e.g. ALSPAC, GenR, Raine) exams, the GCSEs (General Certiﬁcate of Secondary Edu- and disorder-oriented samples (e.g. CLDRC, NeuroDys, SLIC, cation). GCSE performance is a remarkably broad index of

GRaD), from a range of countries including the UK, USA, Aus- a child’s life, extending beyond the cognitive realm to en- tralia, Netherlands, Germany, Spain and Austria. Uniform compass self-regulation, wellbeing and physical and mental pipelines were established for consistent quality control and health. Previous twin research has shown that GCSE perfor- processing of phenotype and genotype data across these di- mance is highly heritable, and to a lesser extent explained verse cohorts. by environmental factors. However, little is known about

Results: Quantitative data of children and adolescents re- whether the same or different genetic and environmental lating to multiple aspects of spoken and written language effects contribute to individual differences in achievement were available from 16 GenLang cohorts with matching over the course of compulsory education. genome-wide SNP data. Extensive efforts were made to Methods: The sample consisted of 6000 pairs of twins harmonize phenotypes obtained across diverse test instru- from the UK-representative Tw i n s Early Development Study ments, languages, and ages. This process led to identifica- (TEDS) using teacher and exam/test grades during compul- tion and alignment of several quantitative traits for which sory education. there was ample overlap. For four traits, combined sam- Analyses used two longitudinal twin models. The simplex ple sizes of > 14,000 individuals were reached for meta- model estimates the extent to which the genetic and en- analysis: single word reading, nonword reading, nonword vironmental influences on a trait are transmitted from age repetition, and spelling. We are in the process of expanding to age, and the extent to which innovative and age-specific sample sizes for additional traits such as phoneme aware- influences emerge. The common pathway model estimates ness and rapid automatized naming through additional co- the etiology of the common latent factor and allows for the estimation of the A, C and E components of the residual ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 51 variance in each measure that is not captured by the latent Background: Suicide is the tenth leading cause of death in construct. the United States, with more than 40,000 suicide deaths per Genomic analyses mirrored the twin analyses. SNP heri- year. Importantly, of the approximately 3,600 per 100,000 tabilities were calculated for overall achievement as well as individuals in the US who exhibit suicidal behavior or for specific subjects. Genome-wide polygenic scores (GPSs) ideation, fewer than 1% actually go on to complete suicide. were calculated using summary statistics from Okbay et al Heritability of completed suicide is estimated at 43%, indi- 2016 GWA analysis of years of education (EduYears). Delta cating that genetic factors almost certainly play an impor- R2 are reported as the estimates of variance explained by tant role. Because of difficulties in data collection, genetic adding the GPS to the regression model that included aca- studies examining completed suicide are rare and under- demic achievement from all earlier ages to assess the extent powered. Here we present results from the largest genome- to which EduYears contributes to age-to-age stability. wide association study (GWAS) of completed suicide to date. Results: Results of our twin analyses showed that educa- Methods: Through collaboration with the Utah Office of the tional achievement is highly heritable ( ∼60%) across school Medical Examiner, we collected blood samples from 1321 years and across subjects studied at school and is highly sta- individuals who died by suicide. Samples were genotyped ble (phenotypic correlations ∼0.70 from ages 7 to 16). Ge- using the Illumina Infinium PsychArray platform and cases netic factors accounted for most of this stability (70%), even of European ancestry were carefully matched to a large co- after controlling for intelligence (60%). Shared environmen- hort of control samples from Generation Scotland, resulting tal factors also contributed to the stability, while change in 1070 suicide cases and 3532 controls (total N = 4602). A was mostly accounted for by individual-specific environmen- mixed-model GWAS of 7 358 674 variants was conducted us- tal factors. ing GEMMA, and comparison analyses were conducted with Our genomic analyses also showed that educational the Utah population of the 1000 Genomes Project. Gene set achievement is heritable (SNP heritability of ∼30%) and and pathway enrichment analyses were employed to char- that EduYears GPS increasingly predicted core educational acterize function in the implicated variants. achievement –about 4% at age 7, 6% for at age 12, 8% at age Results: A total of 126 variants mapping to 4 genes (TLR 1, 14, and 10% for GCSE at age 16. In line with the longitudi- TLR 6, TLR 10, FAM114A1) met genome-wide significance (p nal twin analyses, EduYears GPS’ prediction of educational < 5 × 10-8). An additional 63 variants were nominally signif- achievement was largely stable across compulsory educa- icant at q < 0.05 and mapped to 11 genes, including HLA- tion. That is, our regression analyses indicated little ( < 1%) C and HLA-V. HLA imputation and pathway analysis further age-specific genetic prediction once the stable prediction of implicated major histocompatibility complex and immune- EduYears GPS from all previous ages was taken into account. related genes in risk of suicide completion. Discussion: Our finding of genetically driven stability of ed- Discussion: In the context of other recent findings relat- ucational achievement should provide additional motiva- ing major histocompatibility complex variations to psychosis tion to identify children in need of interventions as early and general inflammatory markers to major depression, as possible, as the problems are likely to remain through- these results help suggest that immune-related genes are in- out the school years. GPS prediction, specifically, might in dicated not only in broad psychopathology, but in extreme, the future provide a tool to identify children with educa- rare outcomes. We discuss potential targets for future re- tional problems very early in life and aid in providing both search, as well as propose that polygenic risk scores for sui- individualized prevention and individualized learning pro- cide completion, calculated from these summary statistics, grams. We hope that with GPS we can move towards preci- may help address the current gap of genetic research on sion education, just as medicine is moving towards precision completed suicide. medicine. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.313 doi: 10.1016/j.euroneuro.2018.08.312

SA91 SA92 A GENOME-WIDE ASSOCIATION STUDY OF COMPLETED THE INFLUENCE OF THE SEROTONIN TRANSPORTER SUICIDE IN UTAH GENE 5-HTTLPR POLYMORPHISM ON SUICIDAL BEHAV- IORS: A META-ANALYSIS

John Anderson 1, Andrey Shabalin 1, Jess Shade 1,

Amanda Bakian 1, Daniel Adkins 1, W. Brandon Callor 2, Giuseppe Fanelli, Alessandro Serretti

Erik Christensen 2, Emily DiBlasi 1, Douglas Gray 1,

Caroline Hayward 3, David Porteous 3, Alexis Edwards 4, University of Bologna

Qingqin Li 5, Hilary Coon 1, Anna Docherty 1 Background: Suicidal Behavior is the second leading cause

1 University of Utah School of Medicine of death among youth worldwide and the tenth among all

2 Utah State Ofﬁce of the Medical Examiner age groups. Inherited genetic differences have a role in

3 University of Edinburgh suicidality, as shown by family, adoption and twin studies,

4 Virginia Institute for Psychiatric and Behavioral Genetics with heritability ranging from 30 to 55%. The serotonergic

5 Janssen R&D, LLC system and the SCL6A4 5-HTTLPR gene variant have been ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 52 Abstracts largely investigated for association with suicidal behaviors, Background: Suicide is a multicausal phenomenon with a with controversial results. biopsychosocial background, including a significant contri- In this work, we sought to determine whether the results bution of genetic factors. While suicide contributes to about of previous meta-analyses were confirmed or modified sub- 800,000 deaths a year, it is a relatively rare event at the sequently to the inclusion of more recent literature data. community level which is a great obstacle for suicide re- Methods: Electronic literature search was performed to search. Suicidal behaviours can be placed along a spec- identify pertinent studies published until April 2018 using trum considering their phenotype from suicidal thoughts Medline/PubMed. Their reference lists were inspected to and ideation through plans and suicidal gestures to different retrieve additional papers not indexed by Medline/Pubmed. types of attempted and completed suicide. However, suici- For meta-analyses, data were entered and analyzed through dal behaviour is not only phenotypically heterogeneous but RevMan v5.3. Furthermore, subgroup and sensitivity meta- also on the genetic level, questioning the appropriateness analyses were performed considering different phenotypes of extrapolating from research on suicide ideators or at- of Suicidal Behavior (e.g. Violent and non-Violent Suicide), tempters when seeking to understand the genetic predictors ethnicity, gender and three major psychiatric diagnostic of completed suicide. Thus, our aim is to develop a complex categories (SCZ spectrum, Mood Disorders and Substance model incorporating several levels of evidence from genet- Abuse Disorders). ics through biochemistry as well as social and psychosocial Results: Our literature search yielded 140 articles on determinants of suicidal behaviour based on completed sui- SCL6A4 gene 5-HTTLPR polymorphism and Suicidal Behavior cide cases in the Hungarian suicide biobank. 5-HTTLPR has association; among these, we identified 43 pertinent case- previously been implicated in suicidal behaviour and vio- control studies (14771 subjects in all). No association was lent completed suicides with contradicting results. The aim found between low-expressing alleles (S + Lg) or S’ carrier of our study was to investigate the association between 5- genotypes (SS, SL, SLg, SLa, LgLa, LgLg) and Suicidal Behav- HTTLPR and suicidal behaviour in our currently developed ior in the general primary analyses, which encompass all the suicide biobank. studies we previously selected. The sensitivity analyses did Methods: During autopsy DNA samples were obtained for not show any significant effect of the 5-HTTLPR polymor- 5-HTTLPR genotyping from 200 subjects deceased due to phism when we considered homogenous data for ethnicity, suicide and 200 controls deceased due to other causes. gender and main diagnostic groups. In spite of this, analyses Chi-square tests and logistic regression analyses were per- suggested that low-expressing alleles and S’ carrier geno- formed according to additive, dominant and recessive mod- types were associated with an increase in the risk of Vio- els to analyze the possible association between 5-HTTLPR lent Suicide Attempt (allele-wise: OR = 1.49, C.I. 1.18-1.88, genotype distribution and suicide. p = 0.0008; genotype-wise: OR = 2.9, C.I. 1.69-5, p = 0.0001). Results: Ratio of violent and non-violent suicides was 81% Discussion: Some clinical, personality and sociodemo- and 19%, respectively. No significant difference was found graphic features may allow to distinguish suicide attempters in the distribution of 5-HTTLPR genotypes between suicidal from completers. The effect of the low-expressing alleles and control samples according to any genetic models (addi- and genotypes are more evident where the psychopatho- tive: χ2 = 0.602, p = 0.740; dominant: χ2 = 0.404; p = 0.525; logical dimension underlying the Suicidal Behavior is more recessive χ2 = 0.457; p = 0.499). No difference was found be- relevant as well as when the social aspects and the general tween violent and nonviolent suicides with respect to geno- health conditions interfere less with the Suicidal Behavior type distribution (additive: χ2 = 1.771, p = 0.412; dominant: diathesis. χ2 = 1.555, p = 0.212; recessive χ2 = 0.913; p = 0.339). Using Our work contributes to clarify the contrasting previous logistic regression, a significant association was found be- evidence by taking into account most recent literature stud- tween sl genotype and suicide at a younger age according to ies about the association of the 5-HTTLPR and Suicidal Be- the additive model (OR = 1.037; p ˂0.001; df = 1; B = 0.036). haviors. Nonetheless, many other modulators, including en- Discussion: Although our small-sample pilot study found no vironmental factors and their interaction with the genome association between 5-HTTLPR genotype and suicide, a sig- through epigenetics mechanisms may act to further increase nificant association was found between the sl genotype and the level of complexity. younger age at suicide which may deepen our understanding of the dynamics of suicide risk and may help us identify Disclosure: Nothing to disclose. targets for early screening and intervention. Given the difficulty of studying suicidal behaviour due to the relatively doi: 10.1016/j.euroneuro.2018.08.314 low number of cases, our results argue for the further development of our suicide biobank and the investigation of further novel genotypes associated with endophenotypes of

SA93 suicidal behaviour in living subjects. DYING YOUNG: 5-HTTLPR SHORT ALLELE IS ASSO- Xenia Gonda is recipient of the Janos Bolyai Research Fel- CIATED WITH YOUNGER AGE AT COMPLETED SUICIDE: lowship of the Hungarian Academy of Sciences. RESULTS FROM A PILOT STUDY IN THE HUNGARIAN SUICIDE BIOBANK Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.315 Janos Bokor, Peter Dome, Elek Dinya, Andras Laszik, Xenia Gonda

Semmelweis University ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 53

SA94 Discussion: This study shows for the ﬁrst time that genomic MACHINE LEARNING ANALYSIS OF ULTRA-DEEP WHOLE- mosaicism caused by retrotransposons can be detected re- GENOME SEQUENCING IN HUMAN BRAIN REVEALS SO- liably from ultra-deep whole-genome sequencing data and MATIC GENOMIC RETROTRANSPOSITION IN GLIA AS can manifest also in glia, i.e. in the non-neuronal cells that WELL AS IN NEURONS comprise roughly half the cells of a human brain. The patterns of the detected somatic retrotranspositions in adult

Alexander Urban 1, Xiaowei Zhu 1, Bo Zhou 1, Steven Sloan 1, brain indicate that the genomic insertions occurred in neu-

Reenal Pattni 1, Anne-Sophie Fiston-Lavier 2, ral precursor cells and spread from there into both the neu-

Michael Snyder 1, Dmitri Petrov 1, Alexej Abyzov 3, rons and glia during differentiation.

Flora Vaccarino 4, Benjamin Barres 1, Hannes Vogel 1, NIMH grants R01MH094740 (to D.F.L.), and U01MH106876-

Carol Tamminga 5, Douglas Levinson 1 01 (part of the Brain Somatic Mosaicism Network consortium project [see also PMID: 28450582] to F. M . V. and A.E.U.). ∗

1 Stanford University sadly, Ben Barres passed away, before completion of this

2 University of Montpellier work.

3 Mayo Clinic Disclosure: Nothing to disclose. 4 Yale University

5 University of Texas Southwestern doi: 10.1016/j.euroneuro.2018.08.316

Background: Somatic retrotransposition contributes to neuronal genomic mosaicism during human neurogenesis and is speculated to contribute to neuropsychiatric conditions. Various methods have been developed to study brain so- SA95 matic MEIs, including retrotransposon capture sequencing MEDIA AND MENTAL HEALTH: HOW DNA DIFFER- (RC-seq), single neuron L1 insertion profiling (L1-IP) and ENCES CONTRIBUTE TO THE GOOD AND BAD SIDE OF single neuron whole genome sequencing. However, capture ONLINE MEDIA USE sequencing and whole genome amplification of single cells both increase the risk of artifacts. In addition, the single Ziada Ayorech 1, Robert Plomin 1, Sophie von Stumm 2 cell approach cannot readily be scaled up to studies of large cohorts, and so far, has only been utilized to study somatic 1 King’s College London retrotransposition in neurons. 2 London School of Economics Methods: Here we describe a novel approach for detecting somatic LINE1 and Alu retrotransposition in a direct and un- Background: By the year 2020, the number of worldwide biased manner, by analyzing ultra-deep whole-genome se- online media users will exceed 4 billion, over half of the quencing, separately of the neuronal and glial cell fractions Earth’s population. Understanding the impact of our in- of the human brain. We developed a random forest clas- creasingly digital world, for good as well as bad, on indi- sification algorithm, RetroSom, to extract features specific vidual’s mental health and wellbeing is of major societal for novel and somatic retrotransposition insertions into the importance given the staggering costs of national rises in genome sequence and to drastically improve the filtering of mental health problems. To date, research on the impact of false positives. We tested RetroSom in three independent online media use on mental health has largely ignored the whole genome sequencing datasets, including 1) multiple role of genetics, which could challenge the assumption that clonal expansions from single neural cells from two sub- media effects are entirely environmentally driven. jects, 2) libraries generated with or without PCRs, and 3) Methods: We address this gap in the literature, by capital- experimental mixing of genomic DNA from multiple individ- izing on over 4000 twin pairs to perform the first geneti- uals with frequency ranging from 0.04% to 25%. We verified cally sensitive investigation of the association between on- that RetroSom is highly precise, performs well in libraries line media use and mental health created with PCR, and detects retrotranspositions with mo- We test for the role of genetics on positive uses of on- saic frequencies of > 1% for LINE1 and > 0.2% for Alu. line media such as posting social media content and watch- Results: We applied RetroSom to ultra-deep sequencing ing video clips, as well as on negative sides of online media data ( > 200x whole-genome coverage) from neurons, glial use such as online victimization and Internet addiction, and cells and non-brain control specimens (heart or fibroblast) their links with mental health using univariate and bivariate of six individuals, including a fetus, an elderly person, and twin analyses two “blind” schizophrenia-control pairs. RetroSom identi- Results: We show that both positive and negative media use fied several somatic retrotranspositions, including two so- are moderately heritable (up to 49%) and that their associ- matic brain-specific LINE1 insertions, found in both neurons ation with mental health and wellbeing is primarily due to and glial cells, as well as two heart-specific Alu insertions. the effect of correlating genetic influences. We orthogonally validated four insertions by digital droplet Discussion: These results suggest efforts to harness online PCR to quantify their mosaic frequencies, and by nested PCR media use for promoting mental health will have greatest to characterize the insertion breakpoints and target site du- impact when adopting an individualized approach, tailoring plications. tactics to individual needs. They also challenge the idea that the impact of media use on mental health is causal and instead suggest that online media use merely reflects ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 54 Abstracts individual genetic propensities to good and bad mental ‘atomic’ at the genetic level, too, with ‘atoms’ on these health outcomes ‘molecules’ being related to better and poorer human functioning. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.317 doi: 10.1016/j.euroneuro.2018.08.318

SA96 GENETIC CONTRIBUTION TO TWO SPECIAL FACTORS SA97 OF NEUROTICISM IS ASSOCIATED WITH AFFLUENCE, COMPUTATIONAL PSYCHIATRY MEETS GENETICS: REIN- BETTER HEALTH, AND LONGER LIFE FORCEMENT LEARNING IN EARLY PSYCHOSIS AND IN RELATION TO CLINICAL AND MOLECULAR GENETIC RISK William Hill, Alexander Weiss, Andrew McIntosh, FOR SCHIZOPHRENIA Catharine Gale, Ian Deary

Graham Murray 1, Marcella Montagnese 1, Franziska Knolle 1,

University of Edinburgh Juliet Grifﬁn 1, Joost Haarsma 1, Alexander Richards 2,

Petra Vertes 1, Bea Kiddle 1, Michael Owen 2, Peter Jones 1, 3 3 1 Background: Higher scores on the personality trait of neu- Peter Fonagy , Michael Moutoussis , Ed Bullmore , 3 1 roticism, the tendency to experience negative emotions, Ray Dolan , Ian Goodyer are associated with poorer mental and physical health.

Studies examining the link between neuroticism and health 1 University of Cambridge typically use the sum of individual items in a neuroti- 2 Cardiff University cism scale. However, this ‘sum-score’ method results in 3 University College London an imprecise measure of neuroticism as it contains error variance, and treats neuroticism as a single pheno- Background: Computational psychiatry offers opportunities type rather than, potentially, being composed of multi- for increased mechanistic understanding of mental disorder ple heterogeneous traits. It was recently shown that the and to aid in the integration between psychiatry and neu- broad trait of neuroticism is composed of narrower traits; roscience. By developing and testing mathematical mod- higher scores on the broad trait of neuroticism were asso- els of behaviour, the computational psychiatry approach ciated with earlier death; on the other hand, an orthogonal aims to provide increased understanding in how disordered Worry/Vulnerability factor was linked with living longer. neurobiology manifests in particular clinical phenotypes. A Methods: Here, using a bi-factor model, we examine a gen- computational approach may further aid in measuring in- eral neuroticism factor and two special neuroticism factors termediate (latent) phenotypes that may be more readily (Worry/Vulnerability and Anxiety/Tension) that were statis- linked to causes (whether genetic or environmental) than tically independent from the general factor. Each of the observed phenotypes. However, as yet, computational psy- special factors was derived from subsets of the same items chiatry researchers have, in the main, focused on patho- used to derive the general factor. Using 332,050 partici- physiology rather than attempting to integrate aetiologi- pants of UK Biobank, we examine the genetic architectures cal factors with computational models of behaviour. Here, of two specific factors of neuroticism (Anxiety/Tension and we take a computational psychiatry approach to investigate Worry/Vulnerability), and how they contrast with the ge- learning in psychotic illness, and test whether modelled (la- netic architecture of the general factor of neuroticism. tent) learning variables relate to molecular polygenic risk Results: First, we show that, whereas the polygenic load for schizophrenia. Reinforcement learning (learning from for the general factor of neuroticism is associated with feedback) has been proposed to be of potential mechanisitc an increased risk of coronary artery disease, a lower level importance in underpinning positive symptoms and/or neg- of cognitive ability and socioeconomic status, and poorer ative symptoms including anhedonia and avolition. self-rated health, the genetic variants associated with high Methods: We first gathered case control data on behav- levels of the two specific factors of Anxiety/Tension and ior during a Go/NoGo reinforcement learning task (GNG) in Worry/Vulnerability are associated with social affluence, three groups of young adults (total n = 91): controls, help- higher cognitive ability, better self-rated health, and longer seeking patients at clinical risk (CR) for psychosis and FEP life. Second, by examining the biological mechanisms as- (First-episode psychosis). The task contains separate con- sociated with the Anxiety/Tension, and Worry/Vulnerability ditions when a “Go” action is required to win a reward, factors, and the general factor of neuroticism, we find fur- or to avoid a punishment, or withholding action (“No-Go”) ther evidence that supports their distinctiveness. Finally, is required to win or avoid punishment. We additionally we identify the genetic variants associated with these pro- gathered behavioural data on the same learning task in tective aspects of neuroticism. 700 healthy adolescents and young adults from NSPN “U- Discussion: Neuroticism is one of the most well-studied per- change” who also provided DNA samples. We tested several sonality traits in the health literature and it has been recog- computational models of task behaviour, and settled on the nized as an important risk factor for personal, societal and best fitting model, which provides 6 latent modelled mea- financial woes in many human societies. The present work, sures thought to underpin performance on the task: Learn- then, joins findings of neuroticism at the level of the phe- ing rate, Go bias (tendency to act), Pavlovian Bias (tendency notype by showing that neuroticism is ‘molecular’ and not to act for reward and withhold action to avoid punishment), ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 55

Sensitivity to reward, Sensitivity to punishment, and Ran- meta-analysis. We explored the linkage disequilibrium re- domness. We examined case control differences on these. lationships between the variants and conducted conditional We generated schizophrenia polygenic risk scores (based on analysis to identify independent signals within CADM2. Data- Petronas et al) in U-Change and related these to modelled mining was used to further explore the locus. task measures. We also plan to examine depression poly- Results: Strikingly, the meta-analysis identified SNPs with genic risk scores in relation to task measures as altered rein- consistent effects on BMI, at genome-wide significance (in- forcement learning may also play a role in the pathogenesis dex SNP rs1549979, risk allele frequency = 0.29, N = 412,850, of depression. Beta = 0.068, Se = 0.01, p = 2.24 × 10-11, heterogeneity- Results: Compared to controls, FEP patients show signifi- I2 = 0, heterogeneity-p = 0.5258). Conditional analysis (in- cantly lower learning rate, higher Pavlovian bias (a tendency cluding the lead SNP as a covariate) rendered all SNPs non- to act to gain rewards and withhold actions to avoid punish- significant, suggesting that the CADM2 locus contains only ment) and lower sensitivity to punishment. After exclusions one signal. Whilst CADM2 is predominantly expressed in the (poor task engagement or performance, genotype failures, brain, rs1549979 demonstrated genotype-specific effects on ethnicities in which polygenic risk scores do not predict CADM2 expression levels in subcutaneous and visceral adi- schizophrenia) DNA and adequate behaviour were available pose tissue. on 390 members of the general population. Schizophrenia Discussion: Our results provide evidence that the effects of polygenic risk score (PRS) did not predict task latent mod- the CADM2 locus on psychological traits and physical health elled measures. traits represent the same signal. Whether the effects of Discussion: There are cognitive deficits in reinforcement CADM2 on obesity are due to mechanisms regulating feed- learning in those presenting with early psychosis, but per- ing, or through functional effects on adipose tissue, or a formance in CR is broadly intact, and molecular genetic risk combination of these, have yet to be clarified. for schizophrenia does not predict task-derived measures in a sample of 390 individuals from the general population. Re- Disclosure: Nothing to disclose. sults will be discussed both in terms of this particular task doi: 10.1016/j.euroneuro.2018.08.320 and the strengths and weaknesses of the general approach.

Disclosure: Nothing to disclose. SA99 doi: 10.1016/j.euroneuro.2018.08.319 GENOME-WIDE ASSOCIATION STUDY IN VESTIBULAR NEURITIS

SA98 Ina Giegling 1, Michael Strupp 2, Annette Hartmann 1,

GENETIC ANALYSIS OF CADM2, A POSSIBLE LINK Bettina Konte 1, Stephan Maul 1, Marko Herrling 2,

BETWEEN MENTAL AND PHYSICAL HEALTH Susanne Himmelein 2, Dan Rujescu 1

Julia Morris 1, Mark Bailey 1, Damiano Baldassarre 2, 1 Martin Luther University Halle-Wittenberg

Breda Cullen 1, Ulf deFaire 3, Bruna Gigante 3, 2 Ludwig-Maximilians University, Munich

Nicholas Graham 1, Anders Hamsten 3, Steve Humphries 4, 1 5 6 Donald Lyall , Bengt Sennblad , Andries Smit , Background: Virus infections affecting the central nervous 7 1 1 Hugh Watkins , Daniel Smith , Rona Strawbridge system are discussed as causative risk factors for a variety of conditions, including diseases as diverse as Alzheimer’s

1 University of Glasgow disease and vestibular neuritis. Persisting vertigo following

2 Università degli Studi di Milano acute vestibular neuritis is also known to be correlated with

3 Karolinska Institutet anxiety and anxiety related apprehension. Vestibular neu-

4 University College London ritis is the third most common cause of peripheral vertigo

5 SciLifeLab and is characterized by an acute onset of sustained spinning

6 University of Groningen vertigo, lasting for many days. Although there is indirect ev-

7 University of Oxford idence that it may be caused by the reactivation of herpes simplex type 1 (HSV-1) its etiology is largely unknown. Background: The CADM2 locus has previously been associ- Methods: Association was assessed using app. 8 million ated with a number of metabolic and psychological traits, SNPs. 131 patients with vestibular neuritis and 2609 controls including BMI, physical activity levels, risk-taking behaviour of European ancestry were included. and educational attainment. The phenotype of Cadm2- Results: Genome-wide associations with vestibular neuritis knockout mice has confirmed this gene’s importance in en- were detected in 4 regions containing protein coding genes ergy homeostasis. The aim of this study was to investigate assignable to two functional groups: virus hypothesis and the effects of CADM2 on psychiatric and cardiometabolic insulin metabolism. traits and determine whether the same signals influence Genes of set 1 are related to viral processes: nuclear re- physical and mental health ceptor subfamily 3 group C member 2 (NR3C2) is a receptor Methods: We systematically evaluated CADM2 genetic vari- for mineralocorticoids and glucocorticoids and was shown ants in UK Biobank, IMPROVE and PROCARDIS data sets for to be a host factor for HSV-1 replication. Ankyrin repeat effects on psychological, psychiatric and cardio-metabolic domain 30A (ANKRD30A) encodes a host factor for human traits using linear or logistic regression and subsequent immunodeficiency virus-1 (HIV-1) infection. It shows rapid ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 56 Abstracts evolution and is induced by interferon stimulation. Media- sion reduced GABA immunoreactivity and GABA levels in the tor complex 30 (MED30), an important member of the medi- culture supernatant. ator complex, has been shown to be involved in replication Discussion: Our study suggests that FAM43A is associated of HIV-1 and a knockdown leads to impaired viral replica- with convergent processes in the pathogenesis of DD and tion. The second set of genes (LIM homeobox transcription ADHD and identifies, for the first time, its role in modulat- factor 1 alpha (LMX1A), solute carrier family 30 member ing the GABAergic pathway. It also prompts further work on 8 (SLC30A8)) is associated to insulin metabolism and resis- the role of the GABAergic pathway in DD and ADHD. tance, a feature of some patients with type 2 diabetes as an accompanying comorbidity of vestibular neuritis. Disclosure: Nothing to disclose. Discussion: Using a GWAS approach to evaluate the etiology doi: 10.1016/j.euroneuro.2018.08.322 of vestibular neuritis these findings give another piece of evidence that it may be caused by viral inflammation. Apart from replication of these results in larger cohorts, a closer look at a possible genetic and phenotypic overlap between SA101

HSV-1 induced diseases is necessary. GENOME-WIDE ASSOCIATION OF WORD READING: OVERLAP WITH RISK GENES FOR NEURODEVELOPMEN- Disclosure: Nothing to disclose. TAL DISORDERS doi: 10.1016/j.euroneuro.2018.08.321 Cathy Barr 1, Kaitlyn Price 1, Karen Wigg 1, Yu Feng 1,

Kristen Blokland 2, Margaret Wilkinson 2, Gengming He 2,

Elizabeth Kerr 2, Sharon Guger 2, Maureen Lovett 2,

SA100 Lisa Strug 2 FAM43A: A NOVEL REGULATOR OF THE GABAER-

GIC PATHWAY IS A COMMON PREDISPOSING GENE FOR 1 The Krembil Research Institute

DEVELOPMENTAL DYSLEXIA AND ATTENTION DEFICIT 2 Hospital for Sick Children HYPERACTIVITY DISORDER Background: Speciﬁc reading disabilities (RD; also known as 1 1 1 Subhashree Devasenapathy , Aditi Charak , Rashi Midha , developmental dyslexia) represent a major health, social, 1 1 2 Teesta Naskar , Bharat Prajapati , Renu Kumari , and educational handicap. RD can cause signiﬁcant aca- 2 2 1 Faruq Mohammad , Mitali Mukerji , Nandini Singh , demic impairment in children and subsequent occupational 1 Subrata Sinha underachievement in adults. Comorbid psychiatric disorders are common in children with RD (e.g., mood disorders, anx-

1 National Brain Research Centre iety, and attention-deﬁcit/hyperactivity disorder), further

2 Institute of Genomics and Integrative Biology impacting academic achievement and social development. RD is a specific neurobiological learning disability character- Background: Developmental Dyslexia (DD) is a neurodevel- ized by difficulties with accurate and/or fluent word recog- opmental disorder often comorbid with Attention Deficit Hy- nition, poor spelling, and decoding abilities. Despite high peractivity Disorder (ADHD). There is little understanding of heritability, there have been limited published GWAS stud- their common underpinnings either in terms of genetic pre- ies. disposition or affected pathways. Methods: We performed a GWAS for a measure of word Methods: We performed exome sequencing of a multigen- reading (WRAT3 or WRAT4) on two samples, one a family- erational family from an endogamous group, segregating for based sample selected for reading difficulties from Toronto these conditions, including comorbidity, to identify genetic and the other a population-based sample from Philadelphia associations and affected molecular processes. (Philadelphia Neurodevelopmental Cohort, PNC). The final Results: Variant filtering methods revealed an association analysis after quality control was performed with > 5 mil- of FAM43A with DD, ADHD and DD-ADHD comorbidity. The lion single nucleotide polymorphisms (SNPs) on 624 children associated variations in FAM43A, a hitherto uncharacterized from the Toronto sample and 4629 individuals from the PNC. gene, extended across a 1.7kb long haplotype and included Results: The results from the SNP based analyses did not five 5’UTR (rs1773221, rs63360263, rs1773219, rs1773218 identify genome-wide significant results, however results and rs813153) and one exonic single nucleotide variations near significance, indicate overlap for genes previously (SNVs) (rs4677673), which are ancestral across non-human identified in GWAS for educational attainment and risk fac- primate and Neanderthal genomes. The 5’UTR variants re- tors for neurodevelopmental disorders, particularly autism sulted in increased luciferase activity implying increased spectrum disorder (ASD). Known or suspected ASD was an expression of FAM43A in the presence of the risk alleles, exclusion criterion for the Toronto sample, thus the over- thereby suggesting a gain-of-function effect. FAM43A overlap with autism suggests shared genetic risk for ASD, pos- expression in SH-SY5Y cells resulted in downregulation of sibly for shared genetic contributions to language difficul- Glutamate Decarboxylase 2 (GAD2) mRNA and immunoreac- ties. Notable among the highly ranked genes were FOXP1 tivity, and Gamma-Aminobutyric Acid Type B Receptor Sub- and RBFOX1. FOXP1 is a transcription factor that forms het- unit 1 (GABBR1) immunoreactivity alone while mRNA re- erodimers with FOXP2, the first gene shown to contribute mained unaltered. We show that FAM43A is a lysosomal pro- to speech and language. FOXP1 has been identified as con- tein and its repressive effects on the GABBR1 protein may tributing to speech delay, language, and cognitive impair- be through this degradative pathway. FAM43A overexpres- ment in addition to ASD. The RBFOX family of RNA splicing ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 57 proteins have been previously implicated in ASD, language precursor of psychotic symptoms. Indeed, across ancestries, and Rolandic epilepsy, a benign epilepsy syndrome associ- we observe a strong phenotypic overlap between PS and ated with a spectrum of learning, language, and reading ADHD - 4% of the sample meets DSM criteria, of which about problems. Further, pathway analysis identified the panther half fall into the PS group P < 2e-16 - as well as a wide range pathway “axon guidance mediated by Netrin”. of ADHD-related symptoms, with OR ranging between 3 and Discussion: The results from the sample thus far implicate 4 and P < 2e-16. However, the observed genetic association genes previously identified for educational attainment and is not driven by symptom overlap: even in the subset of chil- neurodevelopmental disorders, particularly ASD. The find- dren that do not endorse even the mildest ADHD symptoms ings implicating FOXP1 and RBFOX1 are particularly inter- (concentration problems at school, 60%), the association be- esting because deregulation would predict global change tween ADHD PRS and PS risk remains. in transcription and splicing in neural cells. The findings We observe a significant interaction with PRS and age (in from pathway analysis support previous evidence from neu- EA, P = 7.1e-06), with a stronger association for younger roanatomical studies for altered neuronal migration/axon children ( < 12 years). This interaction is recapitulated at the guidance as a contributor to RD. phenotype level. Finally, whilst ADHD and psychosis phenotypic overlap is hypothesized to be partly mediated by sub- Disclosure: Nothing to disclose. stance use, substance use did not drive the phenotypic nor the genotypic correlations in our sample. doi: 10.1016/j.euroneuro.2018.08.323 Discussion: Surprisingly, we observed that ADHD (and not schizophrenia) genetic risk is associated with PS in youth. Children with high genetic risk for ADHD had an almost two-

SA102 fold increased risk for PS compared to those with low risk.

GENETIC AND CLINICAL ANALYSES OF PSYCHOSIS This association holds even in the absence of ADHD symp- SPECTRUM IN A LARGE MULTI-ETHNIC YOUTH COHORT toms, is strongest in young children, and diminishes closer > (N 8,000) REVEAL SIGNIFICANT LINK WITH ADHD to age of onset of schizophrenia. While preliminary, these ﬁndings shed light on how genetic risk can be investigated Loes Olde Loohuis, Eva Mennigen, Carrie Bearden, across early disease trajectories to improve our understand- Roel Ophoff ing of disease risk factors and psychiatric comorbidities. It also highlights the need for increasing ethnic diversity in University of California Los Angeles GWA studies.

Background: Psychosis spectrum (PS) symptoms are herita- Disclosure: Nothing to disclose. ble, and children with PS have an increased risk of conver- doi: 10.1016/j.euroneuro.2018.08.324 sion to a psychotic disorder and other psychiatric disorders later in life. However, the precise role of genetic risk for PS and its interplay with other psychiatric symptoms across development remains poorly understood. SA103

Methods: The Philadelphia Neurodevelopmental Cohort SLEEP IN YOUNG PEOPLE WITH 22Q11.2 DELETION (PNC) is a genotyped population-based sample of > 8,000 SYNDROME youths who received a structured psychiatric evaluation 1 2 2 and a computerized neurocognitive battery. The cohort is Hayley Moulding , Ullrich Bartsch , Nicholas Donnelly , 1 1 2 multi-ethnic, with the majority of participants of European Jeremy Hall , Michael Owen , Matt Jones , Marianne van 1 ( ∼65%) and African ( ∼25%) ancestry. In this sample, ∼20% den Bree of youth were categorized as PS based on elevations in positive or negative/disorganized symptoms. Using a LASSO re- 1 Cardiff University gression model, we aimed to predict PS using polygenic risk 2 University of Bristol scores (PRS) based on GWAS from heritable neuropsychiatric traits. We also performed individual trait PRS associations, Background: Young people with 22q11.2 deletion syn- evaluated ancestry- and age-specific effects. Odds ratios drome (22q11.2DS) are at elevated risk for neurodevelop- (ORs) reported are comparing first and fifth quintile of PRS mental disorders and psychopathology. Many young people scores. Finally, we further investigated the phenotypic di- present with neurodevelopmental disorders such as ADHD mensions on which genetic risk is acting. and autism spectrum disorders which index high rates of Results: We observed that genetic risk for ADHD was the sleep problems. Sleep is a relatively unknown area of inves- most significant predictor of PS in the multi-trait regres- tigation in 22q11.2DS. The prevalence and nature of sleep sion model as well as the individual trait analyses (beta = problems in 22q11.2DS remain undescribed, and links with 0.03, P = 2.41e-05). This effect was driven by the children neurocognitive deficits and psychopathology unknown. The of European ancestry (beta = 0.05, 5.61e-07, OR 1.85), and aim of the study is to describe the prevalence and nature of not observed in the African ancestry group (P = 0.93). None sleep problems in young people with 22q11.2DS and explore of the other neuropsychiatric traits, including schizophrenia the links with neurocognitive function and psychopathology. PRS, were associated with PS in children. Methods: Interviews were conducted with primary care While evidence for shared genetic risk for adult-onset SCZ givers regarding psychopathology and sleep problems. As- and ADHD is only nominally significant (genetic correlation sessments of neurocognitive function were carried out is 0.23, P = 0.009, LDhub), attentional deficits are a known for 140 young people with 22q11.2DS (mean age = 10.1, ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 58 Abstracts

s.d. = 2.46) and 65 unaffected sibling controls (mean 4 UGC Salud Mental, Hospital Universitario Reina Sofía, Cór- age = 10.8, s.d. = 2.26). Exploratory factor analysis and re- doba / Instituto de Salud Carlos III, Centro de Investigación gression analyses were used to explore the relationship of Biomédica en Red de Salud Mental (CIBERSAM) patterns of sleep problems in 22q11.2DS with psychopathol- 5 University of Oviedo ogy and neurocognitive function. Supplementary assess- 6 Unidad de Psicosis Refractarias, Hospital Psiquiátrico de ments were undertaken with a subsample of young peo- Álava ple with 22q11.2DS and unaffected sibling controls including 7 Universitat de Barcelona; Institut de Biomedicina de la high-density electroencephalography and actigraphy. Universitat de Barcelona (IBUB) / Instituto de Salud Car- Results: Sleep problems were identified in 60% of young los III, Centro de Investigación Biomédica en Red de Salud people with 22q11.2DS compared to 23% of unaffected Mental (CIBERSAM) siblings (p < 0.001). Tw o patterns best described the sleep problems in young people with 22q11.2DS: rest- Background: People with major psychiatric disorders have less sleep/tiredness and insomnia. On controlling for more probability of smoking than general population with melatonin use in young people with 22q11.2DS, restless prevalence of 70-90% in schizophrenia (SZ) and 66% in bipo- sleep/tiredness pattern was linked to more ADHD (OR = 1.15, lar disorder (BD). Nicotine dependence is associated with p = 0.001), anxiety (OR = 1.09, p = 0.015) and indicative de- symptom severity and poor outcome in patients (Krishnadas velopmental coordination (OR = 0.966, p = 0.029) symptoms et al. 2012). A shared vulnerability hypothesis has been pro- and impaired higher executive function (OR = 1.02, p = 0.050, posed to explain excessive tobacco use in mental disorders and OR = 0.974, p = 0.013). The insomnia pattern was asso- (Chambers et al. 2001). Nicotinic receptor (nAChR) system ciated with higher symptoms of indicative developmental could be a good candidate to analyze in relation to both to- coordination disorder (OR = 0.942, p = 0.006). After explor- bacco use and mental disorders. The CHRNA5 and CHRNA7 ing interrelationships, the only remaining links with restless genes, coding for different subunits of the nAChR, have sleep/tiredness pattern were elevated ADHD and anxiety been previously associated with SZ, BD and tobacco use. The symptoms. (Preliminary EEG analysis and actigraphy results aim of the present study was to determine whether smoking are currently under analysis but will be available at the time cessation a) is modulated by genetic variation at CHRNA5 of the conference.) and CHRNA7 genes and b) influences the clinical outcome of Discussion: Tw o distinct patterns of sleep problems in patients along 36-week follow-up. 22q11.2DS suggest that there is not a universal treatment Methods: This is a non-randomized open-label, prospective, of sleep problems in these young people, with each type of 9-month follow-up (0, 12, 24, 36 weeks), multicenter study sleep pattern indexing different problems that need to be (Gárcia-Portilla et al. 2016). A sample of 60 patients (68.3% considered in future interventions. Identifying sleep prob- males; mean age = 46 ±8.86; 48 SZ and 12 BD according to lems in 22q11.2DS by a multifactorial protocol including DSM-IV criteria). All subjects gave written information con- neurophysiological biomarkers of sleep disturbance will help sent. Severity and changes in global psychopathology was to better understand the severity of sleep problems and assessed by the Clinical Global Impression - CGI (Guy, 1976). the involvement in psychiatric and cognitive impairment Smoking cessation therapy was based on transdermal in young people and throughout their development. Clini- nicotine patches and varenicline. Nicotine dependence was cians should be aware that sleep problems are common in evaluated using the Glover-Nilson Smoking Behavioral Ques- 22q11.2DS and index psychiatric risk and neurocognitive im- tionnaire (Nerin et al. 2005) and the Fagerström Test for pairment. Nicotine Dependence (Becona et al. 1998). Pattern of tobacco use was defined by: i) the self- Disclosure: Nothing to disclose. reported number of cigarettes per day (CPD), ii) breath doi: 10.1016/j.euroneuro.2018.08.325 CO level. Independently from smoking cessation therapy, at week 36 patients were classified as abstinent (ABS) (CPD = 0 and breath CO level < 9 ppm) and no-abstinent (no-ABS). The SNPs rs680244, rs16969968 (CHRNA5) and rs6494223 SA104 (CHRNA7) were genotyped using TaqMan exonuclease as-

SMOKING CESSATION IMPROVES CLINICAL OUTCOME IN says (Applied Biosystems). All SNPs showed Hardy-Weinberg

PATIENTS WITH SCHIZOPHRENIA AND IS MODULATED equilibrium. BY GENETIC VARIABILITY AT CHRNA5 GENE Results: At baseline, males presented higher mean of CPD (p = 0.021), there was a positive correlation between CPD 1 2 3 Marina Mitjans , MP García-Portilla , L. García-Alvarez , and psychological dependence (p = 0.015), physical depen- 4 5 5 F. Sarramea , G. Galvana , E. Díaz-Mesa , dence (p = 0.017) and CGI (p = 0.001). Moreover, T-carriers of 3 3 6 T. Bobes-Bascaran , S. Al-Halabi , E. Elizagarate , the CHRNA5-rs680244 smoked more CPD that CC homozy- 2 2 7 2 C. Iglesias , PA Sáiz-Martínez , L. Fañanás , J. Bobes , gotes (p = 0.029). 7 Bárbara Arias At week 36, the group of ﬁnal ABS (40%) present a better global improvement (CGI) in comparison to No-ABS at week

1 Universitat de Barcelona 12, 24 and 36 (p = 0.019, p = 0.012 and p = 0.021). In relation

2 University of Oviedo / Instituto de Salud Carlos III, Centro to CHRNA5-rs680244, T-carriers has 4 times more risk for de Investigación Biomédica en Red de Salud Mental (CIBER- no-ABS than CC homozygotes (p = 0.031; OR = 4; IC95% [1.14, SAM) 14.09]).

3 Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 59

Also, regarding the CHRNA5-rs680244, the longitudi- quality control was performed using standard criteria and nal study show a significant decrease of CPD along the only patients of Caucasian ethnicity were included. Imputa- time (F = 65.817, p < 0.001), no genotype effect (F = 0.057, tion was performed using HRC v. 1.1 2016 reference panel. p = 0.945) and a significant effect of genotype x time inter- SNP, gene and pathway analyses were carried out using action (F = 2.785, p = 0.041). Plink and MAGMA, respectively. Covariates were ancestry- Discussion: Previous studies has observed that smoking can relevant principal components, baseline symptom severity worse psychiatric symptomatology in schizophrenic patients and center of recruitment. Corresponding phenotypes were (Bobes et al. 2010), our study show that smoking cessa- calculated in STAR ∗D and GENDEP and a fixed-effects meta- tion improve global clinical symptomatology. These results analysis was performed. Suggestive findings (p < 5e-06) were should encourage clinicians to treat their patients for smok- functionally annotated using FUMA. ing cessation. In addition, genetic variability at CHRNA5 can Results: After quality control, 1148, 1316 and 761 subjects modulate the effectiveness of tobacco use and cessation as (total = 3225) were included in the analysis of TRD vs. oth- it has been shown in previous studies (Pintarelli et al. 2017). ers, from GSRD, STAR ∗D and GENDEP, respectively, while Larger longitudinal samples are needed in order to confirm 759, 1119 and 336 subjects (total = 2214), respectively, for these results. the analyses including only TRD patients and responders. In Acknowledgements: CIBERSAM; Instituto de Salud Carlos III GSRD, no genome-wide significant locus or gene was iden- (PI16/00998), Comissionat per a Universitats i Recerca del tified. GO:0043949 (regulation of cAMP mediated signaling) DIUE (2017SGR1577). was associated with TRD vs. response (p corrected = 0.03). In the meta-analysis, no genome-wide significant locus or Disclosure: Nothing to disclose. gene was identified. Genes in the regions of suggestive loci showed enrichment in gene sets involved in transcrip- doi: 10.1016/j.euroneuro.2018.08.326 tion regulation, apoptosis, calcium signaling, synaptic transmission, second messenger cascades. These genes showed higher expression in brain cerebellar hemisphere, pituitary

SA105 and hypothalamus. GO:0000183 (regulation of chromatin

A GENOME-WIDE ASSOCIATION STUDY OF TREATMENT- structure) was associated with TRD (p corrected = 0.027). RESISTANT DEPRESSION AND META-ANALYSIS OF THREE Discussion: We did not identify single variants or genes as- INDEPENDENT SAMPLES sociated with TRD because of limited power. GO:0043949 and GO:0000183 were associated with TRD. The top genes in 1 2 2 Chiara Fabbri , Siegfried Kasper , Alexander Kautzky , these gene sets were CRTC3 (CREB regulated transcription 2 2 3 Lucie Bartova , Markus Dold , Joseph Zohar , coactivator 3), PDE10A (phosphodiesterase 10A) and SIRT2 4 5 5 Daniel Souery , Diego Albani , Ilaria Raimondi , (sirtuin 2). CRTC3 stimulates the release of corticotropin re- 6 7 8 Dimitris Dikeos , Dan Rujescu , Rudolf Uher , leasing factor, the major regulator of the neuroendocrine 1 9 10 Cathryn Lewis , Julien Mendlewicz , Alessandro Serretti stress response, while PDE10A and SIRT2 inhibitors were demonstrated to have antidepressant potential. Members

1 King’s College London of these gene sets are possible biomarkers of TRD but also

2 Medical University Vienna interesting candidates for the development of antidepres-

3 Tel Hashomer, and Sackler School of Medicine sants with alternative mechanisms of action.

4 Universitè Libre de Bruxelles and Psy Pluriel

5 IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" Disclosure: Nothing to disclose.

6 Athens University Medical School, doi: 10.1016/j.euroneuro.2018.08.327 7 Martin-Luther-University Halle-Wittenberg

8 Dalhousie University

9 Universitè Libre de Bruxelles

10 University of Bologna SA106 GENETICALLY DETERMINED GABA METABOLISM IS

Background: A relevant proportion ( ∼30%) of patients ASSOCIATED WITH BENZODIAZEPINES’ EFFECTIVENESS with major depressive disorder (MDD) develop treatment- IN ALCOHOL WITHDRAWAL SYNDROME resistant depression (TRD) and the associated sequelae. 1 1 Nevertheless, TRD has been marginally investigated in pre- Anastasiia Bryleva , Dmitriy Ivashchenko , 2 1 3 vious pharmacogenomic studies. This study aimed to con- Мaria Solov’eva , Zastrozhin Michael , Eugene Bryun , 2 3 tribute to ﬁll this gap in knowledge through a genome-wide Alexander Kibitov , Dmitriy Sychev association study of TRD.

Methods: A European multi-centric sample (GSRD) including 1 Russian Medical Academy of Continuous Professional Edu- 1375 MDD patients was characterized for the occurrence cation of TRD (non-response to at least two antidepressant treat- 2 Serbsky National Medical Research Centre on Psychiatry ments that were adequate in terms of drug dose and and Addictions duration). Investigated phenotypes were TRD compared 3 Moscow Research Practical Center of Addiction Medicine to response to the ﬁrst antidepressant, TRD compared to response + non-response to one antidepressant (TRD vs. Background: Glucamate acid decarboxylase (GAD) is an en- others) and percent symptom improvement in TRD and zyme that catalyzes the conversion of glutamate into GABA. responders. Patients were genotyped (Inﬁnium PsychArray), There are two isoforms GAD GAD67 and GAD65, which are ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 60 Abstracts

encoded by the genes GAD1 and GAD2. GAD1 is involved in 1 University of Pennsylvania cytosolic GABA synthesis and is responsible for maintaining 2 National Institute on Drug Abuse Intramural Research Pro- basal GABA levels, whereas GAD2 is predominately involved gram in synaptosomal GABA release, and can be rapidly activated 3 National Institutes of Health when there is high demand for GABA. The genotype and al- 4 Corporal Michael J. Crescenz VA Medical Center lele frequencies of rs2236418 (GAD2) are associated with alcohol dependence, in which the G allele was related to Background: Opioid use disorder (OUD) is a significant pub- increased risk. Carriers of A alleles had a low expression of lic health issue in the United States and globally. FDA- GAD65 protein, and carriers of G alleles had high expression approved treatment for OUD includes opioid substitution of GAD65. therapy (OST) with medications such as methadone and AIM. To evaluate associations of GAD2 rs2236418 poly- buprenorphine. While OST has been shown to be effective, mophisms with effectiveness of benzodiazepine tranquilizer many patients do not have successful treatment outcomes. in patients with alcohol withdrawal syndrome. Understanding the factors that predict reductions in illicit Methods: 102 male patients with non-complicated alcohol opioid use during treatment would allow clinicians to make withdrawal syndrome (AWS, F 10.3 by ICD-10) were involved more informed therapeutic decisions, selecting medications into the study in 24 hours after their admission to hospital. that are most likely to benefit individual patients. During 6 days of dynamic observation each participant Methods: The START trial was a 24-week open-label ran- was prescribed benzodiazepine tranquilizer phenazepam domized trial of methadone and buprenorphine for the (bromdihydrochlorphenylbenzodiaepine). 38 participants treatment of OUD. Weekly urine drug screens were per- were added Pagluferal (contains phenobarbitalum, natrium formed. Treatment efficacy was defined by the proportion of caffeine-benzoate, bromisoval, papaverine) and/or Carba- opioid positive urine tests. A generalized estimating equa- mazepine. 5 ml of venous blood was collected from each tion (GEE) was used to determine if variants were asso- participant for genotyping. Blood samples were analyzed to ciated with treatment efficacy in African-Americans (AA; detect GAD2 rs2236418 (A > G) polymorphisms by real-time n = 77). A replication population (n = 75) was collected from polymerase chain reaction. Effectiveness of therapy was AA patients who had previously participated in OST trials at evaluated with Visual analogue scale (VAS) of the condition the NIDA Intramural Research Program. Urine drug screens of the AWS. Data analysis was performed with SPSS Statistics were performed three times per week. For a meta-analysis, 21.0. weeks 17-24 were analyzed since they represent the last Results: Distribution of genotypes rs2236418 (GAD2 gene two months of data available for both cohorts. Responders GAD65 enzyme) corresponded to the Hardy-Weinberg equi- were defined as patients who a) were retained in treat- librium (Chi-square = 1,085, p > 0.05). There were 72 car- ment until at least week 17 and b) were opioid positive riers of AA homozygous, 29 - of AG genotype and 1 of for less than 50% of their urine drug screens in weeks 17- GG. Significant associations of polymorphism of the GAD65 24. For luciferase analysis, 15bp regions surrounding the C rs2236418 gene with efficacy parameters of phenazepam or T allele of rs678849 were cloned into luciferase vectors have been established. Homozygous AA were noted a and transfected into neuroblastoma cells. Luciferase activ- greater severity of AWS according to VAS severity scale at ity was measured by dual-luciferase reporter assay system. 6th day (2.69 ± 1.79 vs 3.52 ± 2.07, p = 0.042), but they Cy3-conjugated dsDNA probes representing those same 15bp also demonstrated faster dynamics of change in severity regions were incubated with neuroblastoma cell nuclear ex- AWS measured by AWS VAS severity scale (-2.91 ± 2.24vs- tract for electrophoretic mobility shift assays (EMSA). 1.78 ± 2.82, p = 0.034). Results: In the START trial, rs678849 was associated with Discussion: A connection between the gene polymorphism the efficacy of methadone (p = 0.001) and buprenorphine GAD2 rs2236418 and the effectiveness of AWS pharma- (p = 0.008) in treating OUD in AA patients. The pharma- cotherapy by benzodiazepine tranquilizers has been found. cogenetic effect on buprenorphine (p = 0.021), but not Carrying the allele A (genotypes AA and AT) have a greater methadone (p = 0.087), was replicated in the independent effectiveness. Also, those patients had more severe AWS AA population from NIDA IRP. In a combined analysis of than G-allele carriers. weeks 17-24 of both data sets, patients with the C/C genotype had a significantly higher proportion of opioid posi- Disclosure: Nothing to disclose. tive urine drug screens (56%) than T allele carriers (39%, < doi: 10.1016/j.euroneuro.2018.08.328 p 0.0001). Patients with the C/C genotype were also significantly less likely to meet responder criteria (28%) than other patients (62%, p = 0.0012). The number needed to treat (NNT) was 3 for the responder analysis. Luciferase as- SA107 say found that the vector containing the C allele had lower A FUNCTIONAL OPRD1 VARIANT PREDICTS BUPRENOR- luciferase activity than empty vector, while the T allele was PHINE EFFICACY IN AFRICAN-AMERICANS WITH OPIOID not significantly different than empty vector. EMSA revealed USE DISORDER that the T allele probe was bound by a single specific complex, which consisted of a ∼40kDa and ∼50kDa protein. In

Richard Crist 1, Karran Phillips 2, Melody Furnari 2, contrast the C allele probe was weakly bound by the ﬁrst

Landhing Moran 3, Glenn Doyle 1, Alexander Zhang 1, complex, as well as a second, larger complex.

Laura McNicholas 4, James Cornish 1, Kyle Kampman 1, Discussion: These data suggest that a variant in the OPRD1

Kenzie Preston 3, Wade Berrettini 1 gene has a large pharmacogenetic effect on buprenorphine ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 61 efficacy in the AA population and that the variant may have BDNF and NR3C1 had no significant associations with CLZ re- effects on expression by altering transcription factor bind- sponse. Candidate genes within neurotransmitter pathways ing. Further in vitro studies will be needed to dissect the continue to be explored including dopaminergic (DRD1- complete mechanism and a prospective clinical trial that 4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, confirms this pharmacogenetic effect will be necessary be- SLC6A9, GRIA1, GAD1). Despite promising trending data, fore rs678849 can be used as a biomarker in clinical care. no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic ef- Disclosure: Nothing to disclose. fect of COMT Met and DRD4 single 120bp duplicate associated with improved CLZ response OR 0.15 (95% CI 0.03- doi: 10.1016/j.euroneuro.2018.08.329 0.62) while COMT Val/Val confer a risk of CLZ non-response OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through HLA and other genetic loci but have yet

SA108 to ﬁnd statistically or clinically meaningful results. CLOZAPINE PHARMACOGENOMICS: A REVIEW OF EFFI- Discussion: The current evidence base is limited by inves- CACY, PHARMACOKINETICS, AND AGRANULOCYTOSIS tigations with low power secondary to small sample size, a lack of standardized experimental design with widely vary- 1 1 2 2 Kevin Li , Haley Solomon , Candice Hu , Alexis Clay , ing outcome measures, and homogenous patient popula- 3 Lynn DeLisi tions limiting generalizability of results. Future studies must aim at standardizing outcome measures, increasing sam-

1 Harvard Medical School ple size, and including ethnogeographically diverse popula-

2 Boston University School of Medicine tions. Thus far, there are still no candidate genes that could

3 VA Boston Healthcare serve as a locus of diagnostic testing to provide insight into stratification of CLZ efficacy, pharmacokinetics, or agranu- Background: Treatment resistant schizophrenia (TRS) ac- locytosis. counts for roughly one-third of all schizophrenia cases. Clozapine (CLZ), the only FDA approved drug for TRS, has Disclosure: Nothing to disclose. the best evidence for improving quality of life, reducing doi: 10.1016/j.euroneuro.2018.08.330 mortality, and reducing self-harm and suicidality, boasting a 30-60% estimated response rate. Despite requiring more intensive clinical monitoring for neutropenia, CLZ is cost- effective, shown to reduce number of hospitalizations and SA109 has lower lifetime treatment costs compared to other an- GENE EXPRESSION EFFECTS OF VALPROIC ACID IN tipsychotics. Despite its cost-effectiveness and efficacy, CLZ A SEROTONERGIC CELL LINE carries a number of serious adverse effects including agranulocytosis, seizures, cardiotoxicity – myocarditis and car- Priyanka Sinha, Simone Cree, Diana Balasubramanain, diomyopathy, pneumonia, and fatal bowel ischemia. Given John Pearson, Martin Kennedy CLZ’s unique efficacy and potentially fatal adverse effects, it has become a popular target for pharmacogenetic inves- University of Otago tigation with the aim of developing genetic tests to guide clinicians in terms of risks of adverse effects, probability of Background: Valproic acid (VPA) is one of the most widely response, and dosing. used and effective mood stabilizer drugs, and yet we still Methods: Building upon past reviews, a systematic lit- have a poor understanding of its mechanisms of action. VPA erature search of articles since 2015 of the following is recognized as an inhibitor of chromatin modifying histone databases: Pubmed, OVID, EMBASE, EBSCO, Psycinfo deacetylase (HDAC) enzymes, and part of its therapeutic ac- with MESH/keywords clozapine and Boolean combi- tion in mood disorders may relate to modification of gene nations of “genetic ∗, genomic ∗, pharmacogenetic ∗, expression via this chemical property. We have carried out pharmacogenomic ∗. 184 articles were found. Abstracts a range of experiments to test the effects of VPA on gene were independently reviewed by three of the co-authors. expression in a cell line (RN46A) that is derived from the Articles were only excluded if consensus of all three medullary raphe nucleus of rat, and which represents a rel- reviewers was obtained. 108 articles were excluded for evant cellular target for the mood stabilizing effects of VPA. non-relevance and 1 article was excluded because of non- Methods: We carried out RNA-Seq analysis to identify differ- English language. In-depth full text review was completed entially expressed genes (DEG) induced by 72-hour exposure of the remaining 75 articles. 58 articles were again ex- of RN46A cells to 0.5mM VPA or lithium. These data were cluded for non-relevance. The remaining 17 articles were analyzed using four different algorithms (DESeq2, Cuffdiff2, included in the review. kallisto-sleuth and Salmon-Wasabi), to provide high confi- Results: Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) dence DEG. Validation of differentially expressed genes and along the hypothalamic pituitary adrenal axis have been in- analysis of other drugs and compounds was carried using the vestigated as targets for CLZ response. Homozygous FKBP5- nCounter Analysis System (nanoString). rs1360780, homozygous NTRK2-rs1778929, and homozygous Results: We did not detect significant gene expression NTRK2-rs10465180 conferred significant risks for CLZ non- changes after exposure to lithium at 0.5mM, how- response - 2.11x risk (95% CI 1.22–3.64), 1.7x risk (95% CI ever VPA induced widespread changes in expression of 1.13–2.59), and 2.15x risk (95% CI 1.3–3.55) respectively. many genes, with > 700 significantly upregulated and ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 62 Abstracts

> 400 downregulated. Functional annotation indicated a systematic review and meta-analysis of randomized con- over-representation of pathways related to nervous system trolled trials (RCTs) that examined the effect of these tools development and neuronal function for the upregulated on remission rates in major depressive disorder. genes, and cellular responses to cytokines or organic Methods: Medline, Embase, Google Scholar, Pubmed and substances for downregulated genes. the Cochrane Database of Systematic Reviews were We selected the top 23 DEG based on significance, fold- searched. Studies were selected, and quality assessed by change and biological relevance, and used the nCounter two independent reviewers using the Cochrane Collabora- Analysis System (NanoString) platform to validate these in tion Criteria. Random-effects meta-analyses were used to an independent series of cell culture experiments. Clear calculate pooled relative risk (RR) of remission across the validation was observed for ADAM23, LSP1, MAOB, MMP13, eligible RCTs. PAK3, SERPINB2, SNAP91, WNT6, and ZCCHC12. We also Results: Five prospective RCTs with a total of 1737 eli- found that lithium at 1mM and 2mM co-regulated LSP1. The gible subjects were identified and assessed. Although no- mood stabilizer lamotrogine did not appear to have signifi- table risks of bias and a high degree of between study het- cant regulatory effects on any of these genes. erogeneity (I-squared = 71%) were present in all five stud- Using the NanoString platform, we also explored the ef- ies, random-effects meta-analysis of the five RCTs revealed fects of the VPA analogue valpromide, and HDAC inhibitors that individuals receiving pharmacogenetic-guided therapy (HDACi) including trichostatin A and CI994, on the selected (n = 887) were 1.71 (95% CI = 1.17 – 2.48, p = 0.005) times genes. Expression of eight of the selected genes was mod- more likely to achieve symptom remission relative to indi- ified by exposure of RN46A to HDACi: ZCCHC12 was upreg- viduals who received treatment as usual (n = 850). ulated by VPA and CI994 but downregulated by trichostatin Discussion: The current evidence suggests these phar- A; SHANK3 was upregulated by CI994 but downregulated by macogenetic decision support tools might improve treat- TSA; CDKN1C, MAOB, NGFR and WNT6 were upregulated by ment outcomes, particularly symptom remission among CI994 only, and MMP13 and VGF were upregulated by TSA those with prior treatment failure/intolerance. However, only. industry-independent replication studies are required. Discussion: We observed extensive gene expression changes in this serotonergic cell line when exposed to VPA for 72 Disclosure: Nothing to disclose. hours, and many of these genes are involved in neuronal doi: 10.1016/j.euroneuro.2018.08.332 function or nervous system development. For the selected subgroup of genes, we observed complex regulatory effects of different HDACi or the non-HDACi VPA analogue valpromide, suggesting that VPA can exert its regulatory effects SA111 via both HDACi-dependent and independent properties. UNDERSTANDING EPIGENETICS OF SCHIZOPHRENIA Understanding the broader gene regulatory effects of VPA USING GENETIC AND PHARMACOEPIGENOMIC AP- in this serotonergic cell model should provide insights into PROACHES how this widely used drug works, whether other HDACi com- 1 1 1 pounds may have similar gene regulatory effects, and per- Moinak Banerjee , Swathy Babu , Saradalekshmi KR , 2 3 haps highlight molecular processes that may underlie regu- Indu Nair , Chandrashekaran Nair lation of mood.

1 Rajiv Gandhi Centre for Biotechnology

Disclosure: Nothing to disclose. 2 Mental Health Center, Thiruvananthapuram

3 Nair’s Hospital, Ernakulam doi: 10.1016/j.euroneuro.2018.08.331

Background: Schizophrenia is known to be inﬂuenced by both gene and environment. Based on this hypothesis the SA110 genetics and epigenetics have been extensively investi- PHARMACOGENETIC DECISION SUPPORT TOOLS AND gated. DNA methylation is one of the most common signa-

SYMPTOM REMISSION: A META-ANALYSIS OF PROSPEC- tures of the environmental impact on the host epigenome.

TIVE RANDOMIZED CONTROLLED TRIALS IN MAJOR Several reports suggest differences in the pattern of DNA DEPRESSIVE DISORDER methylation both at global and gene specific level in Schizophrenia. However, many of these observations could 1 2 Chad Bousman , Katarina Arandjelovic , not be replicated unanimously. In the present study we 3 3 4 Serafino Mancuso , Harris Eyre , Dunlop Boadie present the influence on epigenetics in the background of its genetic and antipsychotic medications.

1 University of Calgary Methods: We ﬁrst investigated the genetics of methylation

2 Deakin University by evaluating the genetic variation in DNMTs, folate cycle,

3 University of Melbourne methionine cycle and transulfuration cycle. The observa-

4 Emory University tions from these will indicate how genetic variations can influence the methylome. Subsequently we investigated Background: The clinical utility of pharmacogenetic deci- how antipsychotics can influence the host methylome. For sion support tools remains uncertain and has been the topic this we first tried in an in-vitro cell culture system, and of much debate. To assist antidepressant prescribers in their then followed it up in a clinical setting. For in-vitro we evaluation of these decision support tools, we conducted selected a human liver and a neuronal cell line. Cell lines ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 63 were treated with antipsychotic drugs including haloperi- Background: Categorical syndrome such as schizophrenia dol, clozapine and olanzapine either individually or in could be the complex of many continuous mental struc- combination, in various concentrations for different time ture phenotypes including several personality develop- intervals. The effect of antipsychotic drugs on global DNA ment/degeneration dimensions. This is the study to search methylation and histone modifications were monitored. heritability and familiality of SCL psychopathologic dimen- The expression status of various epigenetic genes the DNA sions in the Korean schizophrenic LD (Linkage Disequilib- methyltransferases, methylCpG binding proteins and DNA rium) families. demethylases and various pharmacologically relevant genes Methods: We have recruited 204 probands (with schizophre- that are substrate for the antipsychotic drugs were as- nia) with their parents and siblings whenever possible. We sessed. DNA methylations of promoter region of these genes have used SCL questionnaires for measuring psychopatho- were performed by bisulfite sequencing. The expression logic dimensions. Heritabilities of symptomatic dimensions status of the microRNAs targeting the methylation and the in total 543 family members were estimated using Se- pharmacogenomic machinery were monitored. quential Oligogenic Linkage Analysis Routines (SOLAR). Psy- Results: The results from the genetic variants in the methy- chopathologic dimensions in total family members were lation machinery indicate that the DNMT1 MTR, MTRR and compared with those in 307 healthy unrelated controls for SHMT were significantly associated with an increased risk of measuring the familialities using ANOVA analysis. developing Schizophrenia. Our observations on the role of Results: Seven of the 10 SCL variables were significantly antipsychotic drug in methylation machinery using in-vitro heritable and were included in the subsequent analyses. The system, indicates that antipsychotic drugs do alter global three groups (control, unaffected 1st degree relative, case) DNA methylation patterns. These alterations in methylation were found to be significantly different with the expected can be attributed to the variability in underlying epigenetic order of average group scores for all heritable dimensions. gene expressions which in turn was observed to be regulated Discussion: Our results show that the aberrations in sev- by their target microRNAs. In clinical setting too, similar eral symptomatic dimensions could form the complexity of trend in global DNA methylation, epigenetic gene expres- schizophrenic syndrome as a result of genetic-environment sion and miRNA expression was observed and was markedly coactions or interactions in spite of some limitations (re- associated with drug response rather than disease patho- cruited family, phenotyping). genesis. In-vitro studies show that the antipsychotic drugs influence the expression status of pharmacologically rele- Disclosure: Nothing to disclose. vant genes including multi drug transporter and drug metab- doi: 10.1016/j.euroneuro.2018.08.334 olizing enzymes and this regulation was controlled by their corresponding microRNA. Similar pattern was observed in clinical setting too, which was reflective of good therapeutic response. SA113

Discussion: The study suggests that the host epigenome in INVESTIGATING THE FEASIBILITY OF USING TRAN- schizophrenia can be influenced by host genetics and also SCRIPTOMES AS PREDICTORS OF METABOLIC OUTCOME antipsychotic drugs. The drugs can alter the epigenetic and FOR PSYCHOSIS pharmacogenetic gene expressions by targeting their miR- NAs. These alterations can also modulate the treatment Conrad Osamede Iyegbe, Lauren Allen, John Lally, response. This further suggests that while addressing the Marta Di Forti, Robin Murray, Fiona Gaughran role of epigenetics in pathogenesis and treatment response it is important to investigate the background genetics of Institute of Psychiatry, King’s College London epigenome and other influencing factors such as drugs in this case. Background: Cardiovascular disease is the primary cause of premature death among people with psychosis, even Disclosure: Nothing to disclose. after taking into account deaths resulting from suicide. doi: 10.1016/j.euroneuro.2018.08.333 Overweight and obesity (the major drivers of cardiovascular disease in psychosis populations) are exacerbated by antipsychotic medications, which carry variable propensity to induce weight gain (Van Os et al). Clinical obesity, (defined as Body Mass Index (BMI) as 30 kg/m2 or over), has a myriad of associated negative health outcomes but is also

SA112 a modiﬁable risk factor for premature mortality. HERITABILITY AND FAMILIALITY OF PSYCHOPATHO- Thus, the objective of the study is to determine whether LOGIC DIMENSIONS IN THE KOREAN FAMILIES WITH it is feasible to use transcriptomic proﬁling as a basis SCHIZOPHRENIA for stratifying individuals by their propensity to gain BMI. We explore this by evaluating the stability of the cross-

Hwagyu Suh 1, Byung D. Lee1 1, Je M. Park 1, Young M. Lee 1, sectional BMI signature in 2 unrelated but methodologically-

Eunsoo Moon 1, Hee J. Jeong 1, Soo Y. Kim 1, Kang Y. Lee 1, compatible cohorts at different stages of illness.

Young I. Chung 1, Dae W. Kim 2, Chan H. Park 1 Methods: 100 ﬁrst-episode and 100 chronic cases of psychosis meeting ICD-10 criteria (F20-29 and F30-33) were Pusan National University Hospital recruited as part of 2 independent studies from 3 NHS Pusan National University Yangsan Hospital Trusts: South London and Maudsley (SLAM), Oxleas and Sus- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 64 Abstracts

sex. Cases were ethnically mixed and aged between 18-65. 6 CIBERSAM, IDIVAL, University Hospital Marqués de All participants gave informed consent for biological sam- Valdecilla, Santander pling and a range of physical health assessments. Blood glu- 7 Universitat de Barcelona, Institut de Biomedicina de la cose was measure using HbA1c while height and weight data Universitat de Barcelona (IBUB); Instituto de Salud Carlos were also taken and used to calculate BMI. For FEP subjects III, Centro de Investigación Biomédica en Red de Salud Men- biological measures were taken at baseline, 3 months and tal (CIBERSAM) 12 months post recruitment. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and in- Background: Schizophrenia is a severe psychiatric disorder terrogates, using the Illumina HumanHT-12.v4 beadchip ar- with excess morbidity and mortality mainly due to cardio- ray. Samples were run at the National Institute for Health vascular disorders (Hjorthøj et al., 2017). The Metabolic Research’s (NIHR) Biomedical Research Centre for Mental Syndrome (MetS) was defined to predict cardio-vascular Health (BRC-MH) at the Institute of Psychiatry, Psychology morbi-mortality and encompasses some of the most rele- and Neuroscience. A total of 4756 probes passed a stringent vant cardiovascular risk factors (Alberti et al., 2009). MetS quality control across the 200 samples. is more prevalent among patients with psychosis. It has Results: Normalised BMI data was used to assess the pre- been described for this syndrome a heritability between 10 dictive efficacy of predictors grouped by type (clinical, de- and 30% (Henneman et al., 2008), and there is evidence of mographic, technical and transcriptomic). Predictor classes its polygenic architecture (Malan-Müller et al, 2016), being were either all included, analyzed one at a time or se- some of the genes reported, implicated in both schizophre- quentially removed. In trials using 100 iterations of 10-fold nia and metabolic disorders. cross-validation, exploring 11 values of the alpha across We aim to explore if there is an association between a 500 imputation sets, gene-expression and clinical features polygenic risk score (PRS) and the occurrence of MetS in a were consistently found to be associated with lowest mean sample of patients with psychosis. squared error values. Having established the contribution Methods: 184 subjects presenting a first episode of non- of gene expression to prediction of BMI Weighted Gene Co- affective psychosis were recruited for the present study. All expression Network Analysis (WGCNA) was used to identify of them were drug-naïve and none of them present MetS at the candidate networks involved and investigate their out- baseline. Anthropometric measurements and glycemic and of-sample validity using the same prediction framework. lipid parameters were obtained at baseline and after 3 years Ranks of the 4756 probes were generated for the 500 im- of having initiated treatment. putation sets and an overall consensus ranking taken. After the genotype quality control steps, these sam- Genes in this list were divided into deciles and perfor- ples were imputed using the standard SHAPEIT2/IMPUTE2 mance compared across deciles in order to understand what pipeline. PLINK 1.90 was used for the calculation of PRS. proportion of genetic predictors are useful for this predic- These scores were calculated multiplying the imputation tion problem. probability for each risk allele by the effect size for each Discussion: Further validation of our findings will in- genetic variant as reported in Ripke et al., 2014. The result- volve looking at longer-term prediction accuracy of gene- ing values were summed up in an additive fashion obtain- expression in followed-up patients. ing an individual estimate of the genetic load in each subject. Three different P-value thresholds were used (5 × 10- Disclosure: Nothing to disclose. 8, 0.05, 1). doi: 10.1016/j.euroneuro.2018.08.335 Regression analysis were carried out in order to explore the possible role of PRS as predictor of MetS. Results: 26 patients (14%) developed a MetS in the first 3 years of treatment with antipsychotic medication. The SA114 model obtained from regression analyses (X2(9) = 31.34, R2

POLYGENIC RISK SCORE AND METABOLIC SYNDROME Nalgelkerke = 0.403, p = 0.005) predicted the occurrence of

PREDICTION IN PATIENTS WITH A FIRST EPISODE OF MetS with 89.7% accuracy, and although only classified cor- NON-AFFECTIVE PSYCHOSIS rectly 35% of subjects with MetS, it correctly classified 98.2% of healthy subjects. However, this prediction model was not 1 2 Sergi Papiol , Javier Vázquez-Bougon , significantly improved when adding the PRS. 3 Diana Tordesillas-Gutiérrez , María del Carmen Discussion: The exploratory results presented here suggest 4 5 García-González , Rosa Ayesa-Arriola , that, although the MetS and Schizophrenia may share com- 5 6 Esther Setién-Suero , Víctor Ortiz-García de la Foz , mon genetic variations, a schizophrenia PRS will not be a 7 6 Lourdes Fañanás , Benedicto Crespo-Facorro useful tool in identifying those patients that will develop MetS along the treatment period.

1 Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig Maximilian University, Munich Disclosure: Nothing to disclose.

2 Marqués de Valdecilla University Hospital, IDIVAL, School doi: 10.1016/j.euroneuro.2018.08.336 of Medicine, University of Cantabria, Santander, CIBERSAM

3 IDIVAL-CIBER

4 Valdecilla Biomedical Research Institute, IDIVAL, San- tander

5 Marqués de Valdecilla University Hospital, IDIVAL, School of Medicine, University of Cantabria, Santander ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 65

SA115 1. A 346 kb 3p26.3 tandem duplication overlapping CHL1 THE UBC MAGERS STUDY OF SEVERELY TREATMENT- (Close Homologue of L1) and its two antisense transcripts, RESISTANT PSYCHOSIS: CHROMOSOMAL MICROARRAY in a Caucasian male with onset at 17 of SZAD. FINDINGS IN THE FIRST 25 CASES He also carried an Xp22.33 duplication (VOUS), potentially implicating 3 SCZ-associated genes (Butler, 2016):

Robert Stowe 1, Monica Hrynchak 2, Agata Minor 2, CSF2RA, IL3RA, and SHOX. This CNV was present in an un-

Christine Tyson 1, Prescilla Carrion 1, Ashley DeGraaf 1, affected sister, and absent in an unaffected brother, while

Pedram Laghaei 1, Olga Leonova 1, Mahesh Menon 1, the 3p26.3 CNV was absent in both.

Ivan Torres 1, Veerle Willaeys 3, Randall White 1, 2. A 1.3 Mb tandem duplication at 22q11.23 potentially

Clara Westwell-Roper 1, Clare Beasley 1, William Honer 1 implicating BCR, SMARCB1, and SNRPD3 was found in an abo- riginal male with mild DD/ID, and psychosis onset at age 15.

1 University of British Columbia This participant also had a duplication at 6q22.2-q22.31

2 Royal Columbian Hospital (VOUS) that could interrupt the PLN and SLC35F1 genes.

3 Vancouver Hospital and Health Sciences Centre Seven other VOUS were reported: deletions at 1p11.2- p12.2 (NOTCH2) and 22q11.21 (PRODH and DGCR2); a tripli- cation at 6p21.2 (MDGA1); and four duplications, one each Background: The Metabolic Explorations in Refractory at 6q22.2-q22.31 (SLC35F1), 15q13.3 (CHRNA7), 15q21.3 Schizophrenia (MAGERS) Study is an intensive pilot, multi- (CGNL1), and 22q11.2 (TOP3B). modal –omics and psychiatric genetic counselling research Discussion: Detailed reviews demonstrated that almost all project conducted on the tertiary provincial BC Psychosis of these variants had potential phenotypic and, in several Program (BCPP) research and care unit at the University of cases, potential therapeutic relevance, and will be dis- British Columbia Hospital in Vancouver, Canada. cussed at presentation. CHL1, MDGA1, TOP3B, CGNL1, and We hypothesize that our cohort with “extreme pheno- DGR2 are of particular interest. The yield of clinical CMA in types” of psychosis is likely enriched in potent, rare recur- a severely treatment-resistant population may be as high as rent or novel genetic risk factors, such as chromosomal copy 20%– 25%. number variants (CNVs). Here we present results of chromosomal microarray screening (CMA) in the ﬁrst 25 partici- Disclosure: Nothing to disclose. pants. Methods: All BCPP patients capable of giving consent or as- doi: 10.1016/j.euroneuro.2018.08.337 sent with surrogate consent, and DSM-V diagnoses of DSM-5 SCZ, SZAD, and/or Catatonia Associated with Another Men- tal Disorder were eligible. SA116 Deep phenotyping included structured birth histories, Open Board three-generation pedigrees; neuropsychological testing; medical, neurological, and dysmorphology-oriented exams; and extensive clinical biochemical screening for inborn er- doi: 10.1016/j.euroneuro.2018.08.338 rors of metabolism (IEMs). DSM-V diagnoses were established by multidisciplinary consensus ratings and M.I.N.I. SA117 CMA utilized a SNP-based CNV detection-optimized plat- POLYGENIC RISK SCORE FOR PARKINSON DISORDER form (Cytoscan HD). Chromosome Analysis Suite software IS NEGATIVELY ASSOCIATED WITH PSYCHOTIC DISOR-

CNV calls were curated using standard tools by clinical cy- DERS togeneticists. Additional online tools used included SZGR2, Varsome, denovo-db, DBDGD, and genebook. After exclusion Diego Quattrone 1, Cathryn Lewis 2, Alexander Richards 3, of common polymorphisms, clinical CNVs were identiﬁed at Michael O’Donovan 3, Pak Sham 4, Giada Tripoli 2, ACMG thresholds ( ≥ 200 Kb for deletions, ≥ 400 Kb for du- Craig Morgan 5, Ulrich Reininghaus 6, Robin Murray 5, plications). Marta Di Forti 5 All non-clinical CNVs reported by > 25 markers, and all exonic CNVs with > 5 markers were inspected, and poten- 1 MRC Social, Genetic & Developmental Psychiatry Centre, tially reliable calls are currently being curated. Institute of Psychiatry, Psychology & Neuroscience, King’s Results: A mean admission PANSS Total score of 88.1 con- College London ﬁrms unusually severe psychosis in our cohort. 2 King’s College London Mild dysmorphic features were often present and will be 3 Cardiff University discussed. 4 The University of Hong Kong No pedigrees were consanguineous, and no extended runs 5 Institute of Psychiatry, Psychology & Neuroscience, King’s of homozygosity were detected on CMA. 14 participants had College London ≥ 1st or 2nd degree relatives with SCZ or SZAD, and 8, with 6 School of Mental Health and Neuroscience, Maastricht Uni- affective psychosis. versity Tw o males with childhood-onset SCZ had no clinical CNVs. Clinical CNVs were found in 7/25 (28%).

2 participants (8%) had likely pathogenic CNVs: Background: A consistent body of evidence supports the neurodevelopmental nature of Schizophrenia (SZ) spectrum disorders. On the other hand, Parkinson Disorder (PD) is ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 66 Abstracts a neurogenerative condition characterised by the loss of velopment which may be associated with vulnerability for dopaminergic neurones. Based on the evidence that the later psychosis development. most peculiar symptoms of SZ and PD are associated with There have been relatively few longitudinal studies that opposite striatal dopamine levels, we tested the hypothe- have started assessments of participants with 22q11.2DS in sis that common genetic variants associated with PD would early childhood and have followed them up repeatedly. The be negatively associated with the development of a first aim of this study was to examine longitudinal cognitive de- episode of psychosis (FEP). velopment in individuals with 22q11.2DS across childhood Methods: We used clinical and biological data from the EU- and adolescence compared to control siblings and relate ropean network of national schizophrenia networks study- this to the emergence of prodromal psychotic features in ing Gene-Environment Interactions (EUGEI) study, including late adolescence. 1130 FEP patients and 1497 population controls recruited Methods: Children with 22q11.2DS and control siblings have in 17 sites across 6 countries. Genetic variants were collec- been recruited via UK NHS medical genetic clinics and sup- tively analyzed for about 1900 participants. Summary statis- port charities and are assessed longitudinally. To date 29 tics for 9,830 variants in recent Chang et al. meta-analysis participants with 22q11.2DS (19 male) and 7 siblings (1 were used as base data set. Individuals’ number of risk al- male) have taken part three times. leles in our discovery sample was weighted by the log odds The mean age of participants with 22q11.2DS was 10.1 ratio from the base sample and summed into the PD poly- years (SD = 2.1) at Time 1 (T1), 12.6 (SD = 2.1) at Time 2 (T2) genic risk score (PRS). and 15.2 (SD = 1.9) at Time 3 (T3). The mean age of siblings Regression models were fitted to test for association of was 10.1 years (SD = 2.2) at Time 1 (T1), 12.9 (SD = 2.1) at PD PRS and presence of a psychotic disorder after adjust- Time 2 (T2) and 15.3 (SD = 2.3) at Time 3 (T3). The mean ing for gender and 20 principal components for population time gaps were T1 -T2: 2.5 (SD = 0.4); T1 - T3: 5.1 (SD = 0.8); stratification. T2 - T3: 2.6 (SD = 0.7). Results: We found a significant negative association be- For all participants, Full scale IQ (FSIQ) was assessed at tween PD PRS and FEP. Logistic regression showed that hav- each time point and the Structured Interview for Prodromal ing a high PD PRS reduced the probability to suffer a psy- Symptoms (SIPS) at T3. SIPS scores = > 3 on positive symp- chotic disorder (OR = 0.89; 95% confidence interval [CI]: tom items were classed as prodromal symptoms. 0.80–0.98; p = 0.02). Multinomial logistic regression showed Results: Longitudinal FSIQ change across T1, T2 and T3 that the risk further decreased for presenting with a di- was investigated with repeated measures ANOVA. Mean FSIQ agnosis of non-affective psychosis, such as schizophrenia was significantly lower at each consecutive time point in or schizoaffective disorder (RRR = 0.84; 95% CI: 0.75-0.95; individuals with 22q11.2DS (T1 = 78.5, T2 = 74.9 (drop 3.6 p = 0.005). points from T1), T3 = 70.9 (drop 7.6 points from T1 and 4 Discussion: Our results suggest that, in our sample, FEP pa- points from T2); p < 0.001), but this was not the case for tients had lower PD PRS compared with population controls. siblings (T1 = 113.6, T2 = 107.7 (drop 5.9 points from T1), People carrying high PD PRS had an even lower relative risk T3 = 110.6 (drop 3 points from T1 and gain 2.9 points from of presenting a diagnosis of non-affective psychotic disorder T2); p = 0.553). at FEP. Such findings require to be replicated in independent 21% of children with 22q11.2DS (n = 6) met SIPS criteria discovery samples. for positive prodromal features at T3; none of the siblings did. Baseline (T1) FSIQ and FSIQ change scores (T1 to T3) Disclosure: Nothing to disclose. were compared between those with and without prodromal symptoms using t-tests. Participants experiencing prodro- doi: 10.1016/j.euroneuro.2018.08.339 mal symptoms at T3 had a lower T1 mean FSIQ (80.3 vs 71.8, p = 0.024), but this was not the case when broken down into verbal IQ (82.7 vs 73.8, p = 0.088) or performance IQ (80.9 vs 74.3, p = 0.096).

SA118 There was no difference in T1 to T3 FSIQ, Verbal IQ or Per-

LONGITUDINAL COGNITIVE DEVELOPMENT AND AS- formance IQ change score between those reporting positive SOCIATION WITH PRODROMAL PSYCHOTIC SYMPTOMS prodromal symptoms and those without (FSIQ: -9.0 vs -7.2 IN ADOLESCENTS WITH 22Q11.2 DELETION SYNDROME points, p = 0.581; VIQ: -7.9 vs -5.7 points, p = 0.647; PIQ: -6.3 vs -10.8 points, p = 0.062). Data collection is ongoing, and 1 1 2 Sinéad Morrison , Samuel Chawner , Michael Owen , analysis of speciﬁc cognitive domains is also taking place. 3 Marianne van den Bree Discussion: This study ﬁnds that there may be a general cognitive decline in adolescents with 22q11.2DS, whereas

1 Cardiff University cognitive abilities remain stable in their unaffected siblings.

2 MRC Centre for Neuropsychiatric Genetics and Genomics, Additionally, cognitive differences are present from early Cardiff University childhood in children with 22q11.2DS who experience pro-

3 Cardiff University School of Medicine dromal symptoms later, in adolescence. The ﬁndings indicate the need for psychiatric monitoring in early childhood Background: 22q11.2 Deletion Syndrome (22q11.2DS) is one in this population. of the strongest known genetic risk factors for psychotic disorder in adulthood, and up to half of adolescents with the Disclosure: Nothing to disclose. deletion experience prodromal symptoms. 22q11.2DS is a doi: 10.1016/j.euroneuro.2018.08.340 valuable model for understanding periods of cognitive de- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 67

SA119 ple (r = 0.08, p = 0.0001), and PRS for schizophrenia sig- INFLUENCE OF POLYGENIC RISK SCORES FOR niﬁcantly increased risk of schizophrenia IRR (IRR 1.33 SCHIZOPHRENIA AND REPRODUCTIVE BEHAVIOR ON (1.28 - 1.39) per standard deviation (SD). However, (a) THE ASSOCIATION BETWEEN LATE FATHERHOOD AND PRS for schizophrenia was not associated late fatherhood SCHIZOPHRENIA (r = −0.01, p = 0.07). Furthermore, (b) PRS for paternal age at ﬁrst birth did not predict later schizophrenia risk = Liselotte Petersen 1, Jean-Christophe Philippe Debost 2, IRR 0.87 (0.84 - 0.90). When adjusted for paternal ed-

Esben Agerbo 3, Elise Robinson 4, John McGrath 5, ucational achievement, the relationship between PRS for

David Hougaard 6, Ole Mors 7, Merete Nordentoft 8, age at ﬁrst birth and risk of schizophrenia was attenuated = Anders Børglum 9, Thomas Werge 10, Preben Bo Mortensen 2, IRR 0.95 (0.91 – 0.99).

Carsten B. Pedersen 11 Discussion: The ﬁndings conﬁrm the utility of the two polygenic risk scores to predict their related phenotypes. How-

1 National Centre for Register-based Research, The Lund- ever, they suggest that the common variants related to beck Foundation Initiative for Integrative Psychiatric Re- schizophrenia do not predict age of ﬁrst fatherhood. Cu- search, iPSYCH riously, common variants that predict later age of father-

2 National Center for Register-based Research hood seem to be protective with respect to schizophrenia.

3 CIRRAU - Centre for Integrated Register-based Research, However, this may reﬂect more complex causal pathways re-

National Centre for Register-based Research, Aarhus Uni- lated to higher educational achievements to be correlated versity with later age of fatherhood.

4 Stanley Center for Psychiatric Research, Broad Institute We can conclude (a) that common variants used to gener-

5 QLD Brain Institute ate PRS for schizophrenia do not seem to be associated with

6 Statens Serum Institut age at ﬁrst father, and (b) PRS for paternal age at ﬁrst birth

7 Aarhus University Hospital do not predict increased risk of schizophrenia. Our ﬁndings

8 Mental Health Centre Copenhagen, University of Copen- suggest that other mechanisms (other genetic instruments hagen or psychosocial factors) explain the association of late fa-

9 Aarhus University therhood and schizophrenia, which warrants further inves-

10 Institute of Biological Psychiatry, MHC Sct. Hans, Mental tigation. Health Services - Copenhagen Disclosure: Nothing to disclose. 11 Centre for Integrated Register-based Research National Centre for Register-based Research, Aarhus University, doi: 10.1016/j.euroneuro.2018.08.341 Business and Social Sciences, Aarhus University

Background: Many studies link advanced paternal age to an SA120 increased risk of schizophrenia. However, the mechanisms FAMILY BASED RARE VARIANT STUDY SUPPORTS THE underlying this association remain poorly understood. It has CUMULATIVE CONTRIBUTION OF NEURODEVELOPMEN- been suggested that older paternal age at first child, rather TAL PATHWAY GENES IN SCHIZOPHRENIA ETIOLOGY than paternal age at conception, may account for the increased risk of schizophrenia in the offspring of older fa- BK Thelma 1, Jibin John 1, Prachi Kukshal 1, Triptish Bhatia 2, thers. The aim of this study was to explore the association Vishwajit Nimgaonkar 3, Smita Deshpande 2 between late fatherhood and risk of schizophrenia when adjusted for genetic instruments (polygenic risk scores (PRS) 1 University of Delhi South Campus for (a) schizophrenia and (b) paternal age at first birth). 2 PGIMER-Dr.R.M.L. Hospital We expected both PRSs to correlate to the measured 3 University of Pittsburgh paternal age at first child and the PRSs to be associated with increased schizophrenia risk in the children; accord- Background: Clinical and genetic heterogeneity is well doc- ingly, the PRSs could explain part of the association be- umented in schizophrenia (SZ), a common debilitating neu- tween late fatherhood and schizophrenia in the children. rodevelopmental disorder with a life time prevalence of Specifically, we hypothesized that: (a) PRS for schizophre- ∼1%. The contribution of both common and rare risk vari- nia would be associated with age at first birth, and (b) PRS ants to the genetic architecture of SZ has been witnessed by for paternal age at first birth would be associated with risk genome-wide association studies, whole exome and whole of schizophrenia. genome sequencing approaches. Both common and de novo Methods: From the unique Danish iPSYCH2012 sam- variants have provided notable evidence to likely involve- ple (Mol Psychiatry. 2018;23(1):6-14.), we used in- ment of a range of pathways including glutamatergic, synap- formation on 3468 cases of schizophrenia and 20,126 tic signalling, neurodevelopmental etc. but they have been population-based controls who had been genotyped. This very limited in their contribution to total disease heritabil- sample includes information on confounders from the rich ity and relative risk estimation. As SZ is highly heritable and Danish population-based registers and PRSs obtained from segregates in families, highly penetrant rare variants are external discovery datasets (Nature. 2014; 511(7510):421-7. more likely to be identified through analyses of multiply af- Nat Genet. 2016; 48(12):1462-1472.). fected families. Further, much of the gene mapping studies Results: PRS for paternal age at first birth correlated pos- in SZ have utilized individuals of Caucasian ancestry. Analy- itively with paternal age at first birth in our control sam- sis of other ethnic groups may be informative. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 68 Abstracts

Methods: Tw o multiplex Indian families with SZ diagnosed Methods: Here, we combined large genome-wide associa- based on DSM IV criteria were recruited from Dr.RML hos- tion study (GWAS) data on SCZ (n = 82,315), BD (n = 51,710) pital, New Delhi with Institutional ethical committee clear- and general cognitive ability (n = 269,867) and investigated ance and informed consent. Using venous blood derived DNA overlap in common genetic variants using conditional false samples from all the participating individuals, library prepa- discovery rate (condFDR) analysis. The condFDR method ration and enrichment of exons were carried out using Agi- builds on an empirical Bayesian statistical framework and lent SureSelect Human All Exon V5 + UTR kit and library was integrates summary data from two GWAS to increase sta- sequenced on Illumina Hiseq 2000 at a commercial facility. tistical power to detect overlapping associations. Moreover, Data analysis and variant prioritization was performed using we used the online platform FUMA to functionally annotate standard tools and methods. identified single-nucleotide polymorphisms, determine tis- Results: Whole exome sequencing (WES) data analyzed us- sue expression of implicated genes, and perform Gene On- ing the standard analysis pipeline yielded a large num- tology gene-set enrichment analysis. ber of rare variants. Systematic variant prioritization re- Results: We observed substantial genetic enrichment in vealed rare protein disturbing variants namely p.D1084N in both SCZ and BD conditional on associations with cognitive EGFR, p.D40A in FGFR1 and p.R775Q in MDGA1 segregating ability indicating polygenic overlap. Using condFDR analysis, with disease in family #1; and p.S127N in FGF4, p.S127N in we leveraged this enrichment to increase statistical power FGFR3, and p.A1352T in RERE in family #2. All these rare and identified 75 distinct genomic loci associated with both variants were inferred to be functionally significant based SCZ and cognitive ability and 12 loci associated with both BD on in silico analyses. Several variants in these six genes were and cognitive ability at conjunctional FDR < 0.01. Most SCZ identified on screening of WES data from an independent an- risk alleles (61 out of 75, ∼81%) were associated with poorer cestry matched sample set (n = 350). Of note, in silico char- cognitive performance, whereas most BD risk alleles (9 out acterization of all these variants revealed their deleterious of 12, 75%) were associated with better cognitive perfor- nature. mance. The genes nearest the identified shared loci were Discussion: All the genes with rare variants identified in this significantly overexpressed in human brain regions. Gene- study are notably from the neurodevelopmental pathway. set analysis for shared loci between SCZ and cognitive abil- Literature based evidence from genetic, expression and an- ity implicated biological processes related to neurodevelop- imal studies further support the possible involvement of ment, synaptic integrity and neurotransmission. these genes in SZ etiology and thus strengthen the neurode- Discussion: The study supports prior genetic evidence that velopmental hypothesis of SZ. This familial analysis also sup- SCZ and BD differ in their relation to cognitive ability. We ports the cumulative contribution of rare variants in multi- provide new insights into the known polygenic overlap be- ple genes to the development of this complex disorder. tween SCZ and cognitive ability by identifying several novel shared loci. To our knowledge, the finding of polygenic over- Disclosure: Nothing to disclose. lap between BD and cognitive ability is novel. Altogether, the study increases the understanding of the shared genetic doi: 10.1016/j.euroneuro.2018.08.342 basis underlying SCZ, BD and cognitive ability.

Disclosure: Nothing to disclose.

SA121 doi: 10.1016/j.euroneuro.2018.08.343 GENOME-WIDE ANALYSIS REVEALS EXTENSIVE GE- NETIC OVERLAP BETWEEN SCHIZOPHRENIA, BIPOLAR DISORDER AND GENERAL COGNITIVE ABILITY SA122 STRUCTURAL VARIATIONS OF SCHIZOPHRENIA RISK

Olav Smeland 1, Oleksandr Frei 2, Shahram Bahrami 2, GENE COMPLEMENT COMPONENT 4 (C4) AND BRAIN

Alexey Shadrin 2, Bipolar Disorder Working Group 3, MRI PHENOTYPES

Torill Ueland 2, Srdjan Djurovic 1, Anders Dale 4,

Ole Andreassen 1 Rebecca Shafee 1, Robert Handsaker 2, Nolan Kamitaki 1,

Claire Churchhouse 3, Benjamin Neale 4, Steven McCarroll 5,

1 Oslo University Hospital Elise Robinson 4

2 University of Oslo

3 Psychiatric Genomics Consortium 1 Harvard Medical School

4 UCSD 2 Stanley Center for Psychiatric Research

3 Broad Institute

Background: Schizophrenia (SCZ) and bipolar disorder (BD) 4 Massachusetts General Hospital are severe mental disorders associated with cognitive im- 5 Stanley Center for Psychiatric Research, Broad Institute pairment. In both disorders, cognitive ability is considered of MIT and Harvard a major determinant of functional outcome. Despite this, the etiology underlying cognitive impairment is poorly un- Background: Schizophrenia is a psychiatric disorder that derstood, and no satisfactory cognitive treatments exist. often manifests in late adolescence and early adulthood. Increasing evidence indicates that genetic risk for SCZ may Aberrant brain development has been suggested to increase contribute to cognitive impairment, while the genetic rela- disease susceptibility. Additionally, schizophrenia patients tionship between BD and cognitive function remains unclear. display greater-than-average loss of gray matter in the ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 69 brain, the causal mechanisms of which are unknown. Re- netic variants have yet to be thoroughly investigated. Here cently it was shown that structural variations of the comple- we investigate whether nuclear-encoded mitochondrial ment component 4 (C4) genes, which play a role in synaptic genes play a role in the risk to develop major psychoses. pruning and other biological processes, are associated with Methods: We downloaded the summary association results schizophrenia risk. Specifically, multiple C4 alleles that in- from the SCZ, BIP, and MDD datasets from the Psychi- crease expression of the C4A gene associate with higher risk atric Genomics Consortium (PGC) website. The mitochon- of schizophrenia. Whether this genetic risk manifests in de- drial genes targeted in this study were downloaded from tectable changes in cortical gray matter at the mm-scale in MitoCarta 2.0 dataset. To investigate mitochondrial genes Magnetic Resonance Imaging (MRI) in healthy individuals is predicting risk for each disorder, we conducted gene-based an open question. analysis using MAGMA (default parameters). To examine mi- Methods: We investigated the effect of the structural vari- tochondrial genes predicting risk cross-disorder, we per- ation in C4 on brain MRI phenotypes in more than 9000 informed meta-analysis using the same software. The sam- dividuals (age: mean = 55.3 years, standard deviation = 7.4 ple size for SCZ comprising 35,476 cases and 46,839 con- years) of British ancestry in UK Biobank. We created a cus- trols; for BIP we had 7,481 cases and 9,250 controls; and tom reference panel to impute the structural alleles of C4 for MDD a total of 59,851 cases and 113,154 controls. Gene in each individual; genetically predicted expression levels set over-representation analysis was performed to the gene of C4A were then estimated (from C4 genotypes) using an list obtained from meta-analysis using the (network-based) empirical formula derived from earlier analysis of brain GeneMania software. samples from hundreds of donors. The brain phenotypes Results: For SCZ, 264 out of 1,158 genes showed p-values included 67 volumetric brain MRI measurements including less than 0.05 and 41 genes survived Bonferroni correction subcortical structure volumes and gray matter volumes of (p < 0.05/1158). For BIP, 95 out of 1,158 genes showed different cortical regions. A linear model was used to test MAGMA gene-based p < 0.05 and one gene survived Bon- for association between genetically predicted C4A expres- ferroni correction (p < 0.05/1158). For MDD, 104 out of sion and these phenotypes controlling for age, sex, head 1,158 genes showed p-values less than 0.05 and three genes size, genotype batch and ancestry principal components. survived Bonferroni correction (p < 0.05/1158). For cross- Results: None of the 67 association tests passed correction disorder analysis, we tested a total of 1,086 genes which for multiple comparisons. were present in all three datasets. Of these, 104 genes Discussion: Our results find no detectable effect of C4 were nominally significant associated with the three disor- structural variations on mm-scale volumetric brain mea- ders (p < 0.05), and 18 survived multiple test correction. surements in a sample of 9,000 healthy individuals. Though Enrichment analysis of the 18 genes highlighted mitochon- these results do not exclude the possibility of small effects drial matrix processes to be associated with risk across the that would be detectable in still-larger cohorts, they set an three disorders. upper bound on the size of such effects. Since most MRI sam- Discussion: Our study provides a list of mitochondrial genes ples are usually smaller than the sample used here, our work playing a role in the major psychoses, although replica- provides an initial step towards understanding the effects tion of the finding is still required. Our study provides new of C4 on the human brain. Future work will include more leads for functional and animal model follow up studies. detailed investigation of C4 and structural and functional This study enhances our knowledge regarding the causes of brain phenotypes as well as behavioral phenotypes in the psychosis and provides insight into novel targets for drug UK Biobank. discovery.

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.344 doi: 10.1016/j.euroneuro.2018.08.345

SA123 SA124 ANALYSIS OF MITOCHONDRIAL GENES ACROSS POLYGENIC RISK ASSOCIATION IN INDIVIDUALS AT SCHIZOPHRENIA, BIPOLAR AND MAJOR DEPRESSION ULTRA-HIGH RISK FOR PSYCHOSIS DISORDER

Keane Lim 1, Max Lam 1, Jian-Jun Liu 2, Jimmy Lee 1 Vanessa Gonçalves, Zhi Zhang, James L. Kennedy

1 Institute of Mental Health

Centre for Addiction and Mental Health 2 Genome Institute of Singapore

Background: The genetic risk factors for Schizophrenia Background: Epidemiological studies have revealed psy- (SCZ), Bipolar Disorder (BIP), and Major Depression Disorder chopathological heterogeneity in individuals at ultra-high (MDD) are still not yet fully understood. We hypothesize that risk (UHR) for psychosis. In addition to attenuated psychotic an important cause underlying the pathophysiology of these symptoms, these individuals usually present with accompa- disorders is dysfunctional mitochondria in the brain of pa- nying cognitive deﬁcits, negative symptoms and a comorbid tients. Multiple lines of evidence suggest that mitochondrial diagnosis, with a majority being presented with affective dysfunction is part of the pathophysiology of these psychi- comorbidities of depression or anxiety disorder. Here, we atric disorders but their associations with mitochondrial ge- investigated the association between polygenic risk score ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 70 Abstracts

(PRS) of schizophrenia (PRS-SCZ) and major depressive dis- 7 Georg-August-University Goettingen order (PRS-MDD) in predicting UHR status. Thereafter, we 8 Ludwig Maximillian University, Munich stratified the sample by depression comorbidity to investi- 9 Institute of Psychiatric Phenomics and Genomics, Ludwig- gate the association between polygenic risk score (PRS) of Maximilians-University Munich, Central Institute of Mental schizophrenia (PRS-SCZ) on dimensional symptoms in UHR Health, Mannheim individuals. Methods: A total of 179 East-Asian individuals (107 UHR Background: Bipolar disorder (BD), schizophrenia (SCZ) and cases, 72 healthy controls) were used in this study. Sam- schizoaffective disorder (SZA) can be disabling disorders as- ples were genotyped on the Illumina Zhonghua chip, QC- sociated with severe psychiatric symptomatology. Individual ed, phased with SHAPEIT and imputed via Minimac3 (MACH) psychopathological features often overlap between these to the 1000 Genomes Project Phase 3 reference panel diagnostic groups and their severity can vary widely. More (GRch37). P-value thresholds for PRS-SCZ and PRS-MDD were severe psychopathological features are generally associated calculated using the schizophrenia and depression GWAS with a less favorable outcome. Further, all three diseases summary statistics from the Psychiatric Genomic Consor- are common complex genetic disorders with a polygenic ge- tium. Dimensional symptoms were evaluated using the Pos- netic architecture in the majority of cases. The inherent itive and Negative Syndrome Scale (PANSS). A series of lo- heterogeneity with regard to disease severity has posed a gistic and linear regression, controlling for ancestry specific significant challenge to both the study of the underlying dis- principal components, were performed via PRSice2, using a ease mechanism and the clinical management. Therefore, false discovery rate of 5%. stratification of cases into more homogeneous subgroups Results: A significant polygenic association was observed across diagnoses using both psychometric and genetic infor- for PRS-MDD on UHR case-control status. PRS-SCZ only pre- mation could provide a means to identify individuals with dicted case-control status when stratified by lifetime preva- higher risk for severe illness, mandating earlier and intensi- lence of depression comorbidity. No significant PRS-SCZ fied clinical intervention. case-control status was observed in the current depres- Methods: Individuals included in the study participate in sion comorbidity group or no depression comorbidity group. an ongoing longitudinal, multi-site cohort study carried No association was observed for PRS-SCZ with dimensional out across Germany and Austria ( www.kfo241.de ; www. symptoms in UHR. PsyCourse.de ). Participants were characterized at at least Discussion: This study provides first evidence on the poly- three of four time points over an 18-months period using a genic association in UHR individuals. Particularly, greater comprehensive phenotyping battery. The subsample used in genetic risk for MDD or genetic risk of schizophrenia accom- this study comprised a total of 379 participants (45.0 ±12.7 panied with past depression comorbid diagnosis was associ- yrs; 46.2% female) with DSM-IV diagnoses of SCZ, SZA or ated with risk for UHR status. These results suggest identifi- BD. Peripheral blood DNA samples were genotyped using cation of UHR individuals with comorbid diagnosis of depres- Illumina’s Infinium PsychArray and imputed using the 1000 sion could aid in the prioritising of clinical care delivery. genomes Phase3 data. SCZ-PRS were calculated using PLINK 1.07. Effect sizes and P-values were determined utilizing Disclosure: Nothing to disclose. the PGC2 SCZ summary results as a discovery sample. A set doi: 10.1016/j.euroneuro.2018.08.346 of 67 longitudinally measured variables derived from the Positive and Negative Syndrome Scale (PANSS), the Inven- tory of Depressive Symptoms (IDS) and the Young Mania Rat- ing Scale (YMRS) entered the cluster analyses. SA125 Factor analysis for mixed data (FAMD) was applied to com- POLYGENIC BURDEN ANALYSIS OF LONGITUDINAL pute abstract data dimensions, which were then used to de-

CLUSTERS OF PSYCHOPATHOLOGICAL FEATURES IN rive longitudinal trajectories for each of the psychopathol-

A CROSS-DIAGNOSTIC GROUP OF INDIVIDUALS WITH ogy scales. Trajectories on the first dimension were used SEVERE MENTAL ILLNESS as inputs for flex mix clustering. This yielded five distinct subpopulations. Identified clusters were then employed in a 1 2 3 Eva Schulte , Ivan Kondofersky , Monika Budde , linear regression model as predictive variables for SCZ-PRS 4 5 Kristina Adorjan , Fanny Aldinger , at 11 thresholds. 6 7 5 Heike Anderson-Schmidt , Katrin Gade , Urs Heilbronner , Results: The strongest loadings were observed for items 5 5 2 Janos Kalman , Sergi Papiol , Fabian J. Theis , N1 to N4 on PANSS, item 5 on IDS, and items 2 and 6 on 8 2 9 Peter Falkai , Nikola Müller , Thomas G. Schulze YMRS. Five clusters of longitudinal trajectories were identified in the psychopathologic dimensions. Clusters differed

1 Institute for Psychiatric Phenomics and Genomics, Ludwig signiﬁcantly with regard to Global Assessment of Function- Maximilian Universität, Munich ing (GAF; all clusters), disease course (OPCRIT item 90; all

2 Institute of Computational Biology, Helmholtz Zentrum clusters), and diagnosis (one cluster) while there were no Munich signiﬁcant differences regarding sex, age at baseline, age

3 Institute for Psychiatric Phenomics and Genomics, Univer- at onset, or duration of illness. Cluster membership was not sity Hospital, LMU Munich signiﬁcantly associated with the SCZ-PRS.

4 Institute for Psychiatric Phenomics and Genomics Discussion: Although the results are preliminary and have

5 Institute of Psychiatric Phenomics and Genomics (IPPG), to be interpreted with caution, the approach of longitudi- Medical Center of the University of Munich nal clustering to identify cross-diagnostic homogeneous sub-

6 University Medical Centre Goettingen ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 71 groups of individuals appears to be feasible. The fact that explained by SNPs in different functional categories, in- more severe psychopathological features were not associ- cluding H3K27ac, H3K4me3, and H3K4me1 region etc. Using ated with increased polygenic genetic risk burden for SCZ SMR, we identified 22 casual genes for schizophrenia in a will also be interesting to explore further. cell-specific manner. For example, ZKSCAN3 in neuron etc. Discussion: We extracted cell type-specific expression from Disclosure: Nothing to disclose. bulk brain tissues and examined the cell-specific alternation in psychiatric disorders regarding cell composition, gene ex- doi: 10.1016/j.euroneuro.2018.08.347 pression, genetic regulation and their functional variation. These findings provide new insights into cell-specific molecular alterations in SCZ and BD. SA126 CELL TYPE-SPECIFIC ALTERNATION IN SCHIZOPHRENIA Disclosure: Nothing to disclose. AND BIPOLAR DISORDER doi: 10.1016/j.euroneuro.2018.08.348

Rujia Dai 1, Lulu Chen 2, Sihan Liu 1, Yu Chen 1, Jiacheng Dai 1,

Guoqiang Yu 2, Yue Wang 2, Chao Chen 1, Chunyu Liu 3 SA127

1 Central South University THE ASSOCIATION OF FRAGILE X MENTAL RETARDATION

2 Virginia Polytechnic Institute and State University PROTEIN TARGETS WITH PSYCHIATRIC DISORDERS

3 SUNY Upstate Medical University

Nicholas Clifton 1, Elliott Rees 2, Peter Holmans 3, 3 3 4 Background: Cell type diversity is the basis of complex James Walters , Michael O’Donovan , Michael Owen , 3 3 brain functions, also psychiatric disorders. However how Jeremy Hall , Andrew Pocklington these cell types are involved in psychiatric pathogenesis is largely unknown. Moreover, they are often confounded by 1 Cardiff University School of Medicine each other in studies using bulk tissue of postmortem brain. 2 MRC Centre for Neuropsychiatric Genetics and Genomics, By separating cell types for each postmortem brain samples Institute of Psychological Medicine and Clinical Neuro- computationally, we revealed the distinct role of different sciences, Cardiff University cell types in psychiatric disorders. 3 Cardiff University

Methods: We used bulk tissue RNA-Seq data of 413 pre- 4 MRC Centre for Neuropsychiatric Genetics and Genomics, frontal cortex samples including healthy controls and pa- Cardiff University tients with schizophrenia (SCZ) and bipolar disorder (BD) from PsychENCODE/BrainGVEX project. We applied a novel Background: Fragile X mental retardation protein (FMRP) method called ‘sCAM’ to deconvolute the expression pro- binds selected mRNA species and represses their transla- file of bulk tissue into the cell-specific expression profile for tion. In the brain, FMRP is dynamically expressed in neurons each sample. With that, we constructed co-expression net- where it regulates the dendritic synthesis of a range of pro- works for each cell type and further tested their relevance teins, many of which are modulators of synaptic plasticity. to the disease using MAGMA and trait association. By Inte- The loss of FMRP function causes Fragile X syndrome, whilst grating genotype data, we identified cell-specific eQTLs and genetic variants affecting the targets of FMRP are strongly estimated their heritability in SCZ GWAS through LD score associated with polygenic psychiatric disorders, including regression (LDSR). Further, we applied stratified LDSR to schizophrenia and autism. However, it is not clear whether partition the estimated heritability explained by different this latter association is truly related to binding by FMRP or functional categories of each cell type. Lastly, we identified mediated by the sampling of genes better characterised by possible causal genes for SCZ using Summary-data-based another trait, such as neuronal expression or gene length. Mendelian Randomization (SMR) in a cell-specific manner. With the aim of disentangling this dichotomy, we explored Results: We generated the cell-specific expression and the relationship between the confidence of FMRP binding the proportion of astrocyte, microglia, neuron, and oligo- and the genetic association with schizophrenia and related dendrocyte for each sample. We found the proportions of disorders. microglia and oligodendrocytes increased in patients’ brains Methods: All protein coding genes were ranked by FMRP while the proportion of neuron decreased. After construct- binding probability, derived from a study of mRNA-FMRP ining co-expression networks, we identified nine cell-specific teraction sites in mouse cortical polyribosomes, and split modules and they were enriched in pathways such as RNA into bins of 400 genes. Each bin was subjected to gene splicing and mitochondrion (astrocyte), and phosphorylation set enrichment analysis for association with schizophrenia, and calcium (neuron), cytokine (microglia), and myelination major depressive disorder (MDD), bipolar disorder (BD) and (oligodendrocyte). All these nine modules showed disease- Alzheimer’s disease (AD), using published genotype data. related alternations or enrichment of GWAS signal. We Since FMRP targets represent transcripts that are dispro- identified over 12 million cell-type related eQTLs, in which portionately long, analyses were performed controlling for only ∼5% were shared across cell types and ∼62% were cell- gene length and single nucleotide polymorphism (SNP) den- specific. Using LDSR, we observed SNPs of oligodendrocyte- sity. Secondary enrichment analyses were performed on eQTLs explained the most heritability for schizophrenia subsets of FMRP targets divided by gene function. GWAS summary statistics (h2 = 0.6). Furthermore, we found Results: We observed a clear relationship between FMRP in different cell types, the genetic heritability can be binding confidence and enrichment for association with ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 72 Abstracts schizophrenia through common and rare genetic variation, recruitment visits, especially for history of psychotic disor- beyond that which could be explained by gene length. Fol- der. lowing Bonferroni correction, only the top two bins remained significantly enriched for association. Dividing the Disclosure: Nothing to disclose. top FMRP targets into synaptic and non-synaptic revealed doi: 10.1016/j.euroneuro.2018.08.350 that the association signal was concentrated within synaptic FMRP targets. In a cross-disorder analysis, we observed that, like schizophrenia, only the top two bins of FMRP targets were enriched for association with MDD and BD, whilst no SA129 bins showed genetic association with AD. Interestingly, the THE ROLE OF LONG INTERSPERSED ELEMENT-1 RETRO- association signal for BD exhibited no bias towards synaptic TRANSPOSONS IN SCHIZOPHRENIA or non-synaptic FMRP targets. 1 1 1 Discussion: This study provides evidence that FMRP targets Benjamin Reiner , Glenn Doyle , Richard Crist , 1 1 represent a discrete functional set of genes strongly impli- Rachel Levinson , Esin Namoglu , 1 2 cated in schizophrenia, MDD and, for the first time, BD, Gabriella Arauco-Shapiro , Rashed Nagra , 3 4 rather than being a proxy for large neuronally-expressed Gustavo Turecki , Cyndi Shannon Weickert , 5 1 genes. Of particular note is the division of genetic associa- Thomas Ferraro , Wade Berrettini tion between synaptic and non-synaptic FMRP targets across disorders, which acts to dissociate schizophrenia and MDD 1 University of Pennsylvania from BD. 2 West Los Angeles VA Medical Center

3 McGill University

Disclosure: Nothing to disclose. 4 Neuroscience Research Australia

5 Cooper Medical School of Rowan University doi: 10.1016/j.euroneuro.2018.08.349

Background: Schizophrenia (SZ) is a neurodevelopmental, partially inherited, chronic psychotic disorder effecting 0.5 –1.0% of the population. While current antipsychotic medications can treat the positive symptoms of SZ, including hal-

SA128 lucinations and delusions, there is no FDA-approved therapy

PSYCHIATRIC FAMILY HISTORY AND PSYCHOTIC DIS- for the negative symptoms of SZ, including apathy, avoli- ORDER IN THE MILITARY tion and poverty of thought. Despite evidence that the heritability of SZ is ∼64%, the identification of common alle- Nassim Arfi, Ramzi Tahri, Bakhta Bensatal, Saida Belala, les, via leukocyte DNA, with even a moderate increase in Toufik Merzelkad the risk for SZ has proven difficult. Therefore, alternative approaches to identifying genetic variants associated with Algiers University SZ are needed. We examined the role of neuronal polymorphic and somatic mutation, mediated by long interspersed Background: The stress in the army plays a preponderant element-1 (LINE1 or L1) retrotransposons, a type of mobile role in the occurrence and the expression of mental disor- DNA element, with the potential of disrupting genes, in in- ders in the predisposed individuals. Family history of mental creasing the risk for developing SZ. disorders, like other risk factors, predisposes some people Methods: DNA was isolated from NeuN + dorsolateral pre- to developing mental disorders when they are exposed to frontal cortex (DLPFC) neuronal nuclei from 63 SZ persons military-related constraints. and 63 age, sex and ethnicity matched controls. L1 spe- Methods: the main objective of the study is to evaluate the cific DNA was amplified using PCR, and L1 amplicons were frequency of mental disorders justifying hospitalization at subject to next generation sequencing. Sequence data was the mental health ward of the Army Central Hospital, and aligned to the human reference genome to identify neu- to correlate them with the absence or the presence of a ronally expressed genes with L1 insertions, and bioinformat- family psychiatric history in the first-degree relatives. ics was used to determine the relevant biological pathways. The study included 249 hospitalized soldiers who under- Results: Bioinformatics identified the genomic position of went a multiaxial evaluation of the DSM-IV-TR. Their fam- both reference and novel L1 retrotransposon insertions. In- ily psychiatric history was researched using a questionnaire sertions specifically relevant to SZ and controls were iden- which adapted from Family History Screening. tified. Both reference and novel L1 retrotransposons were Results: Adjustment disorders are the most common mental found among the SZ DLPFC tissues in genes known to be re- disorders. Mood disorders and psychotic disorders are each lated to SZ, including, ZRANB2, CSMD1, PTPRD, KIDIN220, found in nearly one-quarter of the subjects in the study. RAPGEF6, B3GAT2, NALCN and STK32B. Independent PCR These three categories of disorders represent the main di- confirmations are ongoing, with current evidence suggest- agnosis in nearly 90% of patients in our cohort. A family ing these novel L1 insertions are germline, as opposed to psychiatric history is present in 17% of the patients in the somatic. Database for annotation, visualization, and inte- study. Our results showed significant statistical correlations grated discovery (DAVID) gene ontologies showed SZ-specific between psychotic disorders and family psychiatric history. enrichments, including the terms neuron projection, neu- Discussion: These results highlight the importance of sys- ronal cell body, presynaptic membrane, and calcium ion tematically searching for family psychiatric history during transmembrane transport. ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 73

Discussion: These results extend and conﬁrm previous GWAS factors present for that participant. We computed individ- reports and case/control studies of SZ susceptibility alleles uals’ polygenic risk scores according to standard methods. in multiple calcium ion channel subunit genes. The prelim- Population principal components were calculated and used inary observations of L1s in SZ risk genes (ZRANB2, CSMD1, as covariates in all analyses. PTPRD, KIDIN220, RAPGEF6, B3GAT2, NALCN and STK32B) We then conducted a linear regression using PRS as the may expand the nature of risk alleles in these genes beyond independent variable, and ERS as the dependent variable to those detected by GWAS. Taken together, our preliminary address our main research question. We conducted analyses results suggest that L1 retrotransposons may contribute to using standard training set p value thresholds (p < 5 × 10-8, the etiology of SZ. p < 0.05, p < 0.5). Results: Our analysis, restricted to those genetic risk al- Disclosure: Nothing to disclose. leles that are genome-wide signiﬁcant for schizophrenia, indicates the polygenic score for those genetic variants doi: 10.1016/j.euroneuro.2018.08.351 is positively correlated with our poly-environmental score (B = 7.050, p = 0.030). Discussion: Our results indicate a direction of effect that

SA130 is contrary to our primary hypothesis, in that we found

USING POLY-ENVIRONMENTAL RISK SCORING TO ASSESS a weakly positive correlation between ERS and PRS (at WHETHER PEOPLE WITH KNOWN PSYCHOSES HAVE genome-wide significant p value threshold). These results DIFFERENCES IN POLYGENIC RISK SCORING indicate that the genetic risk scores of genome wide significant schizophrenia alleles are positively but weakly asso- Annabelle Hook, Antonio F. Pardiñas, James T. R . Walters ciated with cumulative score of environmental risk factor exposure. These results are hypothesis generating and have Cardiff University led us to revise our original hypothesis for future testing and replication in larger sample sizes to give greater statistical Background: There is established evidence that risk of de- power. Nonetheless the results raise interesting and impor- veloping psychoses is increased in individuals exposed to a tant questions regarding the relationship between genetic range of environmental factors such as obstetric complica- and environmental risk factors for psychosis. tions, adverse life events including child abuse and urban upbringing. Analyses using measures of combined genetic Disclosure: Nothing to disclose. risk (polygenic risk scores (PRS)) have provided novel in- doi: 10.1016/j.euroneuro.2018.08.352 sights into psychiatric disorders in recent years and methods for calculating this polygenic risk score are now well established. SA131 Methods: We sought to build on the PRS methodology to compute a corresponding environmental risk factor score, A MASSIVELY PARALLEL REPORTER ASSAY FOR in order to examine the relationship between genetic and VARIANTS ASSOCIATED WITH SCHIZOPHRENIA AND environmental exposures. Building on the PRS methods we ALZHEIMER’S DISEASE developed an environmental risk score (ERS) mirroring the methodology used for PRS. We aimed to use this score to in- Dimitrios Avramopoulos, Leslie Myint, Kasper Hansen, vestigate the relationship between the poly-environmental Ruihua Wang, Leandros Boukas, Loyal Goff and polygenic risk scores. Given the liability threshold model of schizophrenia, our hypothesis was that the two Johns Hopkins University scores would be inversely correlated in that those with elevated PRS might have a lower ERS. Background: Numerous loci for complex disorders including We performed a literature search using MEDLINE, PUBMED schizophrenia (SZ) and Alzheimer’s disease (AD) have been and EMBASE to identify the most up-to-date meta-analyses reported by recent Genome wide association studies (GWAS) of well-evidenced environmental risk factors for schizophre- Like in most GWAS, the disease-associated variants are lo- nia. From each meta-analysis we documented the odds ratio cated outside protein coding regions and hypothesized to and confidence interval. Mirroring how the polygenic score differentially affect the transcription of nearby genes. is derived, we took the natural logarithm of the odds ra- Methods: To test for loci that support this hypothesis we sys- tio to weight the score for each risk factor if present, oth- tematically assayed 1083 variants in these loci with a Mas- erwise recording 0 for that risk factor. These risk factors sively Parallel Reporter Assay (MPRA) and. Specifically, we were added to give a poly-environmental score. The envi- investigated all variants in high LD with lead variant in 71 SZ ronmental risk factors used were: urban upbringing, sea- and 8 AD. For each we designed a 95 bp sequence centered son of birth, paternal age, obstetric complications, cannabis on the variant and linked it to 5 distinct barcodes, includ- use, life events, physical and sexual childhood abuse and ing positive and negative controls. We generated a plasmid head injury. library using standard protocols, with final oligo represen- We applied this method to the Cardiff COGS dataset tation of 80% (85% of alleles represented by ≥ 3 oligos) and of individuals with a DSM IV research diagnosis of transfected it 3 independent times into K562 chronic myel- schizophrenia (n = 552) and computed each individual’s ogenous leukemia Lymphoblasts (chosen because we have poly-environmental risk score. Each participant’s poly- observed maximum overlap of open chromatin with SZ loci) environmental score was then divided by the number of risk and another 6 independent times into SK-SY5Y human neu- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 74 Abstracts roblastoma cells. We extracted RNA and DNA and made li- of schizophrenia risk alleles and alleles that influence braries for sequencing on a mySEQ sequencer. cognitive ability in the general population. Results: On average, ∼80% of barcodes were represented Methods: Aggregate genetic risk to a disorder or trait for an in DNA and ∼70% in RNA. Activity level in each cell line individual can be measured as a polygenic risk score, which were concordant with its specific digital genomic footprint- is essentially an additive sum of risk alleles in an individual ing, adding validity to our results. We identified 151 SNPs genome, weighted by effect size. We used the general in- showing significant allelic differences in the K562 cells and telligence factor g as a broad measure of cognitive ability 54 in the SK-SY5Y cells with an average of 2.3 such SNPs per in schizophrenia cases, as it is robust to differing cognitive locus and a median of 1. The presence of multiple regula- tests across samples. tory variants in LD in each locus suggests complex regulation We examined the relationship between g and PRS for and potential selection of haplotypes that combine specific EA, population IQ, schizophrenia, bipolar disorder and ma- regulatory alleles. We do not observe any direction prefer- jor depressive disorder in 2825 schizophrenia case samples ence (increased or decreased enhancer activity) for risk vs. from the Psychiatric Genomics Consortium (PGC). PRS and non-risk alleles. g were calculated in 10 subsamples of the PGC data, their Discussion: Our results will be useful for determining the values analyzed with linear regression in R (covarying for driver variant(s) and and guiding functional follow up of dis- age, sex and population principal components), and the re- ease associated loci. sults meta-analyzed using the meta package in R. A common variant GWAS of g was also conducted in schizophrenia cases Disclosure: Nothing to disclose. in these subsamples. Results: No significant relationship was found between doi: 10.1016/j.euroneuro.2018.08.353 cognitive performance (g) in schizophrenia cases and PRS for schizophrenia (p = 0.38), bipolar disorder (p = 0.82) or major depression (p = 0.46). However, a significant positive association was found between g and both popula-

SA132 tion IQ (p = 4.08 × 10-7) and educational attainment PRS THE RELATIONSHIP BETWEEN POLYGENIC RISK SCORES (p = 1.87 × 10-4). No individual variant approached genome- AND G IN PGC2 SCHIZOPHRENIA CASES wide significance in the GWAS of g in schizophrenia cases. Discussion: Cognition in schizophrenia cases is more heavily 1 1 1 Alexander Richards , Aura Frizzati , Antonio Pardinas , affected by PRS that index cognitive traits in the general 1 2 3 Katherine Tansey , Gary Donohoe , Aiden Corvin , population than PRS that index neuropsychiatric disease. 4 5 6 7 Roel Ophoff , Dan Rujescu , Patrick Sullivan , Jim Van Os , This suggests that the mechanisms that underlie cognitive 8 9 10 Ole Andreassen , Jana Strohmaier , Stephan Ripke , deficits in schizophrenia are at least partly independent 1 1 Michael O’Donovan , James Walters from those that predispose to schizophrenia diagnosis itself. Our findings indicate that the variation in cognitive impair-

1 Cardiff University ment seen in those with schizophrenia can be attributed, at

2 National University of Ireland Galway least in part, to genetic factors shared with cognitive per-

3 Trinity College Dublin formance in populations and is not solely due to illness or

4 UCLA Center for Neurobehavioral treatment related factors.

5 University of Halle Furthermore, the results suggest that efforts to elucidate

6 University of North Carolina at Chapel Hill the underlying genetics and biology of cognitive functioning

7 Maastricht University Medical Centre are likely to provide insights directly applicable to cognitive

8 University of Oslo impairments in schizophrenia. Similarly, our results suggest

9 Central Institute of Mental Health that interventions that impact cognitive functioning in pop-

10 MGH ulation samples are likely to benefit the cognitive profile of those with schizophrenia. Background: Cognitive impairment is a clinically important feature of schizophrenia but is not significantly impacted Disclosure: Nothing to disclose. by current treatments. The causes of impaired cognition in doi: 10.1016/j.euroneuro.2018.08.354 schizophrenia are not known. However, as it occurs prior to disorder onset and in the healthy relatives of schizophrenia cases, it is possible that it may have a genetic aetiology, consistent with the neurodevelopmental hypothesis of the disorder. Genome-wide association studies (GWAS) have shown that both IQ and educational attainment (EA) in the general population show heritability due to common genetic variation. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder, depression, EA and IQ, but very few studies have examined the cognitive effect of these PRS within schizophrenia cases. We were interested in establishing the relative contributions to variance in cognition in schizophrenia ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 75

SA133 SA134 GENETIC PREDICTION OF TRANSITION FROM CHILD- POLYGENIC INFLUENCES ON ALCOHOL RELATED NEU- HOOD AND ADOLESCENT PSYCHIATRIC DISORDER TO ROPHYSIOLOGICAL AND NEUROCOGNITIVE PROCESSES SCHIZOPHRENIA ACROSS THE LIFESPAN

Sonja LaBianca 1, Vivek Appadurai 2, Wesley Thompson 2, Jacquelyn Meyers 1, Emma Johnson 2, Jessica Salvatore 3,

Merete Nordentoft 3, iPSYCH-BROAD Working Group 4, Fazil Aliev 4, Ashwini Pandey 1, Chella Kamarajan 1, COGA

Thomas Werge 2, Alfonso Buil 5 Collaborators, John Nurnberger 5, Victor Hesslebrock 6,

Andrey Anokhin 7, Tatiana Foround 8, Jay Tischﬁeld 9,

1 Research Institute of Biological Psychiatry, Mental Health Danielle Dick 3, Arpana Agrawal 7, Bernice Porjesz 1 Centre Sct. Hans

2 Institute of Biological Psychiatry, MHC Sct. Hans, Mental 1 SUNY Downstate Medical Center

Health Services - Copenhagen 2 Washington University in St. Louis

3 Mental Health Centre Copenhagen, University of Copen- 3 Virginia Commonwealth University hagen 4 Virginia Commonwealth University, Karabuk University

4 iPSYCH-BROAD 5 Indiana University School of Medicine

5 Institute for Biological Psychiatry 6 University of Connecticut

7 Washington University School of Medicine

Background: Prodromal signs of schizophrenia (SCZ) can 8 Indiana University present during childhood and adolescents, though they can 9 Rutgers, The State University of New Jersey be difficult to distinguish from mental disorders of childhood and adolescents (C/A). A previous study in the Danish Na- Background: Multimodal studies of brain function (neu- tional health registers show an increases risk of SCZ within rophysiological, neuropsychological, neuroimaging) have the first 8 years after onset of C/A, 8.74% in individuals with identified specific functional and structural deficits in neu- C/A onset at ages 14-17 and 1.68% in individuals with C/A ral circuits (i.e., neural biomarkers) in individuals with al- onset at ages 0-13. Genetic risk factors, including both rare cohol use disorders (AUD) as well as those at risk–pointing and common variants as well as family history of mental dis- to dysfunctional bottom-up reward processing, top-down in- orders have been associated with increased risk SCZ. In this hibitory control networks, and interactions between cog- study we hypothesized that genetic risk factors can predict nitive, affective and frontal executive networks. Neural transition from C/A to SCZ. biomarkers alongside clinical and behavioral data can be Methods: The iPSYCH cohort consist of ∼80000 individu- used to further understanding of how recent GWAS findings als born in Denmark from 1981 to 2005. All the cases with may lead to aberrant brain or neurocognitive functioning at least one of the major mental disorders (schizophre- and have an important role in addiction and related out- nia, bipolar disorder, major depression, anorexia, autism comes. and attention deficit and hyperactivity disorder) were in- Methods: 12,145 individuals (from 1,815 multigenerational cluded ( ∼50000 individuals). The remaining 30000 are a ran- families) from the Collaborative Study on the Genetics of dom sample form the same population. We examined com- Alcoholism, including those densely affected with AUD, suc- mon genetic variants by calculating polygenic risk scores cessive generations of these extended families, and com- for schizophrenia (PRS_SCZ) for the iPSYCH individuals us- parison families, have been studied extensively across mul- ing summary statistics from the PGC2 GWAS for SCZ exclud- tiple domains: clinical, behavioral, neurophysiological, neu- ing Danish samples. We used survival analysis (Kaplan-Maier rocognitive, and genomic. We examined how polygenic risk plots and cox regression) to test if individual polygenic risk scores (PRS) derived from recent GWAS of addiction and re- scores prediction for schizophrenia (SCZ_PRS) is significantly lated neurocognitive outcomes (e.g., Psychiatric Genomics associated with the risk of transition from C/A to SCZ. Consortium GWAS of alcohol dependence, UK Biobank GWAS Results: Within the iPSYCH cohort we identified 26879 in- of alcohol consumption, UK Biobank GWAS of fluid intelli- dividuals with at least one C/A disorder and current age gence, ENIGMA GWAS of intracranial volume) relate to as- above or equal to 18. Among them 2566 (10%) transit onto pects of neurophysiological (neural oscillatory activity mea- SCZ_broad (F20-29) and 1469 (5%) SCZ_narrow (F20). We ob- sured in the resting state and during cognitive tasks) and tained a hazard ratio of 1.1467 (CI: 1.09-1.20) for PRS_SCZ neuropsychological functioning that have been previously and 1.263 (CI: 1.2-1.4) for any mental health disorder in one shown to differ among those with AUD and at-risk for AUD. or both parents, adjusted for current age, sex, C/A diagnosis Results: Preliminary evidence indicates that both alcohol and onset of C/A diagnosis indicating that both carry infor- use/problem and neurocognitive PRS predicted alcohol re- mation about the risk of an individual to transition from C/A lated neurocognitive functioning in COGA participants, with to SCZ. Analysis of rare genetic variants is ongoing. stronger associations observed for neurocognitive PRS (e.g., Discussion: Potentially, positive results could suggest ge- fluid intelligence PRS) than for alcohol related PRS (e.g., netic testing as a tool for outcome prediction and initiation alcohol consumption and alcohol dependence PRS). In ad- of early intervention in relevant cases. dition, preliminary findings show that associations observed among UKBB alcohol consumption PRS and AUD in COGA are Disclosure: Nothing to disclose. partially explained by frontal-related neural oscillations and that associations observed between UKBB fluid intelligence doi: 10.1016/j.euroneuro.2018.08.355 ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 76 Abstracts

PRS and AUD in COGA are partially explained by neuropsy- model (hsa-miR-9-1, hsa-miR-153-1 and hsa-miR-124-3) are chological task performance (Tower of London Task). nominally associated with cocaine dependence in a case- Discussion: From this data, we can conclude that neural control study. biomarkers can be used to further understanding of how ge- Discussion: We highlighted novel miRNAs that may be in- netic risk variants from large GWAS may relate to AUD and volved in cocaine-induced changes of gene expression that related behavior. It is crucial to further understanding of underlie addiction. Moreover, we identiﬁed genetic variants how genetic variants relate to addictive behaviors to push that contribute to cocaine dependence in three of these this research closer to molecular understanding and ulti- miRNA genes, supporting the idea that genes differentially mately clinical translation. expressed under cocaine may play an important role in the susceptibility to cocaine dependence. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.356 doi: 10.1016/j.euroneuro.2018.08.357

SA135 MIR-9, MIR-153 AND MIR-124 ARE DOWN-REGULATED BY COCAINE IN A DOPAMINERGIC CELL MODEL AND SA136 CONTRIBUTE TO COCAINE DEPENDENCE EXPLORING THE RELATIONSHIP BETWEEN POLYGENIC RISK FOR CANNABIS USE, PEER CANNABIS USE, AND

Judit Cabana-Domínguez 1, Concepción Arenas 2, THE LONGITUDINAL COURSE OF CANNABIS INVOLVE-

Bru Cormand 3, Noèlia Fernàndez-Castillo 3 MENT

1 University of Barcelona, Institut de Biomedicina de la Uni- Emma Johnson 1, Collaborative Study on the Genetics of versitat de Barcelona (IBUB), Institut de Recerca Sant Joan Alcoholism 2 de Déu (IR-SJD), Esplugues de Llobregat

2 University of Barcelona 1 Washington University in St. Louis

3 University of Barcelona, Centro Nacional de Investigación 2 Washington University School of Medicine Biomédica en Red de Enfermedades Raras (CIBERER), In- stituto de Salud Carlos III, Institut de Biomedicina de la Background: Few studies have explored how polygenic Universitat de Barcelona (IBUB), Catalonia, Institut de Re- propensity to cannabis use unfolds across development, and cerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat, no studies have yet examined this question in the context of Catalonia environmental factors such as peer behavior. Using a polygenic risk score (PRS) approach, we sought to fill this gap Background: Cocaine is one of the most used psychostim- in the literature by addressing the following question: what ulant drugs worldwide. In a previous study we identified is the relationship between genetic propensity for cannabis genes showing differential expression in a dopaminergic use, perceived peer cannabis use (ages 12-17), and longitu- neuron-like model after an acute exposure to cocaine. The dinal trajectories of cannabis use from ages 12-30? aim of the present study is to identify miRNA molecules dif- Methods: PRS were created using summary statistics from a ferentially expressed in these cells that can be involved in large (N = 32,330) published genome-wide association study the regulation of these genes. (GWAS) of cannabis use. Multinomial logistic and linear re- Methods: We performed a “miRNA target analysis” with the gressions were used to examine associations between the online tool WebGestalt to identify enrichment of miRNA PRS, cannabis use trajectory membership (derived from past binding sites among the differentially expressed protein- year cannabis use frequency over 2-6 follow-up interviews), coding genes. Thus, eleven miRNA were selected and its and perceived peer cannabis use (at ages 12-17), accounting expression assessed by qRT-PCR in neuron-like cells 3 or 6 for familial clustering, in the longitudinal component of the hours after an acute exposure to cocaine 5 μM. The differ- Collaborative Study on the Genetics of Alcoholism (COGA) entially expressed miRNAs were subjected to: i) analysis of study target sample (N = 1,167). We also tested whether gene networks using the Ingenuity Pathway Analysis 8.8 soft- peer use acts as a moderator (via an interaction) or a me- ware, and ii) gene-based association analysis with MAGMA diator (through a path model) of the relationship between 1.05b, using the summary statistics of a GWAS meta-analysis the PRS and cannabis use trajectory membership. of cocaine dependence that includes 2,085 cases and 4,293 Results: Three trajectories reflecting low (n = 846), moder- controls, performed by us from different dbGaP datasets. ate (n = 138) and high (n = 183) cannabis use over time were Results: We found that seven of the selected miRNAs identified. We found that the cannabis PRS were nominally were down-regulated by cocaine: miR-124-3p, miR-124-5p, associated with trajectory membership (p = 0.022), but, sur- miR-137, miR-101-3p, miR-9-5p, miR-369-3p, miR-153-3p. prisingly, more strongly associated with peer cannabis use Gene network analysis revealed that all these miRNAs (p = 0.002). Perceived peer cannabis use explained 13.2% of were present and highly interconnected in a network in- the variance in trajectory class membership, while the PRS volved in “Cell-To-Cell Signaling and Interaction, Nervous explained 0.4% of the variance in the trajectories. There System Development and Function, Inflammatory Disease” was no evidence that peer cannabis use moderated the (Score = 21). Furthermore, we found that three of the relationship between the PRS and cannabis use trajecto- miRNA genes that were differentially expressed in our ries; rather, we found that perceived peer cannabis use ap- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 77 peared to fully mediate the association between the PRS observations (i.e., partners nested within dyads). This mod- and cannabis trajectory membership. eling approach accounts for the correlations between part- Discussion: Even as GWAS sample sizes grow and the predic- ners’ polygenic scores (i.e., assortative mating) as well as tion accuracy of PRS increases, environmental factors such the residual correlation between partners’ ADsx measures. as peer use continue to explain substantially more varia- Results: Males and females endorsed an average of 2.01 tion in many complex traits. In this particular cohort study, and 0.71 ADsx, respectively. Spouses modestly but signifi- polygenic scores for cannabis use were more strongly asso- cantly resembled one another in their ADsx (r = 0.11, p < ciated with peer use than with an individual’s own cannabis 0.01) and in their EduYears-GPS (r = 0.11, p < 0.01). Indi- use trajectory, suggesting that environmental factors such viduals with higher EduYears-GPS had fewer ADsx (beta = as peer influence have genetic underpinnings and remain −0.09, p < 0.01). After accounting for the effects of one’s stronger correlates of cannabis use than current genomic own polygenic score, and the correlations between part- predictors. ners’ polygenic scores, we found that having a spouse with a higher EduYears-GPS was associated with having fewer ADsx Disclosure: Nothing to disclose. (beta = -0.07, p < 0.01). As expected, no such effects were observed for height, our negative control phenotype. doi: 10.1016/j.euroneuro.2018.08.358 Discussion: In married couples from a high-risk sample, spouses modestly resembled one another in their alcohol dependence diagnostic criterion counts and in their edu-

SA137 cational attainment polygenic scores. Participants who had SOCIAL GENETICS EFFECTS ON ALCOHOL DEPENDENCE higher educational attainment polygenic scores or who had IN MARITAL DYADS a spouse with a higher educational attainment polygenic score met fewer alcohol dependence criteria. Our ﬁndings 1 1 1 Jessica Salvatore , Peter Barr , Sally I-Chun Kuo , underscore the potential importance of social genetic ef- 1 2 3 Jinni Su , Laura Almasy , Andrew Brooks , fects for understanding the pathways from genotype to al- 4 5 6 Kathleen Bucholz , Michael Chao , Howard Edenberg , cohol use disorder phenotype.

Tatiana Foroud 6, Victor Hesselbrock 7, John Kramer 8,

John Nurnberger 6, Samuel Kuperman 9, Danielle Dick 1 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.359 1 Virginia Commonwealth University

2 Children’s Hospital of Philadelphia

3 Rutgers, The State University of New Jersey

4 Washington University School of Medicine SA138

5 Icahn School of Medicine at Mount Sinai INVESTIGATING BI-DIRECTIONAL, CAUSAL EFFECTS

6 Indiana University School of Medicine BETWEEN SUBSTANCE USE AND ADHD

7 University of Connecticut Health

8 University of Iowa Carver College of Medicine Jorien Treur, Hannah Sallis, Marcus Munafo

9 University of Iowa University of Bristol Background: The current paradigm for characterizing genetic influences on alcohol use disorders (AUDs) focuses on Background: There is a strong observational link between direct genetic effects, which refer to the influence of one’s substance use and Attention-Deficit Hyperactivity Disorder own genotype on AUDs. Yet, the assumption that only direct (ADHD). Addictive substances (including nicotine, alcohol genetic effects are involved in AUDs is at odds with pre- and cannabis) are used at higher rates among individuals clinical evidence from mouse models that suggests a social who are diagnosed with ADHD, and individuals who show partner’s genotype accounts for 9-18% of the variation in high levels of attention problems and/or impulsivity. While health-related behaviors, including addiction-related out- it is most often assumed that this is because ADHD symptoms comes like stress and anxiety. The goal of this project was lead to (heavier) substance use, there is also compelling ev- to examine social genetic effects on alcohol dependence in idence for causal effects in the other direction – from sub- humans, specifically in the context of marital relationships. stance use to symptoms of ADHD. To interrogate the causal Methods: The sample included 645 opposite-sex spousal nature of these associations, we applied Mendelian random- dyads (n = 1290 individuals) of European ancestry from the ization (MR) analyses. Collaborative Study on the Genetics of Alcoholism. The out- Methods: Summary-level data were available from come was a log-transformed count of DSM-IV alcohol depen- large genome-wide association (GWA) studies on ADHD dence criteria (ADsx). We also examined height as a nega- (N = 55,374), smoking (initiation, N = 632,783; cigarettes per tive control phenotype. Each spouse’s broad genetic predis- day, N = 263,952; cessation, N = 312,817), alcohol (drinks per position to ADsx was indexed using educational attainment week, N = 537,341) and cannabis (initiation, N = 162,082). To polygenic scores (EduYears-GPS). Educational attainment explore causal effects, genetic variants robustly associated was selected in view of its strong, negative genetic correla- with the proposed exposure variable (p-value threshold tion with alcohol dependence and other substance use dis- < 5 × 10-8) were identified to be used as an instrument. orders and the sample size of the corresponding discovery Estimates from individual genetic variants were combined GWAS. Analyses were fit with multilevel actor-partner inter- with Inverse Variance Weighted Regression (IVW) analysis. dependence models to account for the non-independence of We applied two sensitivity analyses which are more robust ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 78 Abstracts to possible violations of the assumptions underlying MR and disorganisation, grandiosity, anhedonia and parent-rated which rely on distinct, contrasting assumptions – Weighted negative symptoms) and regularity of tobacco use. Struc- Median Regression and MR-RAPS (Mendelian Randomization tural equation twin modelling was employed. For DNA-based using Robust Adjusted Profile). analyses, LD-score regression was used to estimate the ge- Results: We found strong evidence for causal effects of netic covariance. Summary statistics for PENS came from a ADHD on smoking initiation (IVW OR 1.07, 95% CI 1.04 to mega-analysis of three community samples of adolescents 1.10, p-value 1.7 × 10-5), cigarettes per day (IVW beta 0.04, (N = 6,297-10,098) and from UK Biobank (N = 336,067) for 95% CI 0.01 to 0.06, p-value 0.006) and smoking cessation smoking initiation. (IVW OR 0.97, 95% CI 0.95 to 0.99, p-value 0.005). We also Results: Tobacco use correlated positively and significantly found an increasing effect of ADHD on cannabis use initia- with paranoia, hallucinations and cognitive disorganisation tion (IVW OR 1.13, 95% CI 1.03 to 1.25, p-value 0.010). These (r = .15-.21, all p < .001) in the adolescent twin study. As- findings were confirmed by both sensitivity analyses, which sociations between tobacco use and grandiosity, anhedo- indicated similar strength and directions of effect, with sim- nia, and parent-rated negative symptoms were of insuffi- ilar statistical evidence. No clear evidence was found for cient magnitude to conduct twin modelling. Bivariate twin causal effects of ADHD on heaviness of alcohol use (IVW OR models showed that tobacco use and specific PEs (para- 0.99, 95% CI 0.96 to 1.03, p-value 0.741). noia, hallucinations and cognitive disorganisation) had sig- Discussion: Using MR analysis, we found strong evidence nificant positive genetic correlations (.37 -.45). Genetic in- that ADHD causally increases the odds of initiating smok- fluences accounted for most of the association between to- ing, the number of cigarettes smoked per day, the odds of bacco use and paranoia (84%) and cognitive disorganisation not being able to quit smoking and the odds of initiating (81%) and familial influences (genetic or shared environ- cannabis use. This emphasizes the importance of focussing ment) accounted for 80% of the association between to- on individuals who are diagnosed with ADHD or who show bacco use and hallucinations. LD-score regression indicated symptoms of ADHD in substance use prevention programs. significant genetic covariation between UK Biobank smok- Analyses testing causal effects in the other direction –from ing initiation with paranoia/hallucinations (.025; SE: .007; substance use to ADHD and related constructs of impulsivity p < .001), cognitive disorganisation (.028; SE: .008; p < .001) such as delay discounting –using both summary-level and and with parent-rated negative symptoms (.018; SE: .006; individual level data, are under way and results will be pre- p = .002) but not with anhedonia (p = .490). sented at the WCPG. Discussion: Using two different approaches, the association between tobacco use and specific PENS in adolescence was Disclosure: Nothing to disclose. partly attributed to shared genetic influences. Most smokers initiate tobacco use, a modifiable risk factor, during adoles- doi: 10.1016/j.euroneuro.2018.08.360 cence. Further analyses should seek to understand whether the overlapping genetic influences point toward causal or shared biological mechanisms underlying smoking and ado-

SA139 lescent PENS. GENETIC ASSOCIATION BETWEEN TOBACCO USE AND SPECIFIC PSYCHOTIC EXPERIENCES DURING ADOLES- Disclosure: Nothing to disclose. CENCE doi: 10.1016/j.euroneuro.2018.08.361

Wikus Barkhuizen 1, Oliver Pain 2, Mark Taylor 3,

Angelica Ronald 1 SA140

1 Birkbeck, University of London GENETIC RISK FACTORS OF ALCOHOL DEPENDENCE

2 Cardiff University AND ANTISOCIAL PERSONALITY DISORDER

3 Karolinska Institutet

Wenqianglong Li 1, Johan Thygesen 1, Andrew McQuillin 1, 1 2 Background: Psychotic experiences and negative symp- Nick Bass , Joel Gelernter tom traits (PENS), an early indication of increased risk of developing mental health disorders, are associated with 1 UCL tobacco use during adolescence. Past research has reported 2 Yale University School of Medicine significant twin and SNP heritabilities for both PENS and tobacco use. Here we apply both twin and DNA-based Background: Epidemiological studies and meta-analyses of approaches to estimate the degree of overlap in genetic twin and adoption studies have provided evidence that al- influences between PENS and tobacco use. We report the cohol dependence (AD) are highly heritable. Improved un- first twin study to explore the degree to which tobacco use derstanding of the genetic architecture will help elucidate and PENS share genetic and environmental influences in the neurobiology of AD and its sequelae. It has been sug- adolescence. Furthermore, we assess whether there is co- gested by laboratory research that AD is often comorbid variation in genetic liability to PENS and smoking initiation with mental disorders including antisocial personality dis- using genome-wide DNA-based data. order (ASPD). There is epidemiological evidence for shared Methods: For the twin study, participants in a community risk between ASPD and AD. Moreover, a family history of AD twin sample (n = 3787 pairs; M age = 16.16 years) reported is a risk factor for ASPD. However, little is known about the on their PENS (including paranoia, hallucinations, cognitive neurobiology of ASPD and how this relates to AD. Elucida- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] Abstracts 79 tion of the genetic relationship between these disorders is genetic or shared environmental factors influenced the an important step in disentangling shared and non-shared covariance of internalizing symptoms and cigarette use biological pathways to these disorders. in a sample of adolescent twins using twin modeling that Methods: Genome-wide association data from the UCL accounts for the contingent nature of cigarette use. Molecular Psychiatry Lab with genome-wide genotype were Methods: We used data (n = 1,411 pairs of twins) from used. DSM-IV was used as the inclusion criteria of Alcohol the Virginia Tw i n Study of Adolescent Behavioral Devel- dependence and antisocial personality disorder. This study opment (mean age = 14.4) to decompose the variance of used quantitative measure of AD and ASPD. internalizing symptoms, cigarette initiation, and quantity Results: Preliminary results from our GWAS of alcohol de- of cigarettes smoked in a trivariate variance decomposi- pendence, comprising of Illumina tion model that included a beta coefficient to allow for Psych Array data from 1,750 cases and 1,100 healthy con- estimates of cigarette initiation to influence quantity of trol subjects from the UK, have revealed genome-wide sig- cigarettes smoked. nificant support for a SNP at the ADH locus on chromosome Results: In biometric models we were able to equate all pa- 4 and suggestive evidence for a SNP on chromosome 11 near rameter estimates by sex. Additive genetic and shared envi- the SYT13 and PRDM11 genes. SYT13 encodes synaptotagmin ronmental effects explained a small percent of the variance XIII which is a brain expressed membrane trafficking pro- in internalizing symptoms and explained a slightly greater tein. Little is known about the function of SYT13 but other share of the variance in cigarette initiation. The covariance members of the synaptotagmin family of proteins act as between internalizing symptoms and cigarette use was pri- Ca2 + sensors for exocytosis at the synapse and elsewhere. marily accounted for by shared environmental factors. The AD samples in our UCL dataset comprised 2424 cases Discussion: This study examined the nature of the comor- (1632 male individuals and 791 female individuals). The bidity in the risk factors for internalizing and cigarette use. AD case-only GWAS result has shown three genome-wide Among adolescents, the overlap in risk factors between in- significant loci chromosome 1: rs849487, Chromosome 16: ternalizing symptoms and cigarette use differs is due to fac- rs78791669, chromosome 5: rs76205837. tors that members of a family share with one another and The ASPD GWAS result in AD case-only samples has shown not to additive genetic effects. As work in psychiatric ge- a promising locus at chromosome 14: rs11626231 (844 indi- netic continues to uncover the genetic basis of disorders we viduals with ASPD quantitative measures). need to also explore how genetic predispositions may in- Discussion: Our results showed three genome-wide signif- teract with environmental factors that may influence the icant results in alcohol dependence case only samples. comorbidity between disorders. Within alcohol dependence cases, we found one promising locus that might link to antisocial personality disorder. Disclosure: Nothing to disclose. These loci might be the genetic risk factors of AD and ASPD. doi: 10.1016/j.euroneuro.2018.08.363 These data (AD and ASPD) will be analyzed again with control samples, and later polygenic risk score will be used to example the genetic relationship between AD and ASPD.

Disclosure: Nothing to disclose. SA142 A WHOLE EXOME SEQUENCING STUDY OF A KOREAN doi: 10.1016/j.euroneuro.2018.08.362 CASE WITH IDIOPATHIC BASAL GANGLIA CALCIFICATION AND ITS DAUGHTER

∗ SA141 Byung D. Lee 1, Dae W. Kim 2, , Ja Y. Kong 1, Chae H. Kwon 1,

SHARED ENVIRONMENTAL ASSOCIATION BETWEEN Je M. Park 1, Young M. Lee 1, Eunsoo Moon 1, Hee J. Jeong 1, ∗ INTERNALIZING SYMPTOMS AND CIGARETTE USE IN Soo Y. Kim 1, Kang Y. Lee 1, Hwagyu Suh 1, , Chan H. Park 1 ADOLESCENCE

1 Pusan National University Hospital

Cristina Bares 1, Judy Silberg 2, Kenneth Kendler 2, 2 Pusan National University Yangsan Hospital

Hermine Maes 2 ∗ Corresponding author.∗ Corresponding author.

1 University of Michigan Background: Idiopathic basal ganglia calciﬁcation (IBGC)

2 Virginia Commonwealth University is characterized by brain calcification and a wide variety of neurologic and psychiatric symptoms. In families with Background: Previous studies examining the comorbidity autosomal dominant inheritance, three causative genes between psychiatric disorders have found support for a have been identified: SLC20A2, PDGFRB, and, very recently, bidirectional relationship between internalizing symptoms PDGFB. Whereas in clinical practice sporadic presentation and cigarette use. When examining the degree of genetic of IBGC is frequent, well-documented reports of true spo- or environmental overlap in liability to experience inter- radic occurrence are rare. nalizing symptoms and cigarette use, previous work has Methods: Methods: We report the case of a 61-year-old not considered the conditionality between initiation and woman who presented depressive and dystonic symptoms quantity of cigarettes smoked which may be obscuring the revealing IBGC. Her 41-year-old daughter was healthy. For exact association between these phenotypes particularly in Whole exome sequencing analysis, 50 nanogram of gDNA was adolescence. The present study examined whether additive used for the target amplification according to the manufac- ARTICLE IN PRESS JID: NEUPSY [m6+; October 1, 2018;18:59 ] 80 Abstracts turer’s instruction (Ion AmpliSeq Exome Kit, LifeTechnolo- ative mutation rate at single-nucleotide resolution. Inter- gies). estingly, the c.1606C > T (p.Leu536Leu) mutation of SLC20A2 Results: We identified in the proband 4 mutations in exon also most likely occurred de novo, although, to our knowl- of PDGFB and 1 mutation in exon of SLC20A2, which was edge, paternity was not verified. We did not find further absent from the daughter’s DNA. This mutation may result mutations of PDGFB and SLC20A2 including the previously in a loss-of-function of PDGF-B and SLC20A2, which has been reported one, in our case-daughter duo. Occurrence of a shown to cause IBGC in humans and to disrupt the blood- PDGFB mutation is therefore probably a quite rare event brain barrier in mice, resulting in brain calcification. among the IBGC cases. However, the mutation is clearly Discussion: IBGC is usually inherited according to an autoso- detrimental, as it is predicted to result in a shortened mal dominant pattern. As clinical expression of brain calci- protein with loss of functionally critical domains includ- fication is not constant, clinically sporadic presentation of ing interface-contributing residues of the PDGF-B:PDGFRb IBGC may be due to mutations inherited from an asymp- complex. To conclude, we demonstrate true sporadic oc- tomatic parent and to offspring in some cases. We demon- currence of IBGC due to a de novo nonsense mutation. Our strate here that a true sporadic occurrence of IBGC, due results further support the involvement of the loss of func- to a possible mutation, can occur. The mutation occurred tion of PDGF-B and SLC20A2 in IBGC and suggest a possible at four positions (c.-51T > C, c.63+2978T > C, c.-53T > C, and hotspot for single-nucleotide substitutions in exon of these c.63+2976T > C) in exon of PDGFB. This suggests a cluster- two genes. ing of mutations in exon of the PDGFB gene. Such a phenomenon has been studied using pangenomic data from con- Disclosure: Nothing to disclose. cordant monozygotic twins with autism, and a mutability in- doi: 10.1016/j.euroneuro.2018.08.363 dex (MI) was calculated for each exon as an estimate of rel-