(WCPG): Poster Abstracts: Sunday

ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] European Neuropsychopharmacology (2018) 000, 1–75

www.elsevier.com/locate/euroneuro

Abstracts of the 26th World Congress of Psychiatric Genetics

Sunday, October 14, 2018 with a 2kb upstream and 1kb downstream region was considered for each gene. Gene-set analysis was conducted using MAGMA, with a principal components regression model for gene-based analyses. Sex, age, the 10 ﬁrst and otherwise as- Poster Session III sociated principal components were included as covariates

4:00 p.m. - 6:00 p.m. in this step. We retrieved a “Hallmark Androgen response” gene-set from MSigDB to be tested in a case-control asso- SU1 ciation study. This gene-set contains 98 curated genes in- ANDROGEN RECEPTOR SIGNALING PATHWAYS IN- volved in the response to androgen receptor signaling. Also, FLUENCE IN ATTENTION-DEFICIT/HYPERACTIVITY a list of 534 annotated genes with at least one occurrence DISORDER of potential transcription factor binding sites (TFBS) for AR was created to investigate potential gene targets related to

Djenifer Kappel 1, Bruna da Silva 1, Renata B. Cupertino 1, ADHD susceptibility.

Diana Müller 1, Vitor Breda 2, Stefania Pigatto Teche 2, Results: No genome-wide association was observed at the

Rogério Margis 1, Luis Augusto Rohde 2, Nina Roth Mota 3, SNPs or gene level. In the gene-set analysis, we found evi-

Diego L. Rovaris 1, Eugênio H. Grevet 1, Claiton Bau 1 dence that the “Hallmark Androgen response” gene-set was signiﬁcantly associated with ADHD susceptibility in our sam-

1 Universidade Federal do Rio Grande do Sul ple (p = 0.039). We also observed that this gene-set seems

2 Hospital de Clínicas de Porto Alegre to be associated with ADHD regardless of gender effects.

3 Radboud University, Nijmegen Medical Centre When analyzed separately in both genders, the gene-set remained significantly associated, although with a larger ef- Background: The differential sex-based prevalence of ADHD fect in men (p = 0.024; p = 0.009, for women and men, re- has long been subject to scrutiny. The role of sex-hormones, spectively). In the secondary analyses, we observed that especially androgens during the neurodevelopmental period from the 534 genes expected to have a TFBS for AR, 14 have has been extensively demonstrated. Androgens regulate and been associated with ADHD previously. Some are from the interact with neurotransmitters and neuromodulators influ- recent ADHD GWAS (FOXP2, TMEM161B), others are classical encing developmental processes. Since androgenic disrup- ADHD candidate genes as BDNF and SNAP25. tors modify these processes it has been suggested that its Discussion: Our results add to the current knowledge that exposure during development was related to ADHD suscep- factors related to the influence of sex-hormones might play tibility. Also, it has been shown that women suffering from a role in ADHD susceptibility. The perspective of the in- the androgenizing polycystic ovary syndrome, have higher volvement of such factors is interesting due to its influence rates of ADHD, and so are their children. We hypothesize during fetal development and also due to sex-hormones ef- that one way by how exposure to androgens and its response fects during puberty. These associations could be represent- network might affect susceptibility to ADHD is through the ing and underlying mechanisms related to ADHD develop- activation of androgen receptor (AR) function as a nuclear ment and differential sex-based prevalence in children and transcription factor. adults. Methods: 407 adults with ADHD (53.1% males, mean age of

33.6 years) and 463 unrelated controls (47.9% males, mean Disclosure: Nothing to disclose. age of 29.4 years) were genotyped with PsychChip array for doi: 10.1016/j.euroneuro.2018.08.365 > 5M SNPs. Annotation from human genome build 37 (hg19)

0924-977X ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 2 Abstracts

SU2 conceptualizations of the externalizing spectrum and ana- RECONCEPTUALIZING PSYCHOPATHOLOGY FOR GE- lytic methods for genetic associations are optimal. NETIC STUDIES USING HIERARCHICAL DIMENSIONAL STRUCTURAL MODELS: THE EXAMPLE OF EXTERNALIZ- Disclosure: Nothing to disclose. ING AND AVPR1A doi: 10.1016/j.euroneuro.2018.08.366

Irwin Waldman SU3 Emory University DESCRIBING THE GENETIC ARCHITECTURE OF ADHD USING LINKED-READ SEQUENCING: A CASE-CONTROL Background: Recent trends in the psychopathology liter- STUDY FROM THE ISOLATED POPULATION OF THE ature have reconceptualized psychopathology in terms of FAROE ISLANDS transdiagnostic or hierarchical dimensional perspectives. Despite these trends, the modal phenotypes used in psychi- August Gabriel Wang 1, Noomi Odmarsdóttir Gregersen 2, atric genetic studies (e.g., in GWASs of psychiatric disorders Ólavur Mortensen 2, Marjun Biskopstø 3, Julia Zachariasen 3, conducted through the Psychiatric Genetics Consortium) are Tórmódur Stórá 3, Gudrun Andorsdóttir 2, Ditte Demontis 4, single, specific psychiatric diagnoses. In this paper, I explore Anders Børglum 4 different conceptualizations of a higher-order Externalizing symptom dimension in children, as well as different ana- 1 Copenhagen University Hospital lytic methods used to characterize this dimension, in its 2 FarGen, Genetic Biobank of the Faroe Islands association with the Arginine Vasopressin 1a receptor gene 3 National Hospital Faroe Islands (AVPR1a), a gene that was genome-wide significantly asso- 4 iSEQ, Aarhus University ciated in a GWAS of aggression. Methods: In phenotypic analyses, data were available on Background: Attention-deficit/hyperactivity disorder parent ratings of DSM-IV symptoms of Attention Deficit Hy- (ADHD) is a mental disorder characterised by an ongo- peractivity Disorder (ADHD), Oppositional Defiant Disorder ing pattern of inattention and/or hyperactivity-impulsivity. (ODD), and Conduct Disorder (CD) from ∼2800 children ADHD is highly heritable and genetic studies show substantia whereas in genetic analyses data were available from ∼600 contribution of common variants to disorder susceptibility. children, all aged 6-16 years old. These three disorders Moreover, a reason meta-analysis show genome-wide sig- were divided into their constituent symptom dimensions. nificance of 12 independent loci comprising evolutionarily These included Inattention, Impulsivity, and Hyperactivity constrained genomic regions and loss-of-function intolerant for ADHD, Negative Affect and Behavioral Dyscontrol for genes. In this study the potential enrichment of ADHD risk ODD, and Aggressive and Rule Breaking dimensions of Con- variants will be explored based on whole-exome data from duct Disorder. In analyses of genetic association six SNPs in linked-read sequencing of individuals from the isolated AVPR1a were used to characterize the gene in a series of population of the Faroe Islands. The demographic history gene-based tests. of the Faroese population may have induced enrichment Results: I contrasted different models for characterizing the of variants rarely seen in outbred European populations, Externalizing symptom dimension with each other, as well including enrichment of risk variants for ADHD. as with models of its constituent diagnoses and symptom Methods: Cases in this study comprises 56 patients with dimensions. Comparisons of these phenotypic models used ADHD, recruited to the ADHD outpatient clinic at the De- the percentage of variance explained and the relative fit of partment of Psychiatry, General Hospital in Tórshavn, Faroe the alternative models to adjudicate among them. In phe- Islands. Diagnosis have been verified by a psychiatrist/child notypic analyses, the best-fitting model contained a higher- and youth psychiatrist, a psychologist and a ADHD special- order Externalizing factor on which the 7 symptom dimen- ized nurse. Further, the diagnostics were verified with the sions loaded, as well as residual correlations among the diagnostic tools: ADHD-RS (Attention Deficit/Hyperactive ADHD dimensions, the ODD dimensions, and the CD dimen- Disorder-Rating Scale), TOVA (Test Variables of Attention), sions. This model fit better than a bifactor model in which BRIEF (Behavioural Rating Inventory of Executive Function) a General Externalizing factor influenced all of the ADHD, and in some cases DIVA (Diagnostic Interview for ADHD in ODD, and CD symptoms directly, as well as a model in which adults) and QbTest (Quantified Behaviour Test Plus). Cases the 7 constituent symptom dimensions were correlated with have been reviewed by experienced psychiatrists and the each other. In gene-based analyses of AVPR1a the higher- diagnostic most solid/robust cases have been selected for order Externalizing higher-order factor was more strongly genetic analyses. Healthy controls in this study comprises associated with AVPR1a than the 7 lower-order symptom di- 200 individuals voluntarily recruited to the FarGen infras- mensions, Conduct Disorder symptom scale composites, and tructure, at the Genetic Biobank of the Faroe Islands. Self- the Conduct Disorder diagnosis. reported healthy status was confirmed by the diagnostic Discussion: Results of these analyses highlight the benefits registry at the National Hospital of the Faroe Islands. High- of conceptualizing and operationalizing psychopathology in molecular weight (HMW) DNA extracted from peripheral terms of hierarchical dimensional models, as well as which blood was barcoded by a gel-bead emulsion (GEM) process in the ChromiumTM controller. The 256 exomes were captured using the SureSelectXT Human All Exon kit and sequenced on the NextSeq 500. The linked-reads were aligned to the ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 3 reference genome (GRGh37/hg19) and variants were called combination of effects is significant. Results from the mul- using GATK. tivariate GWA analysis were used to identify specific genes Results: The exomes were sequenced with an average cov- associated with ADHD traits and response inhibition by con- erage of 56, > 98% of the reads were aligned to the refer- ducting a gene-based association analysis in MAGMA. The bi- ence genome. Due to the barcodes introduced to the DNA ological relevance of the results was assessed by functional fragments in the GEM process we were able to perform mapping and annotation using FUMA. Polygenic risk score molecular phasing, which assign > 85% of the genes under analysis will be conducted to determine if the multivariate 100 kb to a haplotype and phased > 75% of the SNPs. More- GWA results predict clinical ADHD. over, we will present results from single variant and gene- Results: No genome-wide significant risk loci or genes were based association analyses, as well as possible structural identified, however, two variants and six genes reached sug- variants will be presented. gestive p-value thresholds. The top risk loci from the joint Discussion: To our knowledge this is the first study to analysis of ADHD traits and response inhibition were com- use linked-read sequencing to identify susceptibility vari- mon intron variants rs12497498 in SSUH2 (p = 5.76 × 10-7) ants/genes for ADHD. and rs56373513 in GLIS3 (p = 8.13 × 10-7). If two separate univariate GWA analyses were conducted only rs12497498 Disclosure: Nothing to disclose. would have been identified as a risk variant of interest for ADHD traits. The top genes (with p < 0.0001) from the doi: 10.1016/j.euroneuro.2018.08.367 gene-set analysis were RNF148, RNF133, ZMIZ1, FAM163A, PDZRN4, and FGF22. Discussion: Although no genome-wide significant risk vari-

SU4 ants were identiﬁed the regions of interest identiﬁed from

CHARACTERIZING THE GENETICS OF ADHD TRAITS this study warrant further investigation as they will increase WITH COGNITIVE DEFICITS USING A MULTIVARIATE our understanding of the biological mechanisms of with APPROACH ADHD with cognitive deﬁcits. Furthermore, it is hoped that the use of multiple phenotypes in GWA analyses increases 1 1 2 Elizabeth Corﬁeld , Christie Burton , Lisa Strug , the variance explained in clinical ADHD.

Bowei Xiao 1, Paul Arnold 3, Jennifer Crosbie 1,

Russell Schachar 2 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.368 1 Hospital for Sick Children

2 Hospital for Sick Children, University of Toronto

3 University of Calgary SU5

Background: Attention-deficit/hyperactivity disorder A RARE VARIANT ANALYSIS ON ATTENTION-DEFICIT (ADHD) is a common, impairing and persistent disorder HYPERACTIVITY DISORDER of children and youth. Genetic studies usually focus on 1 2 1 univariate methodologies in clinical cohorts. However, Kalle Leppälä , Tetyana Zayats , Ditte Demontis , 1 simultaneously investigating correlated phenotypes using a Anders Børglum multivariate approach could accelerate gene discovery by reducing phenotypic and genetic heterogeneity. Response 1 Aarhus University inhibition (the ability to stop a speeded motor response) is 2 Bergen University a heritable and stable cognitive deficit that is correlated and co-heritable with ADHD. Therefore, this study aims to Background: Attention-deficit/hyperactivity disorder investigate the genetic architecture of ADHD by using a (ADHD) is a common childhood-onset neuropsychiatric con- multivariate genome-wide association (GWA) approach in a dition that often persists into adulthood. The adult form of pediatric community sample with a quantitative measure ADHD is associated with high rate of unemployment, incar- of ADHD traits and a cognitive deficit. ceration, accidental deaths and suicide. Nonetheless, the Methods: The Spit for Science community sample includes biology underlying ADHD as well as its genetic architecture 4,815 Caucasian children and youth (aged 6-17) with geno- is not fully understood. Several twin studies have estimated typing data and measured ADHD traits and response inhi- ADHD heritability to be 70-80%, while the heritability bition, which were used in all analyses. ADHD traits were estimated from the common SNPs varies between 10-28%. measured by The Strengths and Weaknesses of ADHD Symp- The discrepancy in these estimates is often attributed, toms and Normal Behavior Rating Scale, while response in- among other factors, to rare variants (MAF < 1%) as well hibition was measured by the stop-signal reaction time in as the polygenic nature or phenotypic heterogeneity of the the Stop-Signal task. condition. Thus, in this work, we aim to study the genetic A multivariate GWA analysis of 8,786,567 SNPs ADHD architecture of ADHD by focusing on rare variants and traits and response inhibition was conducted with the rel- address the question of polygenicity by examining those evant covariates (age, sex, respondent, batch effects, and associated with ADHD in light of common neuropsychiatric population stratification) using the MultiPhen approach. disorders. This approach uses a reverse proportional odds linear re- Methods: This study is based on the iPSYCH2012 sample con- gression with the genotype regressed on each phenotype. sisting of all the Danes born between 1981 and 2005 and The likelihood ratio test is then used to assess if the joint diagnosed with either schizophrenia (SCZ), autism, ADHD ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 4 Abstracts or affective disorder (about 57000 individuals), as well as ADHD Rating Scale (parent-rated). ADHD symptoms were ex- 30000 randomly selected individuals. The participants were amined in cases and controls separately. As genetics of age genotyped using a custom Illumina PsychChip that contains at menarche in women highly correlate with those of voice about 250000 rare variants. We performed a strict quality breaking in men, males and females were analysed together. control of the genotyped data and excluded variants with Permutation was applied to correct for multiple testing. Em- low genotyping rate or out of Hardy-Weinberg equilibrium pirical p-value (pemp) of 0.05 was considered statistically as well as individuals revealing low genotyping quality, high significant. levels of relatedness or heterozygocity, sex mismatch or Results: The age-at-menarche PRS was not associated non-European ancestry. We will perform genome-wide asso- with ADHD diagnosis (pemp = 0.495). Among ADHD symp- ciation analyses to assess the contribution of rare variants to toms, parent-rated hyperactivity symptom score showed ADHD. The association will be tested in form of regression significant association with the examined PRS in ADHD by grouping the rare variants by (1) their location within cases (pemp = 0.047), but not in controls (pemp = 0.968). known genes, (2) their missense status within known genes, Clinician-rated hyperactivity symptom was not associated (3) their loss of function status within known genes and (4) with the examined PRS both in cases (pemp = 0.184) and con- their location within constrained regions of the genome. trols (pemp = 0.157). We will also examine ADHD associated loci in light of SCZ, Discussion: These results suggest that genetics of puberty autism and affective disorder. onset may play an important role in the development of Results: The results are not ready yet. symptoms of hyperactivity in children with ADHD. Discussion: This study will address the question of missing heritability as well as aid our understanding of genetic ar- Disclosure: Nothing to disclose. chitecture and biological processes underlying ADHD. doi: 10.1016/j.euroneuro.2018.08.370

Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.369 SU7 ASSESSING THE CONTRIBUTION OF NEURODEVEL- OPMENTAL RISK ALLELES TO MATERNAL BEHAVIOURS SU6 AND LIFE-STYLE FACTORS HYPERACTIVITY SYMPTOM IS PREDICTED BY AGE-

OF-MENARCHE POLYGENIC RISK SCORE IN ADHD Beate Leppert 1, Alexandra Havdahl 2, Lucy Riglin 3,

CHILDREN Hannah J. Jones 1, George Davey Smith 1, Kate Tilling 1,

Ted Reichborn-Kjennerud 4, Anita Thapar 3,

Hyo-Won Kim 1, Tetyana Zayats 2, Keejeong Park 1, Evie Stergiakouli 1

Raymond Walters 3, Benjamin Neale 4

1 University of Bristol

1 University of Ulsan Asan Medical Center 2 Norwegian Institute of Public Health and Nic Waals Insti-

2 Bergen University tute, Lovisenberg Diaconal Hospital

3 Massachusetts General Hospital, Broad Institute 3 Cardiff University

4 Massachusetts General Hospital 4 Norwegian Institute of Public Health

Background: Early puberty has been reported to be associ- Background: Exposures to adverse maternal behaviours and ated with a number of attention-deficit/hyperactivity dis- lifestyle factors prenatally have long been considered as po- order (ADHD) symptoms and severity of its impairment, in- tential risk factors for neurodevelopmental disorders and cluding inattention, difficulties in emotion regulation and are biologically plausible because they impact during a sen- risky behaviour. In addition, age at menarche was also re- sitive time in development. However, maternal genetic fac- ported to be inversely correlated with performance IQ. tors could be confounding the association between prenatal However, little is known about the contribution of genetics factors and neuropsychiatric risk in the offspring leading to to the association between puberty onset and ADHD. We in- apparent associations which have no causal relationship. vestigated the possibility of such genetic effect by examin- Methods: Here, we test whether maternal polygenic risk ing the influence of the polygenic risk score (PRS) of age-at- scores for attention deficit/ hyperactivity disorder (ADHD), menarche on diagnosis of ADHD and its two main symptoms, autism and schizophrenia are associated with maternal inattention and hyperactivity. behaviours, lifestyle factors and health during pregnancy Methods: The PRS of age-at-menarche was calculated in within the population-based cohort study ALSPAC. Addi- 324 Korean children (208 cases and 116 controls) utilizing tionally, we tested for associations of adverse birth out- the PRSise software and summary statistics from a large- comes, like preterm delivery ( < 37 week of gestation) and scale (N = 370,000) genome-wide association study on age low birth weight ( < 2500g) with maternal and child genetic at menarche. ADHD was diagnosed based on Diagnostic and risk scores. Polygenic risk scores were derived using the risk Statistical Manual of Mental Disorders, 4th edition (DSM-IV) alleles identified by the most recent GWAS from Demontis and confirmed with the Kiddie–Schedule for Affective Dis- et al. (2017) for ADHD, Grove et al. (2017) for autism and orders and Schizophrenia–Present and Lifetime Version (K- Ripke et al. (2014) for schizophrenia. SADS-PL). Hyperactivity and inattention scores were derived Results: Maternal polygenic risk scores for ADHD were as- from the K-SADS-PL ADHD supplement (clinician-rated) and sociated with a range of adverse maternal behaviour and ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 5 health traits, including maternal smoking during pregnancy trols and rarity in South Asian sample of Exome Aggregation (OR:1.27, 95%CI:1.18-1.36), lower maternal age at deliv- Consortium. ery (OR:0.66, 95%CI:0.59-0.73) and infections during preg- Results: We identified a total of 42 unique rare, non- nancy (OR:1.11, 95%CI:1.04-1.18). There was little evidence synonymous deleterious variants in this study with an av- of association with autism and schizophrenia polygenic risk erage of 5 variants per family. None of the variants were scores. Adverse birth outcomes, including low birth weight shared across families, indicating a private mutational pro- and preterm delivery, were not associated with either ma- file. Twenty (47.6%) of the variant harboring genes identified ternal or child neurodevelopmental risk scores. in this sample have been previously reported to contribute Discussion: We conclude that some of the previously re- to the risk of neuropsychiatric syndromes. These include ported prenatal risk factors for ADHD may not be causally genes which are related to neurodevelopmental processes, linked to the development of ADHD as the associations could or have been implicated in different monogenic syndromes be driven by maternal genetic confounding. However, this with a severe neurodevelopmental phenotype. didn’t seem to be the case for autism or schizophrenia in Discussion: NGS approaches in family-based studies are use- our study. Our results also show no evidence of genetic ful to identify novel and rare variants in genes for complex confounding of other often reported risk factors like low disorders like SMI. The study further validates the pheno- birthweight and preterm delivery with neurodevelopmental typic burden of rare variants in Mendelian disease genes, disorders. This highlights the need for causally-informative indicating pleiotropic effects in the etiology of severe men- study designs and statistical approaches. tal illnesses.

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.371 doi: 10.1016/j.euroneuro.2018.08.372

SU8 EXOME SEQUENCING IN FAMILIES WITH SEVERE MENTAL SU9 ILLNESSES PATIENT-SPECIFIC MICROGLIA CELLULAR MODELS FOR SCHIZOPHRENIA STUDY Suhas Ganesha 1, Husayn Ahmed 2, Ravikumar Nadella 1,

Ravi More 2, Manasa Sheshadri 1, Biju Viswanath 1, Jingchun Chen, Travis Mize, Xiaogang Wu, Xiangning Chen Mahendra Rao 3, Odity Mukherjee 3, Sanjeev Jain 1

University of Nevada, Las Vegas 1 National Institute of Mental Health & Neurosciences

2 National Centre for Biological Sciences

3 Institute for Stem Cell Biology and Regenerative Medicine Background: Schizophrenia is a devastating and prevalent psychiatric illness. Progress in understanding the basic pathophysiological processes underlying this disorder has Background: Severe Mental Illnesses (SMI), such as bipolar been hindered by the lack of appropriate models or tissues. disorder and schizophrenia, are highly heritable, and have Methods: In this study, we generated a cellular model of a complex pattern of inheritance. Genome wide association microglia-like cells (iMGL) in vitro induced from peripheral studies detect a part of the heritability, which can be at- blood cells of live human beings, following the procedure of tributed to common genetic variation. Examination of rare Ohgidani et al. variants with Next Generation Sequencing (NGS) may add Results: Our results indicated that the iMGL cells have mi- to the understanding of genetic architecture of SMIs. We croglial characterizations, such as a ramified morphology; present describe the analysis of WES in 8 multiplex pedi- expressing microglia specific surface markers; and phago- grees with schizophrenia and BD phenotypes. We aimed to cytic activity. To further confirm the similarity of iMGL with identify rare, damaging, exonic variants that co-segregated the microglia from human brain, we conducted RNA-seq with SMI; and to examine the disease relevance and path- from the iMGL cells, and compared with RNA-seq data from way enrichment of the genes which genes that harboured microglia from human brain. Our results showed that iMGL these variants. most closely resemble with microglia from brain, following Methods: As part of a longitudinal study ‘Accelerator Pro- with induced macrophage. gram for Discovery of Brain disorders using Stem Cells’ Discussion: Further function identification of this patient (ADBS) (Viswanath et al., 2018) aimed at understanding the unique iMGL model will be warranted to study many psychi- developmental trajectories and basic biology of SMI, we de- atric or neurodegenerative diseases, such as schizophrenia scribe in this study, the results of WES (Whole Exome Se- and Alzheimer’s disorder. quencing) in 8 multiplex pedigrees with SZ and BD phenotypes from a well characterized Indian cohort. We an- Disclosure: Nothing to disclose. alyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n = 26; schizophrenia, n = 4; schizoaffective disorder, n = 1 doi: 10.1016/j.euroneuro.2018.08.373 schizophrenia like psychosis, n = 1); and 33 healthy individuals by WES. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the con- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 6 Abstracts

SU10 Background: Inﬂammation and cytokines have emerged as a THE DNA METHYLATION PROFILE IN BDNF EXON 1 promising target in mood disorders research, however there PROMOTER REGION IN DRUG DEFAULT PATIENTS OF are still very limited numbers of study regarding inﬂamma- BIPOLAR AFFECTIVE DISORDERS: AN INDIAN STUDY tory alterations among adolescents and young adults with mood disorders. The Macrophage Migration Inhibitory Fac- Sydney Moirangthem, Sanjeev Jain, Meera Purushottam, tor (MIF) and Stem Cell Factor (SCF) are the pleiotropic cy- Biju Viswanath tokines which may play an important role in mood disorders pathophysiology. The aim of this study was to investigate

National Institute of Mental Health and Neurosciences levels of these factors in serum of adolescent and young adults with mood disorders compared to healthy controls. Methods: We involved 79 patients aged 12-24 years in 2- Background: Bipolar Affective Disorders (BPAD) are complex year follow-up study with a primary diagnosis of mood dis- heritable multifactorial psychiatric disorders in which epi- orders: bipolar disorder (BP) and unipolar disorder with BP genetic misregulations play a significant role and may be re- spectrum. Study group includes: 23 males (mean age 19.08, sponsible for monozygotic twin discordance, parental origin SD 3.3) and 56 females (18.39, SD 3.28). Control group con- effects, and fluctuating course of BPAD. A hypermethylation sisted 35 persons: 7 males (20.43, SD 4.23) and 28 females of brain derived neurotrophic factor (BDNF) and subsequent (21.25, SD 2.11). Clinical diagnoses according to DSM-IV-TR decreased levels of serum BDNF are seen in both phases of criteria were assessed using Kiddie-Schedule for Affective BPAD. The study will investigate the methylation status of Disorders and Schizophrenia-Present and Lifetime Version the exon 1 promoter region of the BDNF gene in drug de- (K-SADS-PL) and Structured Clinical Interview for the Di- fault patients. agnostic and Statistical Manual (SCID) in young adults re- Methods: After taking informed consent 50 patients of BPAD spectively. Clinical assessment includes evaluation of clini- (ICD-10 based) are evaluated by a semi-structured interview cal factors and symptoms severity (rated using the Hamil- and tools like Young’s Mania Rating Scale (YMRS) & Hamil- ton Depression Rating Scale and Young Mania Rating Scale). ton’s Depression Rating Scale (HDRS). The assessments will Clinical and biological evaluations were made at control vis- also include the collection of the following demographical its respectively at baseline (week 0), euthymia (at month and clinical variables. Patients in both phases of BPAD, de- 3 or 6) and after 12 and 24 moths. Serum protein concen- pression & mania, & who had defaulted on treatment are tration was determined by Enzyme-Linked Immunosorbent taken for the study. The study has been approved by the Assays (ELISA) method. Human MIF and SCF DuoSet ELISA ethics committee of the National Institute of Mental Health kits were used. In the analyses non-parametric tests were and Neuro Sciences, Bangalore, India. The participants will used: Mann-Whitney U test, Kruskall-Wallis ANOVA, Fried- be recruited from the out-patient, emergency unit & the in- man’s ANOVA, Wilcoxon signed rank test, Spearman correla- patient units of the department of Psychiatry at NIMHANS. tion. We defined statistical significance as p < 0.05. DNA methylation mRNA expression & assay for serum Results: Comparing MIF and SCF levels between acute BDNF levels: DNA and total RNA are extracted from periph- episode of depression/hypo/mania at baseline and eu- eral blood mononuclear cells (PBMC) following standard pro- thymia (at month 3 or 6) we did not find any statistical dif- cedures. DNA is then subjected to bisulphite conversion and ferences. At baseline patients with age above 18 years old PCR with specific primers to amplify the BDNF promoter re- had decreased MIF level compared to patients younger than gion. The extent of methylation at the chosen CpG sites are 18 years. MIF level at baseline positively correlated with age assayed by pyrosequencing. The isolated RNA are then con- (p = 0.004). Positive correlations of SCF level at month 3 and verted to cDNA and real-time PCR was used to determine ex- 6 with depression or mania occurrence at month 24 (p = 0.03 pression levels using Taqman assay. BDNF levels in the serum and p = 0.04, respectively) was detected. Strong correla- were assayed using appropriate kits. tions between MIF and SCF levels at baseline (p = 0.0005) Results: Will be discussed. and month 3 (p = 0.03) were observed. Discussion: Will be discussed. Discussion: Our results did not show any differences in

Disclosure: Nothing to disclose. MIF and SCF levels between acute episode of depression/hypo/mania and euthymia in young patients. Further doi: 10.1016/j.euroneuro.2018.08.374 studies on larger groups are recommended. Grant was founded by National Science Center in Poland no 2011/03/D/NZ5/06146.

SU11 Disclosure: Nothing to disclose. THE MACROPHAGE MIGRATION INHIBITORY FACTOR

(MIF) AND STEM CELL FACTOR (SCF) LEVELS IN SERUM doi: 10.1016/j.euroneuro.2018.08.375 OF ADOLESCENT AND YOUNG ADULTS WITH MOOD DISORDERS: A 2-YEAR FOLLOW-UP STUDY

Pawel Kapelski, Aleksandra Rajewska-Rager, Maria Skibinska, Monika Dmitrzak-Weglarz, Natalia Lepczynska, Piotr Sibilski, Joanna Hauser

Poznan University of Medical Sciences ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 7

SU12 SU13 BEHAVIOURAL EFFECTS OF DEVELOPMENTAL EX- GENETIC VARIATION IN ’CALCIUM VOLTAGE-GATED POSURE TO THE SYNTHETIC CANNABINOID JWH-018 CHANNEL SUBUNIT ALPHA1C (CACNA1C): INTERAC- IN WILD TYPE AND DISRUPTED IN SCHIZOPHRENIA 1 TIONS WITH PREPUBERTAL STRESS AND IMPACT ON (DISC1) MUTANT ZEBRAFISH HIPPOCAMPAL DEPENDENT LEARNING

Judit García-González, Bruno De Quadros, Maroua Akkari, Anna Moon, Nichola Brydges, Kerrie Thomas, Jeremy Hall Caroline Brennan Cardiff University Queen Mary, University of London Background: Genome-wide association studies have con- Background: Cannabinoid abuse and addiction is an estab- sistently demonstrated that variation in the gene calcium lish risk factor for psychiatric disorders and represents a voltage-gated channel subunit alpha1C (CACNA1C) increases public health issue. The increase in risk for psychiatric dis- risk for bipolar disorder, schizophrenia and major depres- orders is stronger for individuals at genetic risk or when con- sive disorder across diagnostic borders. CACNA1C encodes sumption happens while the brain is still developing. How- the Cav1.2 subunit of L-type voltage-gated calcium channels ever, the underlying mechanistic role for the association be- (LTCCs), which have been functionally implicated in a broad tween cannabinoid consumption and psychiatric disorders spectrum of neuropsychiatric syndromes. Although this find- remains poorly understood. Recent advances in genetic ma- ing has been replicated robustly, the mechanisms as to how nipulation and behavioural research make zebrafish (Danio calcium channel dysfunction affects risk for several differ- rerio) a suitable model to study the short and long-lasting ent psychiatric disorders is largely unknown. Therefore, the effects of developmental exposure to cannabinoids. effects of Cacna1c genetic variation on associative learn- The aims of this study are (1) to investigate whether the ing, with a particular emphasis on the formation and expres- developing central nervous system is susceptible to the ef- sion of contextual representations within the hippocampus, fects of the psychoactive ingredients of synthetic cannabi- were analyzed using a novel rat model. noids, namely JWH-018, using zebrafish as an animal model It should also be understood that these disorders are and (2) to test whether the effects of JWH-018 in larvae and largely polygenic and CACNA1C variation only contributes adult zebrafish are moderated by loss of function mutations to a small amount of risk in isolation. Environmental factors in Disrupted In Schizophrenia 1 (DISC1), a gene previously also contribute to potential risk and may interact with ge- associated to psychopathology in humans and other animal netic variants to modulate disorder manifestation. There- models. fore, the developmental influence on the expression of Methods: Zebrafish embryos were exposed to JWH-018 from Cacna1c within the hippocampus and how this gene might one to five days of age. This period corresponds to early be susceptible to environmental regulation in terms of early development, equivalent to pre-natal stages in humans. At life stress was also examined using a rat model of prepuber- five days of age, fish locomotion and response to repeated tal stress (PPS). startle stimuli was assessed. During adulthood, anxiety-like Methods: PPS male and female rats (PND 25-27, 3- and social behaviours were investigated. day unpredictable mild stressors) and control littermates Results: Zebrafish embryos exposed to JWH-018 showed in- (n = 9/group) were analyzed for Cacna1c mRNA and Cav1.2 creased locomotion levels at high doses and reduced their protein expression within the hippocampus by in-situ hy- response to startle stimuli at lower doses. During adult- bridization and western blot analysis. Human post-mortem hood, zebrafish exposed to JWH-018 showed decreased anx- tissue from subjects who had suffered ELS was also in- iety compared with controls but no changes in social be- vestigated using similar methods. Cacna1c + /- male rats haviour were observed. Larvae with loss of function in DISC1 (n = 8/group) and PPS male rats (n = 12/group) were also presented no differences in their response to startle stim- both subject to both delay and trace auditory fear condi- uli compared to wild type controls. During adulthood, they tioning paradigm and tested for conditioned responses by showed increased anxiety levels and were less social. No assessing context and cue-elicited freezing in recall ses- interaction between drug and loss of function mutant ze- sions. brafish were observed. Results: Cacna1c mRNA expression is reduced in the CA1 Discussion: This is the first study that has looked at the be- and CA3 of the hippocampus of male PPS rats (CA1: havioural effects of early developmental exposure to JWH- p = 0.002, CA3: p = 0.04), with no changes in females. 018. Our results suggest that exposure to this drug during There was also a trend to a decrease in Cav1.2 protein early-development leads to short and long term behavioural level (p = 0.06). Human ELS sufferers also have a trend to changes in zebrafish. Although further studies in human pop- decreased Cacna1c mRNA expression in the hippocampus ulations are needed to confirm the harmful effects of syn- (p = 0.098). Cacna1c + /- rats subjected to trace fear con- thetic cannabinoids during pregnancy, these results add fur- ditioning showed increased freezing to cue (p = 0.0257), ther evidence to the increased risk for psychiatric disorders whereas those subjected to delay fear conditioning showed after exposure to cannabinoids during pregnancy. increased contextual freezing (p = 0.0331). PPS rats showed a decreased freezing to cue following trace conditioning Disclosure: Nothing to disclose. (p = 0.047). Discussion: Cacna1c mRNA and protein levels were de- doi: 10.1016/j.euroneuro.2018.08.376 creased following stress in early life suggesting that this ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 8 Abstracts gene may interact with stress to facilitate disease develop- Discussion: Studies in animal models have shown that the ment. Both Cacna1c + /- rats and PPS rats also show a deficit presence of this variant in III NRG prevents the cleavage of in associative learning, highlighting the importance of both the intracellular domain by the enzyme β secretase, and the Cacna1c and stress in hippocampal-dependent learning. extracellular domain by the enzyme γ secretase. This gen- Trace and delay associative learning have been seen to be erates the complete reversal of the signaling pathway and altered in schizophrenia and affective disorders, suggesting an alteration in expression of genes involved in cell survival, a translational aspect of this model. growth and maintenance. Our cell model shows changes in These data point to the importance of the interaction the area and the expression of markers with the p.V266L of genetic and environmental effects impacting on the hip- variant, which might reflect both structural and metabolic pocampal circuity in psychiatric disorders. alterations induced by this mutation also in astrocytes. We found larger astrocytes with larger nucleus in comparisons Disclosure: Nothing to disclose. with studies in animal models. Our results are in agreement with previous research that show that human astrocytes are doi: 10.1016/j.euroneuro.2018.08.377 substantially larger and have more complex processes than rodent cells. Also, we show that the astrocytes in which the variant is present tend to be of a larger size. The explanation of this difference between astrocytes with and with-

SU14 out the variant could be mediated by the differences in ex-

MORPHOLOGICAL AND IMMUNOCYTOCHEMICAL CHAR- pression of markers used in this study. GFAP and CD44 par- ACTERIZATION OF HUMAN-DERIVED ASTROCYTES FROM ticipate in the dynamics of the cellular cytoskeleton while SUBJECTS WITH THE NRG1 P.V266L GENETIC VARIANT S100B and ALDH1L1 are involved with growth and proliferation processes. These results support a possible func- 1 2 Daniela Ugalde Araya , Laura Stertz , tional role for the p.V266L NRG1 variant in modulating as- 2 1 Consuelo Walss-Bass , Henriette Raventós trocytic morphology and activity, and may have implications for schizophrenia. In addition, these results prove the feasi-

1 University of Costa Rica bility and utility of this cell model to functionally character-

2 University of Texas Health Science Center at Houston ize the p.V266L NRG1 variant and other genetic mutations in human astrocytes derived from EBV LCL through the iPSC Background: A valine to leucine variant (p.V266L) in the technique. transmembrane domain of neuregulin 1 (NRG1) was associated with schizophrenia in the Central Valley of Costa Rica Disclosure: Nothing to disclose.

(CVCR) population. To determine its functional significance, doi: 10.1016/j.euroneuro.2018.08.378 we are studying its biological effects in different cell types. Due to the importance of the glial cells in the Central Ner- vous System, we have generated astrocytes derived from induced pluripotent stem cells (iPSCs) from unaffected CVCR SU15 subjects, with and without the p.V266L variant, to explore USING GENETIC MODULATORS OF THE STARTLE RE- the role of this variant in these cells. SPONSE TO INVESTIGATE ANXIETY ETIOLOGY Methods: Lymphoblastoid cells lines (LCLs) from 4 unaffected subjects were transformed into iPSCs using Episomal Julia Tomasi, Arun K. Tiwari, Clement Zai, Deanna Herbert, iPSC Reprogramming Kit. Neuronal Precursor Cells were gen- Anashe Shahmirian, Nicole King, Natalie Freeman, erated using AggreWell methodology and cultured in N2B27 James L. Kennedy medium complemented with 5ng/mL CTNF, 10ng/mL BMP4 and 20ng/mL FGF2 for differentiation into astrocytes. Lipo- Centre for Addiction and Mental Health fectamine transfection was used to evaluate the morphology of the astrocytes (area) and the diameter of the nucleus Background: Anxiety symptoms are frequently observed was measure using DAPI. Immunocytochemistry was used to across several psychiatric disorders, with these symptoms measure total corrected cell fluorescence (TCCF) of GFAP, often leading to worse prognosis. Anxiety disorders have a CD44, S100B, and ALDH1L1 markers. The astrocytes with the high worldwide prevalence rate of 12%. Given the exten- NRG1 variant had larger areas than the non-mutated ones, sive and detrimental influence of anxiety, it is crucial to whereas no significant differences between both groups understand the etiology of pathological anxiety. The pres- were found when the diameter of the nucleus was com- ence of anxiety can be assessed through measuring the star- pared. The TCCF of GFAP, CD44, and S100B was higher in tle reflex, as this reflex is increased when an individual cells with the variant; only ALDH1L1 did not present signif- is in a state of anxiety. The presence of an exaggerated icant differences between groups. The TCCF was measured startle response is a strong indicator of anxiety disorder. using ImageJ and the results were analyzed using R. Genes such as CRHR2 (corticotropin releasing hormone re- Results: Astrocytes with the NRG1 variant have larger ar- ceptor 2), GLRB (glycine receptor beta), and GRIK3 (gluta- eas (p < 0.05), while no significant differences were found mate ionotropic receptor kainate type subunit 3) have been for the diameter of the nucleus (p = 0.0545). The TCCF of associated with elevated startle reactivity. This study aims S100B, GFAP and CD44 was higher in cells with the variant to examine genes associated with alterations in startle re- (p < 0.05); only ALDH1L1 did not present significant differ- activity to determine whether they are associated with anx- ences (p = 0.26) between groups. iety symptom severity across psychiatric patients. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 9

Methods: The study sample consists of patients with a clin- is known to be highly effective in the treatment of spe- ical psychiatric diagnosis from the pharmacogenetic IMPACT cific phobias. DNA methylation patterns have already been study (im-pact.ca) that have been administered the Gener- shown to be altered in anxiety disorders and to mediate and alized Anxiety Disorder 7-item Scale (GAD-7) and provided correlate with treatment response. For example, dynamic a saliva sample for the genetic analysis. We are currently changes in DNA methylation patterns of the monoamine ox- progressing with Infinium Omni 2.5 chip typing on over 1000 idase A (MAOA) gene were identified during the course of patients. First, we conducted a small pilot investigation us- CBT in patients with panic disorder. In the present study, we ing 17 genes and 18 SNPs to determine the effect of startle- aimed at extending these previous findings in panic disorder altering genes on anxiety symptoms in psychiatric patients to specific phobias and analyzed MAOA gene DNA methyla- (N = 46). Second, we conducted this same analysis, but in a tion patterns in patients with acrophobia during the course subset of individuals with an anxiety disorder diagnosis. The of exposure-based CBT. GAD-7 quantitative score served as the phenotype, and the Methods: DNA methylation at 13 CpG sites (MAOA pro- associations were analyzed using a linear regression under moter/exonI/intronI region) was analyzed via direct se- both additive and dominant genetic models. quencing of sodium bisulfite treated DNA extracted from Results: In an initial small pilot analysis, rs6298 from HTR1B whole blood in Caucasian patients with acrophobia (N = 28, (serotonin receptor 1B; p = 0.01) was significant under a female) at baseline (T0) and after (T1) a standardized two- dominant genetic model. In patients with anxiety disorders, week exposure therapy using virtual reality technology ther- rs2159100 from CACNA1C (calcium voltage-gated channel apy. Acrophobia symptoms were assessed at T0 and T1 us- subunit alpha1 C; p = 0.03, 0.02) was associated with anxi- ing the Acrophobia Questionnaire (AQ, Anxiety Subscale) ety symptoms in additive as well as dominant genetic mod- and the Attitude Towards Heights Questionnaire (ATHQ). els, respectively (all p values unadjusted). All analyses were controlled for potential confounding fac- Discussion: The preliminary results of this small study thus tors such as MAOA VNTR genotype. Additionally, the func- far suggest that genes associated with alterations in startle tional relevance of differential MAOA methylation was in- reactivity may be associated with anxiety symptomatology vestigated via luciferase-based reporter gene assays. present in psychiatric patients, including among those with Results: Acrophobia symptoms (AQ-Anxiety and ATHQ) de- anxiety disorders. The top SNPs that have been identified creased significantly after therapy (all ps < .001). From T0 in this study have not previously been reported in the con- to T1, patients displayed a significant increase in aver- text of anxiety. Therefore, although very preliminary, the age MAOA methylation (p = .040) and in methylation at results outlined may have promise as biomarkers of patho- CpG4 (p = .040), CpG6 (p = .036), CpG8 (p = .004), and CpG9 logical anxiety. We are currently investigating these SNPs (p = .004). Furthermore, clinical symptom improvement was in a much larger sample. Overall, this study provides ini- associated with a significant increase in average MAOA DNA tial support for the approach of exploring genes associated methylation (AQ Anxiety: r = -0.465, p = .019; ATHQ Danger: with startle reactivity to identify biomarkers of pathological r = -0.496, p = .012). Functional analysis revealed that non- anxiety. Hopefully this approach will be useful in identifying methylated vector constructs led to a significantly elevated novel treatment targets for those suffering from anxiety. normalized Lucia luciferase activity as compared to methylated constructs (p < .001). Disclosure: Nothing to disclose. Discussion: The present study serves as the first replication study of dynamic MAOA gene DNA methylation patterns doi: 10.1016/j.euroneuro.2018.08.379 to be associated with therapy response in anxiety disorders and suggests an increasing MAOA methylation as an SU16 epigenetic correlate of treatment response in acrophobia.

MONOAMINE OXIDASE A (MAOA) GENE DNA METHY- The investigated MAOA gene region and its DNA methyla-

LATION IN ACROPHOBIA: EPIGENETIC CORRELATE tion patterns were furthermore shown to be of functional relevance for gene expression. The emerging evidence of OF RESPONSE TO COGNITIVE BEHAVIORAL THERAPY changing epigenetic patterns as a potential biological mech- (CBT)? anism of fear extinction might lead to probing pharmacological treatment enhancers such as MAO-inhibitors as augmen- Christiane Ziegler 1, Miriam Schiele 1, Leonie Kollert 2, tation strategies for lasting extinction effects. This might Andrea Katzorke 2, Daniel Gromer 2, Paul Pauli 2, further contribute to an individual and thus more effective Jürgen Deckert 2, Martin Herrmann 2, Katharina Domschke 1 treatment based on individual epigenetic information.

1 University of Freiburg Disclosure: Nothing to disclose. 2 University of Wuerzburg doi: 10.1016/j.euroneuro.2018.08.380 Background: Speciﬁc phobias such as acrophobia, the extreme fear of heights, are the most frequent anxiety disorders. Exposure-based cognitive behavioral therapy (CBT) ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 10 Abstracts

SU17 netic variance is shared with symptoms. This suggests that TREATMENT-SEEKING FOR INTERNALISING SYMPTOMS: treatment-seeking is unlikely to confound genomic studies GENE-ENVIRONMENT CORRELATION ANALYSES IN THE of treatment response. UK BIOBANK Disclosure: Nothing to disclose. 1 1 1 Christopher Rayner , Jonathan Coleman , Kirstin Purves , doi: 10.1016/j.euroneuro.2018.08.381

Rosa Cheesman 1, Genevieve Morneau-Vaillancourt 2,

Gerome Breen 1, Thalia Eley 3

SU18 1 King’s College London POLYGENIC RISK SCORES REVEAL SUBTYPES OF AUTISM 2 Laval University THAT DIFFER IN CODING DE NOVO MUTATIONAL LOAD 3 Institute of Psychiatry, Psychology & Neuroscience, King’s College London Brian Lohman, Hilary Coon, Gabor Marth, Aaron Quinlan, Anna Docherty Background: The high prevalence of anxiety and depressive disorders (i.e. internalizing disorders) is not proportional to University of Utah School of Medicine the level of service use and associated treatment-seeking behaviour. The decision to seek help is expected to be in- Background: The rapid advance of DNA sequencing is poised fluenced by symptom severity. However, treatment-seeking to revolutionize research and treatment of human disease, may also depend on other genetically influenced charac- both at the population and individual levels. To this end, the teristics and their impact on active treatment-seeking be- Simons Foundation Autism Research Initiative (SFARI) has haviour. Only those who seek treatment will receive it, made a major contribution by generating whole genome se- which has considerable implications for studies investigat- quence for 2076 individuals in 4-member family units; each ing treatment efficacy and genomic studies of treatment re- family containing parents and both a child diagnosed with sponse. For example, individuals who believe in treatment Autism Spectrum Disorder (ASD; proband) and an unaffected are more likely to have a positive response. sibling. These data have provided a powerful opportunity to Methods: We defined three treatment seeking phenotypes map the genetic basis of ASD and discover genome-wide de in the UK Biobank: treatment-seeking (from a professional), novo mutations. However, very large GWAS have confirmed self-help (self-sourcing a remedy) and self-medication (us- a complex and highly polygenic architecture for all major ing drugs or alcohol). Multivariate logistic regressions we psychiatric disorders. Such complex traits are the product used to examine the effects of the environment and indi- of many common loci of small effect, and few rare vari- vidual characteristics (N ∼ 45,000). Genome-wide associa- ants. Polygenic risk scores (PRS), aggregating the effects of tion and LD score regression analyses were used to exam- thousands of loci, have been used to successfully subtype ine SNP heritability in the whole sample (N ∼ 70,000) and individuals into latent genetic classes, and to predict clini- then stratified by a diagnostic interview derived lifetime cal symptoms and prognosis, not only for many cancers but internalizing disorder diagnosis (Ncases ∼30,000; Ncontrols also for psychiatric disorders, including schizophrenia and ∼20,000). We also tested for genetic correlations with psy- major depression. chiatric, behavioural and cognitive traits. Methods: Here, using polygenic risk scores for 35 physical Results: Several environmental and individual characteris- and psychological phenotypes (e.g. coronary artery disease, tics were associated with treatment-seeking. Of particular HDL/LDL, schizophrenia and major depression), we trained note, we found that men are considerably less likely to seek- a decision tree model on Phase1 of SFARI (n = 519 fami- treatment and are much more likely to self-medicate than lies) to predict case status and to classify probands into dis- women. The ability and frequency participants are able to tinct subtypes. Our model identified two distinct subtypes of confide in others increases the odds of treatment-seeking probands, driven by high- and low-ASD PRS. We then tested and decreases the odds of self-medicating. Each full logistic for differences in the number of de novo mutations between model explains ∼20% of the variance in treatment-seeking, subtypes. ∼5% of the variance in self-help and ∼25% of the variance Results: We identified significant enrichment for coding mu- in self-medication. Findings from genomic analyses indicate tations in the low-ASD PRS subtype. This result is consistent that treatment-seeking is mildly heritable (h2 ∼ 7%; s.e with the hypothesis that larger effect, more penetrant de ∼ 1%). Treatment-seeking has a high, positive correlations novo variants may require less burden of polygenic risk to with depressive symptoms, MDD, and neuroticism (rG: 64 – result in expression of the ASD phenotype. Conversely, in 84%). cases with higher polygenic risk for ASD, such variants may Discussion: The finding that men are less likely to seek-help be more elusive. but more likely to self-medicate, over and above the effects Discussion: Our work demonstrates that successful genetic of symptoms is reflected in the higher prevalence of alcohol subtyping of individuals, while accounting for critical co- use disorder in men in the UK. The higher prevalence of variates like sex and ancestry, produces distinct groups alcohol use (and also suicide) in men is likely to be associ- with more homogenous genetic backgrounds, simplifying ated with differences in coping mechanisms for internaliz- downstream analysis and revealing previously unseen pat- ing symptoms. Genomic analyses indicate that treatment- terns that would be missed by traditional GWAS. We will seeking is not substantially heritable and much of the ge- present our efforts to replicate both our subtyping method ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 11 and enrichment of de novo mutations in the low ASD PRS is certain to play a crucial role in the diagnosis and inter- subtype in SFARI Phases 2, 3, and 4 (n = 1,868 families). vention of autism in the future.

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.382 doi: 10.1016/j.euroneuro.2018.08.383

SU20 SU19 AUTISTIC TRAITS AND COGNITIVE DYSFUNCTIONS IN A SEARCH FOR RARE GENETIC VARIANTS IN A FAMILY- CHILDREN WITH PATOGENIC COPY NUMBER VARIANTS: BASED STUDY OF AUTISM A PILOT STUDY FROM SERBIA

Fiana Ní Ghrálaigh, Elaine Kenny, Louise Gallagher, Marina Mihaljevic 1, Milica Pejovic-Milovancevic 2,

Lorna Lopez Hristina Janeski 3, Vanja Mandic-Maravic 2,

Roberto Grujicic 2, Danijela Drakulic 4, Milena Stevanovic 4,

Institute of Molecular Medicine, Trinity College Dublin Goran Cuturilo 3

Background: Autism is a neurodevelopmental disorder with 1 Clinic for Psychiatry, Clinical Center of Serbia a population frequency of ∼1 in 88, often co-morbid with 2 Institute of Mental Health other psychiatric disorders. While it is accepted that autism 3 University Children’s Hospital is a highly heritable disorder (h2 > 0.8), much of the ef- 4 Institute of Molecular Genetics and Genetic Engineering fect of genetic variation on autism remains unclear. A major search is currently underway to seek out the variation Background: Copy number variants (CNVs) have been re- underpinning this disorder. 40% of all autism cases are cur- ported to be associated with a broad range of neurode- rently unexplained. It is predicted that these cases may be velopmental disorders (NDDs), including autism spectrum the result of so far unidentified de novo and rare inherited disorders and schizophrenia. Current knowledge regarding variants. Family studies are a key tool in gene discovery due phenotypic outcomes and pathological mechanisms is in- to the control of background genetic variation and environ- sufficient to translate genetic findings of CNVs into clini- mental factors to a certain extent. The aim of this study is cal practice. Therefore, a pan-European network MINDDS to take a family-based approach to identify the rare variants (Maximising Impact of research in Neuro-Developmental Dis- resulting in autism. orderS) creates large trans-national patient cohorts with Methods: A family was ascertained comprising of unaf- pathogenic CNVs associated with high risk for NDDs, which fected parents and four autism-affected offspring. DNA was aim is to increase understanding and facilitate research of extracted from saliva samples using Perkin Elmer Prepito D pathogenic CNVs. Particularly, MINDDS will challenge this is- cytopure kit. All six samples were sequenced using SOPHiA sue by combining multi-dimensional research approaches, GENETICS Whole Exome Panel, covering 26,000 genes. Cap- including clinical deep phenotyping, imaging, animal mod- tured libraries were sequenced on the Illumina HiSeq 4000 els and patient-derived iPS cell studies. To the best of our (2 × 250). Quality control was performed as standard. Data knowledge, there are no research groups in Serbia who in- analysis was carried out using SOPHiA DDM. vestigated psychiatric phenotype in patients with CNVs. Be- Results: The identification and annotation of variants impli- coming a part of MINDDS network, the first aim of Serbian cated in autism will be reported. Medical annotation will be research team will be to explore psychiatric phenotype in carried out by predicting the functional effect of variants an already existing cohort of CNV carriers. Beside pheno- on their respective genes, overlaying the variants called type measures, we will collect biological samples which will with autism candidate genes and comparing variants with be used for different genetic and iPS cell studies. well-established autism databases. Family analysis will be Methods: A cohort of 41 children (age range: 4-14) with carried out in interpretation of the variants through segre- pathogenic CNVs for NDDs has been recruited through a gation analysis and observing genotype-phenotype correla- medical genetics unit at University Children’s hospital. The tions. We will then classify the variant-containing genes and cohort includes: 22q11.2 deletion (N = 28), 22q11.2 dupli- seek to identify candidate risk genes. cation (N = 2), 16p11.2 deletion (N = 1), 16p11.2 duplica- Discussion: This study will contribute to the autism ge- tion (N = 2), 15q11.2 deletion (N = 6), 15q11.2 duplication nomics field with the most up to date technology in a clin- (N = 2) and 7q11 deletion (N = 1). Phenotype measures, such ically relevant family-based study. This multiplex family, as autistic traits and cognitive functions, are assessed by which shows a definite clustering of autism, holds particular Autism Diagnostic Interview − revised (ADI −R) and psycho- promise for revealing highly penetrant genetic risk factors logical tests (The Wechsler Intelligence Scale for Children for autism. The genes identified will add to those already as- and Vineland II). sociated with autism, giving a deeper understanding of the Results: Results will be presented at the congress. genomics of the disorder. In turn, this genomic understand- Discussion: This is the first study to explore psychiatric phe- ing will bring a clearer picture of the mechanism of disease, notype of CNV carriers in Serbia. Currently there are around both on an individual level and on a global level. This gives 200 detected children with pathogenic CNVs for NDDs, and the opportunity to develop personalised therapies and man- they will be tested during next year. As a part of MINDDS agement strategies, improving patient outcomes. Genomics network, Serbia has an important opportunity to implement ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 12 Abstracts integrative CNV research approach in this region and to fur- Discussion: Our twin analysis results show different pat- ther contribute to CNV investigation worldwide. terns of geographical variation in genetic and non-shared environmental influences on symptoms of ASD and ADHD. Disclosure: Nothing to disclose. This indicates that where we grow up effects the aetiology of these traits. For example, it appears that more densely doi: 10.1016/j.euroneuro.2018.08.384 populated areas show greater heritability for ASD in both the UK and Sweden, while patterns for ADHD appear more complex. We also found geographic variation in polygenic SU21 risk score associations across the Bristol area, providing GEOGRAPHICAL VARIATION IN GENETIC AND ENVIRON- complementary evidence that where we live moderates the

MENTAL INFLUENCES ON AUTISM SPECTRUM DISORDER effect of known polygenic risk on these outcomes. AND ATTENTION DEFICIT HYPERACTIVITY DISORDER IN SWEDEN AND THE UNITED KINGDOM USING BOTH TWIN Disclosure: Nothing to disclose. ANALYSES AND POLYGENIC RISK SCORES doi: 10.1016/j.euroneuro.2018.08.385

Zoe Reed 1, Henrik Larsson 2, Robert Plomin 3,

Claire Haworth 1, George Davey Smith 1, Paul Lichtenstein 4, SU22 Oliver Davis 1 AN UNUSUAL HIGH FREQUENCY OF NATURAL FETAL LOSS IN AUTISM SPECTRUM DISORDER 1 University of Bristol

2 Örebro University 1 1 2 Claudia Lattig , Diana Nuñez , Andrea Lopez , 3 King’s College London 1 3 Yvonne Gomez-Maquet , Roberto Chaskel 4 Karolinska Institutet

1 Universidad de los Andes Background: Our previous work has shown that geographi- 2 Hospital Universitario Fundacion Santa Fe de Bogota cal location affects the balance of genetic and environmen- 3 Instituto Colombiano del Sistema Nervioso tal influences on many developmental disorders and traits. For example, we may find greater heritability for a disor- Background: Autism spectrum disorders (ASD) are neurode- der in a city Centre, suggesting that the urban environment velopmental disorders that share difficulties in communica- draws out genetic influences. In this study we applied our tion, social interactions and stereotyped behaviors. ASD has spACE approach using twin data to estimate genetic and en- a heritability of 64 – 91% indicating a high genetic compo- vironmental influences on autism spectrum disorder (ASD) nent. Clinically recognized pregnancy loss is relatively com- and attention deficit hyperactivity disorder (ADHD) at loca- mon in the population with an estimate between 12-20%. tions across Sweden and the UK. We also explored how poly- However, this risk increases substantially, frequencies be- genic risk for these traits varies across a single city region tween 58-65%, for genetic diseases such as Edwards and using data from Bristol in the UK. Patau syndromes. Here we describe an unusual high rate of Methods: We first used twin data from Sweden’s Child and previous natural fetal losses in a cohort clinically diagnosed Adolescent Tw i n Study to estimate spatial patterns of ge- with ASD. netic, shared environmental and non-shared environmental Methods: We have clinically ascertained 65 family trios of influences on symptoms of ASD and ADHD measured using Colombian origin composed of mother, father and at least the Autism-Tics, A/HD and other Comorbidities inventory at one child with autism. All individual met criteria for ASD by ages 9 and 12. We fitted spACE structural equation models psychiatric and genetic evaluation as well as psychological at thousands of locations across the country, with each twin (ADIR/ADOS) evaluation. Informed consent was approved by pair’s contribution weighted by their inverse Euclidean dis- all the participating institutions and signed by all partici- tance from each location. We compared the resulting maps pants. to our previous analyses in the UK’s Tw i n s Early Development Results: An unexpected number of mothers in our cohort Study using the Childhood Asperger Syndrome Test and the which 26 mothers (40%) had previous natural fetal losses; 17 Conner’s Parent Rating Scale at age 12. For our single-city- of them had one previous natural fetal loss, and 9 mothers region polygenic risk score analyses we used data from the had two or more previous natural fetal losses. Age of the Avon Longitudinal Study of Parents and Children (ALSPAC) mother was not a critical factor in our cohort. in weighted linear regression models to determine the as- Discussion: Previous pregnancy losses have not been de- sociation of published polygenic risk scores with symptoms scribed in ASD. Here we present a small cohort with an of ASD and ADHD at multiple locations. Phenotype data in unusual number of cases of clinically recognized pregnancy ALSPAC were collected at age 7 using the Skuse social score loss. In order to determine if this risk increases in families for ASD and the Strengths and Difficulties Questionnaire hy- with at least on individual with ASD, a follow-up on these peractivity scale for ADHD. families is highly recommended. Results: We found geographical variation in genetic and non-shared environmental influences for both ASD and ADHD Disclosure: Nothing to disclose. in Sweden, paralleling our previous results from the UK. In our analysis of polygenic risk scores, we also found evidence doi: 10.1016/j.euroneuro.2018.08.386 of geographical variation on a local scale in the city of Bris- tol and surrounding areas. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 13

SU23 SU24 A MACHINE LEARNING FRAMEWORK FOR CROSS-OMICS NEW COMMON GENETIC VARIANTS ASSOCIATED WITH PREDICTION CHRONIC PAIN: CONDITIONAL FALSE DISCOVERY RATE ANALYSIS WITH MAJOR DEPRESSIVE DISORDER Junfang Chen, Emanuel Schwarz

Keira Johnston 1, Daniel Smith 1, Mark Bailey 1, Mark Adams 2,

University of Heidelberg Barbara Nicholl 1, Andrew McIntosh 2

Background: Technological advances in molecular high- 1 University of Glasgow throughput techniques and the necessity of embracing 2 University of Edinburgh systems-approaches to shed light on the etiology of complex illnesses have led to substantial interest in computa- Background: Chronic pain is defined as pain lasting longer tional approaches. Integrative analysis of omics data has than 12 weeks. It is highly prevalent worldwide, imposes the potential to elucidate biological mechanisms underlying a significant socioeconomic burden, and contributes to ex- complex illnesses that are hallmarked by numerous subtle cess mortality. Chronic pain can be considered a complex changes distributed across data modalities. The objective trait phenotype with moderate heritability (Hocking et al of this work was to develop a machine learning framework 2012). To date, no common genetic variation has been as- for predictive pattern transfer across omics data. Since sociated with chronic pain via Genome Wide Association the joint analysis of multiple modalities commonly requires Studies (GWASs) (Zorina-Lichtenwalter et al 2016). An al- data to be derived from an overlapping set of subjects, a ternative strategy for variant discovery is Conditional False specific aim of this study was to develop an analysis frame- Discovery Rate (cFDR) analysis on existing GWAS outputs. work that was independent of this requirement. This approach leverages pleiotropy with a related secondary Methods: We present CrossP, a cross-omics prediction trait. One trait which shares genetic and environmental risk framework that does not require different modalities to factors with chronic pain is Major Depressive Disorder (MDD) be acquired on an overlapping subject cohort. CrossP (McIntosh et al 2016). uses machine learning to compress modality-specific data Methods: Summary statistic data were collected from the into pathway-level prediction scores that are then used MDD GWAS meta-analysis carried out by Wray et al (2018). for cross-modality prediction. We demonstrate the utility Results from 23andMe and UK Biobank research partici- of this approach using genome-wide expression and DNA pants were removed, to give a dataset with cases = 45, 591 methylation data acquired from patients with schizophre- controls = 97,674. Summary statistic data from the Pfizer- nia. 23andMe GWAS of von Korff chronic pain grade (1-4) vs con- Results: Our results show that CrossP can be used to map trols (von Korff et al 1992, McIntosh et al 2016) was obtained omics signatures predictive of schizophrenia case control (cases = 10, 543, controls = 12, 758). SNPs with association status from lymphoblastoid cell line derived gene expres- data on both traits were LD pruned, to give a dataset of sion to whole blood DNA methylation data. These predic- 774, 292 SNPs. cFDR and conjunctional cFDR (ccFDR) values tions were illness-specific against three non-psychiatric con- for each SNP for MDD given CPG and vice versa were calcu- ditions and driven by overlapping illness-associations across lated as previously detailed (Andreassen et al 2013, Liley & the broad set of KEGG pathways. Wallace 2015) using the statistical software R. Discussion: The present results demonstrate that the CrossP To examine genes in putative linkage with significant framework has utility for integrative analysis of multi-omics SNPs, NCBI dbSNP search was performed using the R pack- data, particularly when data is not available for the same age ‘rsnps’ (Chamberlain et al 2016). The UCSC Genome set of subjects. Notably, the possibility to map predictive Browser (build GRCh38/hg38) was searched within a window patterns across omics-modalities can also facilitate the ex- of 0.5mbp around the position of each SNP. clusion of confounding effects present in individual modali- Results: Eleven SNPs were found to be associated with ei- ties. By mapping omics data to pathway-specific latent vari- ther CPG or MDD, or both, at cFDR < = 0.01. Six CPG- ables, CrossP further facilitates systems-based exploration associated and nine MDD-associated SNPs were found at of factors underlying the signal shared across modalities. cFDR < = 0.01, in comparison with three and zero MDD Therefore, CrossP may be a useful tool to elucidate systems- and CPG-associated SNPs respectively found via the original biological alterations underlying complex illnesses such as GWAS analyses. Four SNPs on chromosome 14 were found to schizophrenia. be pleiotropic (ccFDR < = 0.01). SNPs associated with CPG only were linked to SLC16A7 on chromosome 12, whereas Disclosure: Nothing to disclose. SNPs associated with MDD only were linked to LINC01360, doi: 10.1016/j.euroneuro.2018.08.387 LRRIQ3, FPGT, FPGT-TNNI3K on chromosome 1 and to LRFN5 on chromosome 14. SNPs found to be pleiotropic were also linked to LRFN5. Discussion: SLC16A7 encodes MCT2, a predominantly neuronal metabolite transporter (Pierre et al 2002, Debernardi et al 2003). Pain chronification may involve structural and functional-connectivity changes in the brain (Baliki et al 2010, 2012, Hashmi et al 2013). SLC16A7 could therefore affect chronic pain development via MCT2 involvement ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 14 Abstracts in neuronal-cell energy use. LRRIQ3 encodes leucine-rich Results: Whole genome polygenic risk scores training on repeat (LRR) and IQ motif containing protein 3. LRR-domain IQ predicted cognition better in schizophrenia cases over containing proteins in general are involved in cell-cell a polygenic risk score trained on schizophrenia. The FMRP communication, innate immunity and neuronal develop- targets [9] gene-set preferentially captured variance in cog- ment (Bella et al 2008, Ng et al 2011). FPGT encodes nition in schizophrenia over other previously associated fucose-1-phosphate guanylyltransferase, involved in fucose schizophrenia gene-sets when the GWAS of IQ was used metabolism (reviewed by Becker & Lowe 2003) which is to define risk alleles. One important observation was in important for cell-cell communication and neuronal devel- marked contrast to genome wide polygenic risk score anal- opment (reviewed by Becker & Lowe 2003). Lrfn protein, yses, many gene-set polygenic risk scores capture maximal including Lrfn5 encoded by LRFN5, assist in cell-cell interac- variance when risk alleles are defined at the genome wide tion, and consequently in neuronal development (Morimura significant threshold. et al 2006, Nam et al 2011) and synapse formation (Choi Discussion: Our results support the hypothesis that shared et al 2016). Multiple hits found in the LRFN5 region are common genetic factors exist between the variance in cog- putatively independent, suggesting pleiotropic effects here nitive ability in schizophrenia and intelligence in the gen- may contribute to both MDD and CPG pathology. eral population. They also suggest that this is relatively enriched in particular functional gene-sets. The fact that opti- Disclosure: Nothing to disclose. mal prediction for functional gene-sets was often obtained using genome wide significant risk alleles points to alleles doi: 10.1016/j.euroneuro.2018.08.388 within these gene-sets playing the most important roles and demonstrates the importance of testing multiple thresholds in functional gene-set analyses. SU25 USING POLYGENIC RISK SCORE APPROACHES TO Disclosure: Nothing to disclose. INVESTIGATE THE COMMON-VARIANT GENETIC AR- CHITECTURE OF COGNITION IN SCHIZOPHRENIA References John Hubert, Antonio F. Pardiñas, Alexander Richards, Darnell, J.C., et al., 2011. Cell 146, 247–261. Sophie Legge, Amy Lynham, Andrew J. Pocklington, International Schizophrenia Consortium, 2009. Nature 460, 748–

Michael Owen, Michael C. O’Donovan, James T.R. Walters, 752. Valentina Escott-Price de Leeuw, C.A., et al., 2015. PLOS Computational Biology 11, e1004219. MRC Centre for Neuropsychiatric Genetics & Genomics, Lynham, A.J., et al., 2018. Journal of Psychiatry and Neuroscience. Cardiff University Pardiñas, A.F., et al., 2018. Nature Genetics. Pocklington, A.J., et al., 2015. Neuron 86, 1203–1214. Ripke, S., et al., 2014. Nature 511, 421–427. Background: Schizophrenia is known to have a substantial Savage, J.E., et al., 2017. bioRxiv, 184853. common-variant polygenic component [1] . Polygenic risk Sniekers, S., et al., 2017. Nature Genetics 49, 1107–1112. scores [1] directly estimate common polygenic liability in individuals regardless of their affected status and have shown doi: 10.1016/j.euroneuro.2018.08.389 weak prediction of schizophrenia affected status in independent case-control datasets [2] . With the recent discovery of gene-sets associated with schizophrenia [3] , and oth- SU26 ers to cognitive ability [4] , we investigated whether limiting A WEIGHTED BURDEN TEST USING LOGISTIC RE- the polygenic risk score to relevant functional sections of the genome may improve our understanding of cognition in GRESSION FOR INTEGRATED ANALYSIS OF SEQUENCE cases of schizophrenia. VARIANTS, COPY NUMBER VARIANTS AND POLYGENIC Methods: Polygenic risk score profiles were calculated for RISK SCORE the CardiffCOGS cohort [5] (1024 samples total) by training on the CLOZUK + PGC2 GWAS meta-analysis [3] (inde- David Curtis pendent from CardiffCOGS; 39,651 cases; 64,643 controls) and a GWAS of IQ [6] (78,308 individuals). Three types of University College London polygenic risk scores were created for each training set on LD pruned SNPs: a risk score including the entire genome, Background: Previously described methods of analysis al- a score limited to exonic regions (including regulatory re- low variants in a gene to be weighted more highly according gions; 10 kb downstream, 35 kb upstream), and a score lim- to rarity and/or predicted function and then for the vari- ited to gene-sets associated in each training set. Identifica- ant contributions to be summed into a gene-wise risk score tion of association-enriched gene-sets in each training set which can be compared between cases and controls using was derived from 134 central nervous system (CNS)-related a t test. However, this does not allow incorporating covari- gene-sets shown to capture the excess burden in schizophre- ates into the analysis. Schizophrenia is an example of an ill- nia for copy number variants [7] . Gene-set analysis in each ness where there is evidence that different kinds of genetic training set was performed using MAGMA [8] . All three types variation can contribute to risk, including common variants of polygenic risk score profiles were tested for association contributing to a polygenic risk score (PRS), very rare copy with cognition within schizophrenia. number variants (CNVs) and sequence variants. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 15

Methods: A logistic regression approach has been imple- cus, SNP and gene levels. Risk loci across 501 traits covered mented to compare the gene-wise risk scores between more than a half the genome. 10.2% of SNPs and 58.1% of cases and controls while incorporating as covariates pop- protein coding genes in the genome reached genome-wide ulation principal components, the PRS and the presence significance in at least one trait. Pleiotropy is ubiquitous of pathogenic CNVs and sequence variants. A likelihood across the genome; 59.6% (76.6%) of SNPs (genes) that are ratio test is performed comparing the likelihoods of lo- associated with at least one trait are pleiotropic (associated gistic regression models with and without this score. The with more than one trait) and 31.0% (63.3%) of SNPs (genes) method was applied to an ethnically heterogeneous exome- are highly pleiotropic (associated with traits from more than sequenced sample of 6000 controls and 5000 schizophrenia one domain). Pleiotropic risk loci showed higher gene den- cases. sity compared to genomic regions that are not associated Results: In the raw analysis the test statistic is inflated but with any trait. inclusion of principal components satisfactorily controls for The recently proposed omnigenic model postulates that this. In this dataset the inclusion of the PRS and effect any regulatory variant and gene that is active in a certain from CNVs and sequence variants had only small effects. tissue is likely to be associated with many or even all traits The set of genes which are FMRP targets showed some ev- that are modulated through the same tissue. Under this idence for enrichment of rare, functional variants among model, active regulatory variants and genes expressed in cases (p = 0.0005). many or all tissues are more likely to have associations with Discussion: This approach can be applied to any disease in more number of traits. Indeed, our results showed that SNPs which different kinds of genetic and non-genetic risk factors and genes that are more pleiotropic are less tissue-specific. make contributions to risk. Discussion: We show widespread variation in genetic architecture across hundreds of complex traits and widespread Disclosure: Nothing to disclose. pleiotropy. Our results provide novel insights into how genetic variation contributes to trait variation based on a vast doi: 10.1016/j.euroneuro.2018.08.390 amount of empirical results. Our results support the omnigenic model where genes widely expressed in a variety of tissues are more likely to be associated with multiple traits. SU27 A GLOBAL VIEW OF GENETIC ARCHITECTURE AND Disclosure: Nothing to disclose. PLEIOTROPY IN HUMAN COMPLEX TRAITS doi: 10.1016/j.euroneuro.2018.08.391 Kyoko Watanabe, Sven Stringer, Tinca Polderman, Danielle Posthuma SU28 VU Amsterdam MODELLING GENETIC ASSOCIATIONS VIA THE INTE- GRATION OF GWAS AND EQTL DATA Background: Despite more than a decade of genome-wide association studies (GWAS), the proportion of segregating Josefin Werme, Sophie van der Sluis, Danielle Posthuma, variants that contribute to variation of complex traits, the Christiaan de Leeuw degree of polygenicity and the extent of pleiotropy are still largely unknown. Here we curated 3,795 GWAS summary VU Amsterdam statistics for 2,822 traits in 28 trait domains and systematically analyzed these to investigate two main fundamental Background: Genome-wide association studies (GWAS) have questions: what is the nature of the genetic architecture of aided the detection of vast numbers of genetic variants complex traits, and what is the extent of pleiotropy. associated with complex traits. Results from these studies Methods: We compiled a database of 3,795 GWAS summary have emphasized their complex genetic architecture, and statistics (including 3,184 publicly available and 611 UK high levels of polygenicity has all but facilitated any func- Biobank release 2 GWAS performed in this study) for 2,822 tional interpretation. Enrichment of non-coding regions and unique traits across 28 domains. For the purpose of compar- regulatory elements suggests that altered gene expression ing GWAS outcomes across traits, we selected GWAS’s with plays an important role, and thus, integrating regulatory in- s sufficiently large sample size ( > 50,000) resulting in GWAS formation such as expression quantitative trait loci (eQTL) for 501 unique traits across 23 trait domains. data may help elucidate their aetiology. A number of meth- Results: The nature of the genetic architecture was mea- ods, such as PrediXcan and TWAS, have been developed for sured in terms of the polygenicity of traits. We used a uni- this purpose. However, whilst these methods may prioritize variate Gaussian mixture for GWAS summary statistics to es- relevant genes, they do not allow for any inference regard- timate pi_1 (the fraction of causal SNPs) and sigma_beta ^ 2 ing the involvement of genetically regulated expression (de- (variance of effect sizes of causal SNPs). Over 90% of traits spite their results often being interpreted as such). With the showed high polygenicity (1e-4 < pi_1 < 0.01) with moder- aim of addressing this, we have developed a novel method ate discoverability (2e-7 < sigma_beta ^ 2 < 1e-3), and most of that adopts a competitive hypothesis testing framework, these traits required over a million subjects to reach 90% of akin to that in gene-set analysis, into the integrated analysis discovery. of GWAS and eQTL data. We evaluated the extent of pleiotropy by counting the Methods: We obtained information on the genetically regu- number of associated traits and trait domains at the risk lo- lated component of gene expression using blood-eQTL data ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 16 Abstracts from the Framingham cohort. Integrating this with indepen- forms of the illness, thus we tested the association of PTRS dent, user-provided GWAS summary statistics, our tool ap- with dimensional measures of behavioral functioning that plies a Bayesian penalized regression model with spike and are intimately related to pediatric BD (i.e., aggression, anx- slab priors to simultaneously model the gene expression pat- iety with depression, and attention problems). Regression terns that mediate the observed genotype–phenotype asso- analysis revealed that PTRS for BD was significantly pre- ciations. The performance of our method is evaluated via dictive of aggression in a sample of school-aged children simulation studies and subsequently applied to real data. (n = 92). Results: Results from our simulation studies show that our Discussion: Our study demonstrates the potential utility of method can successfully identify genes whose genetically PTRS for risk prediction, thereby enabling further molecular regulated expression plays an important role in phenotypic characterization of complex disorders and phenotypes. aetiology. It allows us to detect convergent effects from multiple loci as well as detect trans-regulated genes that Disclosure: Nothing to disclose. would have otherwise been missed. By contrast, existing doi: 10.1016/j.euroneuro.2018.08.393 methods were found unable to distinguish genetic association patterns that were due to expression regulation, functioning essentially akin to standard gene analysis.

Discussion: There is a pressing need for statistical ap- SU30 proaches that further aid the functional interpretation of ANALYSIS OF WGS DATA FROM 108 INDIVIDUALS OF 8 GWAS ﬁndings. Integration of additional sources of biolog- SPANISH FAMILIES AFFECTED WITH BIPOLAR DISORDER ical information, such as eQTL data, may help attain this 1 2 3 goal. Although there are existing methods that aim to ac- Sascha Fischer , Charlotte Ng , Martin Fink , 1 4 5 complish this, their statistical and conceptual foundations Céline Reinbold , Anna Maaser , Fabian Streit , 6 7 7 limit the conclusions that can be drawn. Here, we presented Jose Guzman Parra , Fabio Rivas , Fermin Mayoral , 1 5 4 a novel tool that overcomes these limitations, thus allowing Stefan Herms , Marcella Rietschel , Markus Nöthen , 1 4 1 the detection of phenotypically relevant gene expression Per Hoffmann , Andreas Forstner , Sven Cichon regulation and providing an additional layer of interpretation for GWAS results. 1 University of Basel

2 Institute of Pathology, University Hospital Basel

Disclosure: Nothing to disclose. 3 Novartis Pharma AG

4 Institute of Human Genetics, University of Bonn, School of doi: 10.1016/j.euroneuro.2018.08.392 Medicine & University Hospital Bonn

5 Central Institute of Mental Health, University Medical Center Mannheim/University of Heidelberg

SU29 6 Institute of Biomedicine (IBIMA), University Hospital of PREDICTING PSYCHOPATHOLOGY WITH POLYTRAN- Malaga

SCRIPT RISK SCORES 7 Carlos Haya Regional University Hospital

Jonathan Hess, Stephen J. Glatt Background: Bipolar Disorder (BD) is a genetically complex neuropsychiatric disorder with an estimated heritability of SUNY Upstate Medical University approximately 70%. Recent GWAS have shown that common risk factors substantially contribute to the development of Background: Polygenic risk scoring (“the Purcell method”) BD. Yet, common alleles cumulatively explain only 25-38% has become a widely used technique for summarizing small of the phenotypic variance, suggesting that other so far un- risk-associated effects across thousands of genetic vari- known genetic factors must play a role. Rare variants with ants to predict liability for complex disorders. An analo- higher penetrance might explain some of the hidden her- gous method has not yet been introduced for application itability and may particularly be present in families with in transcriptomic data. Here, we present a novel method multiple individuals affected with BD. A research strategy called polytranscript risk scoring (PTRS) which measures to identify such rare variants is Whole Genome Sequencing transcriptome-wide changes in gene expression associated (WGS) of promising multigenerational families with BD. In with a disorder or phenotype. the present study we conducted WGS of 108 individuals in a Methods: PTRS is a single variable that can be easily com- set of 8 extended multigenerational and multiply affected puted and incorporated into standard machine learning families of Spanish origin. On average we sequenced 14 af- models for objectives such as risk prediction. In this study, fected and unaffected individuals per family. we constructed PTRS for bipolar disorder (BD) using our Methods: Library enrichment was done PCR free with the multi-site transcriptomic mega-analysis that compared pe- KAPA HTP/LTP Library Preparation Kit and WGS was per- ripheral blood gene expression profiles in a predominantly formed at 30X on an Illumina HiSeq2500v4 system. Variant adult sample of cases affected with BD (n = 95) with non- calling files (VCF) were created for all individuals using an affected comparison subjects (NCs, n = 111). in-house developed pipeline based on GATK´ s best practice Results: PTRSs explained a significant proportion of risk guidelines. For the visualization and data handling we set for BD and could accurately discriminate BD-affected cases up an analysis workflow based on the CRAN package vcfR from NCs with an average AUC of about 70% (p < 0.0001). and in-house developed R-scripts. We conducted a gene We hypothesized that PTRS for BD may generalize to other set/pathway analysis for the resulting genes using Ingenuity ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 17

Pathway Analysis and ConsensusPathDB. In addition to that Methods: Isolation of genomic DNA with the salting out we conducted Polygenic Risk Score analysis (PRS) in the sub- technique from fasting blood of study participants with BD set of the 8 WGS analyzed families. (n = 32). Methylation analysis of the clock gene ARNTL (CG Results: In our analysis we focused on rare variants with site cg05733463) was performed with bisulfite treatment/ a minor allele frequency (MAF) below 1% (according to the Epitect kit, PCR and pyrosequencing. The microbiome was ExAC database). Our first analysis is an “extended exome” analyzed with 16S rRNA gene analysis. analysis of WGS data. We applied a narrow analysis model Results: The methylation status of the cg05733463 site to identify overlapping, rare, co-segregating variants in the of ARNTL correlated significantly with bacterial diversity affected individuals in one family which are not shared by (Simpson Index: r = -0.389, p = 0.0238) and evenness (Simp- healthy individuals within the same family. In addition, we son evenness index: r = -0.358, p = 0.044). also applied an analysis model in which we take into ac- Discussion: If the methylation of the clock gene ARNTL count incomplete penetrance. All synonymous, missense, was influenced by the gut-microbiome diversity, probiotics nonsense and frameshift variants were included. In total we could putatively have an “antidepressant” effect, because identified 1 protein truncating and 9 missense variants. PRS the molecular clock is connected with mood regulation (the analyses in the families show very diverse risk profiles for transcription of the clock gene ARNTL correlates positively healthy and affected individuals among the 8 analyzed fam- with the transcription of the serotonin, noradrenaline and ilies. dopamine degrading enzyme MAOA). Probiotics are espe- Discussion: Most identified variants are classified as not dis- cially promising for those not benefitting from common an- ease causing and are typically not carried by all affected tidepressant treatments or for patients suffering from side individuals in one family. Gene set enrichment analyses effects. Nevertheless, further research is necessary. (IPA and ConsensusPathDB) mainly highlight immunological genes suggesting a possible role of immunological processes Disclosure: Nothing to disclose. in BD which has also been reported for schizophrenia. As doi: 10.1016/j.euroneuro.2018.08.395 a next analysis step we will include information on clinical subgroups, such as BDI and BDII and analyze the combined effect of PRS data and rare variants on clinical phenotype. Based on our results we plan re-sequencing of iden- SU32 tified promising genes in an independent cohort of 1000 BD GENETICS OF SLEEP DURATION AND BIPOLAR DIS- cases and 1000 controls of German origin to further support ORDER their potential role in BD. We are currently working on the 1 1 1 incorporation of other types of genetic variation (structural Katie Lewis , Alexander Richards , Ganna Leonenko , 2 1 1 variation) and the establishment of analysis pipelines for in- Katherine Gordon-Smith , Liz Forty , Sarah Knott , 2 1 1 tergenic regions. Lisa Jones , Valentina Escott-Price , Michael Owen ,

Nick Craddock 1, Ian Jones 1, Michael O’Donovan 1,

Disclosure: Nothing to disclose. Arianna Di Florio 1 doi: 10.1016/j.euroneuro.2018.08.394 1 Cardiff University

2 University of Worcester

Background: Bipolar disorder (BD) is associated with sleep

SU31 disturbances independently of mood state, and has been

METHYLATION ANALYSIS OF THE MOLECULAR CLOCK proposed to be an endophenotype for BD. However, genome AND BACTERIAL DIVERSITY IN BIPOLAR DISORDER wide association studies have reported mixed results when calculating genetic correlations between sleep traits and 1 1 Susanne Bengesser , Sabrina Mörkl , BD. BD is a multifactorial and heterogeneous disorder; thus, 1 1 Jolana Wagner-Skacel , Frederike Fellendorf , sleep disturbances may play a more potent role in the aeti- 1 1 1 Martina Platzer , Konstantin Bauer , Tanja Kirchschlager , ology of the disorder for some individuals and not others. 1 1 1 Annamaria Painold , Bettina Halwachs , Eva Reininghaus , We therefore hypothesized that polygenic risk scores for 1 1 2 Carlo Hamm , Alexander Maget , Andreas Waha sleep phenotypes could be used to identify particular clinical strata of individuals with BD.

1 Medical University of Graz Methods: Participants were 4863 individuals with BD re-

2 University of Bonn cruited from the Bipolar Disorder Research Network (BDRN) and 5714 controls recruited from the 1958 British Birth Co- Background: The gut-brain-axis, which is an extensive bidi- hort and UK Blood Services. All participants were white and rectional communication network between the gastroin- recruited within the United Kingdom between January 1 testinal tract and the brain, is in the spotlight of research 2000 and December 21 2013. Clinical subphenotypes of BD nowadays. Nevertheless, little is known about the mecha- were ascertained via semi-structured psychiatric interview nisms of this gut-brain-axis. There are results, which sug- (the Schedules for Clinical Assessment in Neuropsychiatry) gest that metabolites of microbiota affect gene regulation and case notes. Polygenic risk scores (PRS) for sleep traits in the human body. Thus, we investigated, whether bacte- were derived from publicly available genome wide associ- rial diversity is interconnected with epigenetic changes in ation study summary statistics. Binary and multinomial lo- the peripheral blood. gistic regression analyses examining associations between ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 18 Abstracts

PRS for sleep traits (at p value threshold ≤ 1) and outcome were used to choose a 1-to-1 case-control sample matched variables were adjusted for 10 population principal compo- on selected covariates. The variants were annotated using nents. variant effect predictor (VEP) and dbNSFP. Loss of function Results: After quality control, a maximum of 92,234 SNPs singletons are defined as variants that appear only once in were used to generate PRS at a p value threshold ≤ 1 in 5714 the dataset and are annotated either as frameshift, essen- controls and 4863 individuals with BD. Using multinomial lo- tial splice sites or nonsense. We will use Mendelian clinically gistic regressions, PRS for sleep duration were significantly applicable pathogenicity (M-CAP) score to define missense- associated with severe clinical phenotypes of BD compared damaging variants. We will use logistic regression to assess to controls, but not less severe BD clinical phenotypes. whether bipolar cases have more missense-damaging vari- Discussion: Sleep duration PRS may identify clinically mean- ants. In addition to exome-wide analyses, we will use large ingful substrata of individuals with BD, suggesting that per- gene sets previously found to be associated with schizophre- turbations in the sleep-wake regulation systems play a more nia, including constrained genes and targets of fragile X significant role in the aetiology of BD for these individuals. mental retardation protein (FMRP), to test for enrichment Our results also potentially explain the lack of significant of rare loss of function and missense damaging variants. genetic correlations found between BD and sleep duration Results: Loss of function singleton association results show in previous research. that bipolar cases have significantly more loss of function singletons than the controls (p = 0.0385, beta = 0.046). Av- Disclosure: Nothing to disclose. erage numbers of loss of function singletons in each control and bipolar patient are 3.94 and 4.24, respectively. This dif- doi: 10.1016/j.euroneuro.2018.08.396 ference is similar to results from exome sequencing study of schizophrenia (a difference of 0.12 variants per person). Discussion: Results from GWAS studies suggest a polygenic

SU33 architecture for bipolar disorder. With ∼1000 bipolar cases, ANALYSIS OF WHOLE EXOME SEQUENCING OF 1000 we remain underpowered to identify any significant rare BIPOLAR PATIENTS variants or genes associated with the disorder. Neverthe- less, we are able to detect a nominally significant rare vari- 1 1 2 Weiqing Wang , Tan Hoang Nguyen , Shaun Purcell , ant burden exome-wide in bipolar disorder cases. We expect 3 4 1 Mikael Landen , Patrick Sullivan , Eli Stahl multiple rare variants that may converge in specific pathways contribute to the risk of bipolar.

1 Icahn School of Medicine at Mount Sinai

2 Brigham & Women’s Hospital Disclosure: Nothing to disclose.

3 Gothenburg University doi: 10.1016/j.euroneuro.2018.08.397 4 University of North Carolina at Chapel Hill

Background: Bipolar disorder (BD) is a common, severe SU34 mood disorder that affects more than 1% of the worldwide population. Despite the high genetic component in the dis- CSMD1 GENETIC VARIANT IS ASSOCIATED BOTH WITH order, the genetic architecture of bipolar remains elusive. ALZHEIMER’S DISEASES AND SCHIZOPHRENIA IN A Meta-analysis of genome-wide association studies (GWAS) RUSSIAN POPULATION with over 20,000 BD cases reveals over 20 loci associated 1 1 1 with BD. Despite GWAS’s success in uncovering robust asso- Anna Bocharova , Kseniya Vagaitseva , Oksana Makeeva , 1 2 2 ciations between common variants and the BD trait, it is es- Andrey Marusin , Natalya Zhukova , Irina Zhukova , 2 2 1 timated that the total variance in liability to BD that can be Valentina Alifirova , Maria Matveeva , Vadim Stepanov explained by all common SNVs does not exceed 25%. Exome sequencing has revealed a significant burden of deleterious 1 Research Institute of Medical Genetics rare variants in patients with schizophrenia, which overlaps 2 Siberian State Medical University with bipolar disorder clinically and genetically. Therefore, rare variants may be expected to explain additional risk for Background: Common neuro-psychiatric disorders including BD. We present analysis of rare coding variation in bipolar Alzheimer’s disease (AD) and schizophrenia (SHZ) are the disorder cases and controls from Sweden. We try to identify subject of intensive genetic research. The genetic etiology any burden of rare variants in genes, gene sets or exome- of AD and SHZ is heterogeneous. Genetic variants associ- wide that are associated with bipolar disorder. ated with impairments in language, memory and executive Methods: 1169 blood-derived DNA samples from bipolar functions, which are an important endophenotypes for AD disorder patients were collected as part of the Sweden and SHZ, have been revealed by GWAS. Potentially, the in- dataset, which also includes 4970 schizophrenia cases and creased prevalence of AD and schizophrenia may be related 6245 controls. DNA samples were sequenced with Agilent to a shared genetic liability. The aim of this study was to SureSelect Human All Exon Kit and Agilent SureSelect Hu- analyze associations of 42 SNPs reported in GWAS with AD man All Exon v. 2 Kit in 12 waves. We performed rigorous and SHZ in Russian population. All SNPs had been previously quality control and removed individuals and variants based identified by GWAS as genetic susceptibility factors for AD, on covariates including sequencing metrics, principle com- SHZ or cognitive impairments. ponents, genotype missingness and number of heterozygous Methods: 190 patients with AD, 711 healthy controls, sites. Nonparametric matching methods (MatchIt r package) and 350 SHZ patients, 670 healthy controls matched ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 19 to the patients by age, gender, and ethnicity were in- plex patterns of brain MRI phenotypes less susceptible to a cluded in the study. 42 SNPs were genotyped by MALDI- priori assumptions. In this regard, independent component TOF mass-spectrometry using MassARRAY Analyzer 4 (Agena analysis (ICA) may provide sensitive neuroimaging biomark-

Bioscience TM). Allele specific ORs and associated p-values ers for finding genetic influences on selectively vulnerable were calculated. brain structures. Results: Three susceptibility loci for AD were identi- Methods: We extracted a data-driven signature of structural fied in our study in Russian patients: rs12989701 at brain covariation in 1,100 participants of the ADNI cohort LOC105373605 locus (OR = 1.46, p = 0.0459), rs2616984 at using MRI data, ICA and Tensor-Based Morphometry (TBM). CSMD1 gene (OR = 1.33, p = 0.02) and rs1532278 at gene Brain morphometry maps of the population were fed into CLU (OR = 1.28, p = 0.04). Seven loci was found in asso- ICA to extract spatial components of anatomical brain vari- ciation with the SHZ in Russian patients: rs2247572 at ation with informative power in AD discrimination. After ex- KCNB2 gene (OR = 1.276, p = 0.0468), rs2616984at CSMD1 tracting the most sensitive 3D signature of AD by a compu- gene (OR = 1.73, p = 0.0337), rs12807809 at intergenic re- tational whole-brain search, which robustly mapped to the gion SPA17-NRGN (OR = 1.33, p = 0.0337), rs11064768 at neuroanatomy of the memory limbic system, it was used in CCDC60 gene (OR = 1.79, p = 0.001), rs16887244 at LSM1 a whole-genome-sequencing based association study (read gene (OR = 1.31, p = 0.0221), rs7004633 at intergenic re- depth = 30-40x) to identify genetic polymorphisms with sig- gion LOC100129100-LOC100509857 (OR = 1.34, p = 0.0134), nificant correlation with volume deficits in this brain com- rs7561528 at LOC105373605 gene (OR = 1.85, p = 0.0231). ponent. The top-hit variant was subsequently explored in Discussion: We observed the common association of the ge- the UK Biobank dataset for potential association with ma- netic variant in the CSMD1 gene with AD and SHZ in the Rus- ternal and paternal history of AD in more than 290,000 par- sian population. The CSMD1 gene encodes an important cell ticipants. adhesion molecule which plays pivotal roles in the develop- Results: Logistic regression showed that the most promi- ment, connection and plasticity of brain circuits. The CSMD1 nent imaging predictor of AD is a neuroanatomical com- might be an important factor in susceptibility to both AD and ponent which performed better than hippocampal volume SHZ. measure in predicting subjects with AD and mild cognitive This work was supported by the Russian Science Founda- impairment from the cognitively normal group. This com- tion (project # 16-15-00020). ponent was bilaterally symmetric, and spanned voxels of amygdalae, hippocampi, entorhinal cortex, insula, mammil- Disclosure: Nothing to disclose. lary bodies, and fornix with a network-like topology in 3D. Whole-genome association revealed that a missense vari- doi: 10.1016/j.euroneuro.2018.08.398 ant in SHARPIN, coding for a synaptic scaffold protein, is correlated with brain volume deficits in this critical compo-

nent (rs34173062, p = 2.1 ×10 −¹0). The same variant was also

SU35 correlated with parental history of AD in the UK BioBank

GENOME-WIDE SEQUENCING AND DATA-DRIVEN NEU- cohort (p both parents = 2.3x10 −6; p maternal = 0.0012; p

ROANATOMICAL MRI ANALYSIS SUGGESTS SHARPIN paternal = 5.1x10 −4), with a biologically consistent effect di- MISSENSE VARIANT FOR ALZHEIMER’S DISEASE rection of the risk allele (A) across the ADNI and UK BioBank datasets. 1 1 Sourena Soheili-Nezhad , Emma Sprooten , Discussion: Our exploratory search reveals that AD is cor- 1 2 Christian F. Beckmann , Sebastian Guelfi , related with deficits in a unified anatomical structure span- 3 4 5 Reza Khosrowabadi , Andrew J. Saykin , Neda Jahanshad , ning regions of the limbic system engaged in memory for- 5 6 Paul M. Thompson , Mojtaba Zarei mation and retrieval. We report a new locus in SHARPIN as a genetic modifier of this limbic-specific MRI signature and

1 Donders Institute for Brain, Cognition, and Behaviour, also show its strong correlation with a positive family his- Radboud University Medical Centre, Nijmegen tory of AD. SHARPIN codes for a SHANK scaffold synaptic

2 University College London (UCL) Institute of Neurology protein and links the postsynaptic density neurotransmit-

3 Institute for Cognitive and Brain Sciences, Shahid Beheshti ter receptors with the actin cytoskeleton. SHARPIN is also a University known modulator of the NF- κB signaling pathway with roles

4 Center for Neuroimaging, Indiana University School of in learning and memory. Our ﬁndings show that exploratory Medicine imaging measures aid in discovering novel genetic risk loci

5 Imaging Genetics Center, USC Mark and Mary Stevens of AD with signiﬁcant inﬂuence on pathways of disease pre- Neuroimaging and Informatics Institute, Keck School of disposition. Medicine of USC

6 Institute of Medical Science and Technology, Shahid Be- Disclosure: Nothing to disclose. heshti University doi: 10.1016/j.euroneuro.2018.08.399

Background: Alzheimer’s disease is a heritable neurodegenerative disorder, but much of the responsible underlying molecular and system-level brain mechanisms remain elusive. Hippocampal volume loss is commonly used as an imaging biomarker of AD. Data-driven source separation methods are emerging as a promising tool for capturing more com- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 20 Abstracts

SU36 SU37 THE ASSOCIATION OF GENETIC RISK FOR ALZHEIMER’S INCREASED GENETIC RISK LOAD FOR MAJOR DEPRES- DISEASE WITH COGNITIVE MEASURES, EDUCATIONAL SION IN PATIENTS ASSIGNED TO ELECTROCONVULSIVE ATTAINMENT AND BEHAVIOURAL OUTCOMES IN CHIL- THERAPY DREN

Jerome Foo 1, Fabian Streit 1, Josef Frank 1, Stephanie Witt 1,

Roxanna Korologou-Linden, Emma L. Anderson, Jens Treutlein 1, Major Depressive Disorder Working Group

Hannah Jones, George Davey Smith, Laura Howe, of the Psychiatric Genomics Consortium, Bernhard Baune 2,

Evie Stergiakouli Susanne Moebus 3, Karl-Heinz Joeckel 3,

Andreas J. Forstner 4, Markus Nöthen 4, Marcella Rietschel 1, 1 1 MRC Integrative Epidemiology at the University of Bristol Alexander Sartorius , Laura Kranaster

1 Background: The lack of effective therapies for Alzheimer’s Central Institute of Mental Health 2 disease has placed added importance into the identification University of Adelaide 3 of modifiable risk factors prior to disease onset. Lower ed- University Clinics Essen, University Duisburg-Essen 4 ucational attainment is the only risk factor to have been University of Bonn consistently associated with Alzheimer’s disease. Recent studies have identified genetic variants associated with Background: Electroconvulsive therapy (ECT) is the treat- Alzheimer’s disease, but it is not currently known how they ment of choice for severe and treatment-resistant depres- increase the risk of disease. One possibility is that ge- sion, but its underlying mechanisms remain poorly under- netic risk influences cognitive development early in life. stood; unfavorable treatment response is thought to be in- We used polygenic risk scores (PRS) to examine whether a fluenced by genetic factors. Increasing evidence shows that genetic risk for Alzheimer’s disease is associated with cog- severity of psychiatric disorder is associated with higher ge- nitive, educational attainment and behavioural outcomes netic burden for disorder; depression has been shown to be through childhood and adolescence without the selection a highly polygenic disorder (i.e. the result of the contribu- bias present in late-life studies. tion of many genetic variants). Methods: PRS were computed for children from the Avon Methods: In this study, we tested whether ECT assign- Longitudinal Study of Parents and Children (ALSPAC) co- ment and response/non-response were associated with an hort based on the summary statistics from the genome- increased genetic burden for major depression (MD) us- wide association study (GWAS) of Alzheimer’s disease by ing polygenic risk scores (PRS), which summarize the con- the IGAP consortium. A PRS was calculated for each par- tribution of disease-related common risk variants. Fifty- ticipant with genetic data using PLINK (version 1.9). Each two psychiatric inpatients suffering from a major depres- score was calculated from the effect size logarithm odds- sive episode underwent ECT. MD-PRS were calculated for weighted sum of associated alleles within each participant. these inpatients, as well as a separate population-based PRS were created for the following significance thresholds: sample (n = 3547 healthy; n = 426 self-reported depression) 5x10-8 (genome-wide significance threshold), 5x10-2, and based on summary statistics from the Psychiatric Genomics 5x10-1 (and including/excluding apolipoprotein E (ApoE)). Consortium MDD working group (Cases: n = 59,851; Controls: Results: The PRS at the most liberal p-value threshold ex- n = 113,154). amined (p ≤5x10-1) was associated with lower educational Results: Response to ECT was positively correlated with be- attainment at ages 14 and 15 years. One standard devia- ing male (rho = 0.332, p = 0.045), having a positive family tion increase in PRS was associated with 0.03 (95% confi- history for affective disorders (rho = 0.358, p = 0.029) and dence interval [CI]: -0.05,-0.003) lower standardized exam negatively correlated with diagnosis of personality disorder points at Key stages 4 and 5. Additionally, one standard de- (rho = -0.335, p = 0.029). In association analyses, MD-PRS viation increase in PRS (at p ≤5x10-2 and p ≤5x10-1) was as- explained a significant proportion of disease status between sociated with 0.03 (95% CI: -0.06, -0.01) and 0.04 (95% CI: ECT patients and healthy controls (p = 0.022, R2 = 1.173%); -0.07, -0.02) lower standardized total IQ at age 8 years, re- patients showed significantly higher MD-PRS. MD-PRS in spectively. No associations were observed for PRS at 5x10-8 population-based individuals self-reporting depression were or behavioural outcomes. Associations were similar includ- intermediate between ECT patients and controls (n.s.). Sig- ing/excluding ApoE. nificant associations between MD-PRS and ECT response Discussion: Our study is the first to examine the associa- (50% reduction in Hamilton Depression Rating Scale Scores) tion between genetic risk of Alzheimer’s disease and both were not observed. educational/cognitive and behavioural outcomes in child- Discussion: Our findings indicate that ECT cohorts show an hood/adolescence. Our findings suggest that genetic over- increased genetic risk load for MD and are consistent with lap may exist between Alzheimer’s disease, educational at- the hypothesis that treatment-resistant MD patients repre- tainment, and cognitive measures at liberal PRS thresholds. sent a subgroup characterized by an increased genetic risk for MD. Going forward, ECT should be should be given fur- Disclosure: Nothing to disclose. ther consideration as a model to examine the etiology of antidepressant response by applying time-sensitive molecular doi: 10.1016/j.euroneuro.2018.08.400 ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 21 methods to take advantage of its clear pre-post treatment SU39 design. GENETIC VARIATION IN THE MAJOR HISTOCOMPATI- BILITY COMPLEX AND ASSOCIATION WITH DEPRESSION Disclosure: Nothing to disclose. 1 1 1 doi: 10.1016/j.euroneuro.2018.08.401 Kylie Glanville , Jonathan Coleman , Ken B. Hanscombe ,

Jack Euesden 1, Shing Wan Choi 1, Kirstin Purves 1, Major

Depressive Disorder Working Group 2, Paul F. O’Reilly 1,

Cathryn M. Lewis 1 SU38

EARLY ONSET DEPRESSION: CHARACTERISING DE- 1 King’s College London

VELOPMENTAL TRAJECTORIES AND THE ROLE OF 2 Psychiatric Genomics Consortium NEUROPSYCHIATRIC GENETIC RISK VARIANTS Background: The prevalence of depression is higher in indi-

Frances Rice 1, Lucy Riglin 1, Ajay K Thapar 1, Jon Heron 2, viduals suffering from autoimmune diseases, but the mech-

Richard Anney 1, Michael O’Donovan 1, Anita Thapar 1 anisms underlying the observed comorbidities are unknown. Epidemiological ﬁndings point to a bi-directional relation-

1 Cardiff University ship - depression increases the risk of developing an autoim-

2 School of Social and Community Medicine, University of mune disease, and vice-versa – and shared genetic etiology Bristol is a plausible explanation. In this study, we tested whether genetic variation in the MHC region that increases risk of

Background: Depression often ﬁrst manifests in adoles- autoimmune disorders, also confer risk for depression. cence. Thereafter individual developmental trajectories Association between genetic variation in human leuko- vary substantially but it is not known what shapes de- cyte antigen (HLA) genes and autoimmune diseases is well pression trajectories in youth. Recent evidence from adult established. Recent ﬁndings indicate that the HLA class III genome-wide association studies suggests that schizophre- complement component 4 (C4) haplotypes are associated nia genetic risk may contribute to earlier onset depression. with schizophrenia. The Psychiatric Genomics Consortium

Methods: A longitudinal sample of adolescents who re- (PGC), which performed the largest GWAS of depression ported on depression on multiple occasions between age to date, found association in the MHC region. Highly poly-

10.5 years and 18.5 years. Trajectories based on self- morphic alleles and long-range linkage-disequilibrium in the reported depressive symptoms dichotomized by the clinical HLA region complicate the interpretation of SNP associa- cut-point for the scale. MDD, schizophrenia and Attention tions.

Deﬁcit Hyperactivity Disorder (ADHD) polygenic risk score Methods: We ﬁne-mapped the classical MHC region

(PRS) were predictor variables. (chr6:29,640,000–33,120,000), imputing 216 HLA alleles and

Results: Latent class growth analysis identiﬁed three four C4 haplotypes in a PGC subsample and the UK Biobank distinct trajectory classes –a persistently low class (UKB) to investigate the role of these loci in the suscepti-

(73.7%), a late-adolescent-onset class (17.3%), and an early- bility to depression. In the PGC, 15,805 cases, 23,340 con- adolescent-onset class (9.0%). The late-adolescent class, trols had genotype-level data available. Cases met a life- which had features of a ‘typical’ post-pubertal-onset de- time diagnosis of major depressive disorder, determined by pression trajectory, was associated with an elevated ge- a structured diagnostic interview. In the UKB, 29,344 cases netic risk for depression as indexed by MDD PRS, but not and 63,358 controls were identiﬁed from an online mental with liability to neurodevelopmental disorders. In the early- health questionnaire, based on the Composite International adolescent onset class, depression had an onset by age 12, Diagnostic Interview Short Form. The total sample size was and was associated with the neurodevelopmental as well 45,149 cases and 86,698 controls. as MDD genetic risk, with the strongest association coming HLA alleles were imputed using SNP2HLA with the Type = from genetic liability to ADHD. 1 Diabetes Genetics Consortium reference panel (n 5,225).

Discussion: We found evidence of distinct depressive tra- C4 haplotypes were imputed with the HapMap CEU refer- = jectories, primarily distinguished by age-at-onset. The more ence panel (n 110), assayed by the McCarroll Lab to cap- typical depression trajectory with onset of clinically sig- ture structural variation (long and short alleles) and copy nificant symptomatology at around age 16 was associated number variation in C4A and C4B genes. Imputed SNPs were with MDD genetic risk. The less common depression trajec- already available for analysis in both the PGC and UKB. tory, with a very early onset, was particularly associated We tested for association between depression status and with ADHD and schizophrenia genetic risk. These findings imputed MHC variants in each study using additive models are consistent with emerging evidence for a neurodevelop- and controlled for six principal components. We then per- mental component to some cases of depression and suggest formed an inverse-variance weighted meta-analysis across that this is more likely when onset is very early. the PGC and UKB samples. Results: No HLA alleles or C4 haplotypes were associated Disclosure: Nothing to disclose. with depression in the PGC, UKB or meta-analysis. The meta-analysis revealed independent signal from one indel doi: 10.1016/j.euroneuro.2018.08.402 in the classical class I region at the level of region-wide significance (rs368739359, p = 1.05e06, OR = 1.03). ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 22 Abstracts

Discussion: We investigated whether genetic variation in associated co-methylation module (P = 0.04). Interestingly, the MHC region that increases risk for autoimmune diseases, the depression-associated module was highly enriched for also increases risk for depression. We found no evidence pathways related to immune function and was also associ- that HLA alleles, which play a major role in the genetic ated with TL and IL-6 cytokine levels. susceptibility to auto-immune disorders, or C4 haplotypes, Discussion: In summary, our genome-wide DNA methylation which are strongly associated with schizophrenia, harbor analysis of individuals with and without a self-reported his- risk for depression. We found suggestive evidence for asso- tory of depression identiﬁed several candidate DMRs of po- ciation of an indel, rs368739359, which mirrors results from tential relevance to the pathogenesis of depression and its the full PGC MDD GWAS. Collectively, these results do not associated immune-dysfunction phenotype. support the theory that comorbid depression and autoimmune diseases are driven by shared genetic etiology in the Disclosure: Nothing to disclose. MHC region. doi: 10.1016/j.euroneuro.2018.08.404

Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.403 SU41 GENETIC INFLUENCES ON SUICIDAL BEHAVIOR IN A SAMPLE OF CHINESE WOMEN WITH MAJOR DEPRESSIVE SU40 DISORDER DNA METHYLATION AND INFLAMMATION MARKER

PROFILES ASSOCIATED WITH A HISTORY OF DEPRES- Alexis Edwards 1, Murray Stein 2, Anna Docherty 3,

SION Hilary Coon 3, Jonathan Flint 4, Kenneth Kendler 5

Bethany Crawford 1, Zoe Craig 1, Georgina Mansell 1, 1 Virginia Institute for Psychiatric and Behavioral Genetics

Isobel White 1, Adam Smith 1, Steve Spaull 1, Jennifer Imm 1, 2 University of California, San Diego

Eilis Hannon 2, Andrew Wood 1, Hanieh Yaghootkar 1, 3 University of Utah School of Medicine

Yingjie Ji 1, Major Depressive Disorder Working Group 3, 4 University of California Los Angeles

Niamh Mullins 4, Cathryn Lewis 4, Jonathan Mill 1, 5 Virginia Commonwealth University

Therese Murphy 1 Background: Suicidal behavior (SB) is a leading cause of

1 University of Exeter death and a critical public health issue worldwide. SB, in-

2 University of Exeter Medical School cluding thoughts of death, suicidal ideation, or attempts,

3 Psychiatric Genomics Consortium is a symptom of depression, and its prevalence among indi-

4 King’s College London viduals with depression is substantially higher than among the population at large. Previous studies have implicated Background: Depression is a common and disabling disor- genetic factors in SB, but most research has been conducted der, representing a major social and economic health is- in samples of European descent; the extent to which ge- sue. Moreover, depression is associated with the progression netic risk is shared across ancestry is unknown. Further- of diseases with an inflammatory etiology including many more, the genetic relationship between depression-related inflammatory-related disorders. At the molecular level, the SB and other psychiatric outcomes has not been fully char- mechanisms by which depression might promote the onset acterized. of these diseases and associated immune-dysfunction are Methods: We used data from the China, Oxford, and VCU Ex- not well understood. perimental Research on Genetic Epidemiology (CONVERGE) Methods: In this study we assessed genome-wide patterns project, a study of Han Chinese women with recurrent of DNA methylation in whole blood-derived DNA obtained major depressive disorder (MDD). Cases reported on sui- from individuals with a self-reported history of depression cidal ideation, plans, and attempts within the context of (n = 100) and individuals without a history of depression their worst depressive episode (N = 2591-5802). We con- (n = 100) using the Illumina 450K microarray. Polygenic Risk ducted within-case genome-wide association studies (GWAS) Scores (PRS) were calculated using the P-values and log odds on these three outcomes, controlling for age and principal ratios from the most recent genome-wide association study components. We then submitted SNP-level results to Func- (GWAS) from the PGC MDD working group (7), without ex- tional Mapping and Annotation of Genome-Wide Association ternal meta-analysis study 23andMe. Finally, known biologi- Studies (FUMA) for gene-based tests and functional charac- cal markers of inflammation, telomere length (TL) and IL-6, terization of implicated loci. Finally, we examined whether were measured in DNA and serum samples respectively. polygenic risk for suicidal behavior, major depression, or Results: Our analysis identified 6 significant (Sidak cor- risk-taking behavior in European-descent samples was as- rected P < 0.05) depression-associated differentially sociated with suicidal behaviors in CONVERGE. methylated regions (DMRs); the top-ranked DMR was located Results: No individual marker met genome-wide signifi- in exon 1 of the LTB4R2 gene (Sidak corrected P = 1.27 cance across the three GWAS, potentially due to limited x 10-14). Next, we employed a systems-level approach to statistical power. Aggregate genetic analyses were more identify networks of co-methylated loci associated with a fruitful. Tw o genes met the corrected significance thresh- history of depression, in addition to depression PRS, TL old: FBXW8 (suicide plan) and SYK (attempt). Mutations in a and IL-6 levels. Our analysis identified one depression- mouse homolog of FBXW8 are associated with dendrite pat- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 23 terning. SYK is a putative modulator of epithelial cell growth to estimate the joint genetic correlation matrix between that may be inhibited by selective serotonin reuptake in- all traits and then calculated the partial genetic correlation hibitors. Implicated gene sets included drug transmembrane between depression and each trait after removing the vari- transport, catecholamine metabolic process, odorant bind- ance shared with neuroticism. ing, CD40 pathway, and other immune-related processes. Results: Using pairwise GWAS, we identified 9 genomic seg- Polygenic risk score (PRS) analyses were inconsistent across ments containing loci that influence depression but do not discovery and outcome phenotypes: PRS based on suicide associate with neuroticism. Genes associated with MDD, but completion, suicide attempt, and risk-taking behavior were not with neuroticism, were associated with glycosylation suggestively associated with suicidal ideation, plans, or and coronary heart disease. In contrast, there were 25 ge- attempts in CONVERGE, but PRS based on major depression nomic segments containing genetic variants that have ap- showed no associations. Only a small proportion of variance parently pleiotropic effects on both depression and neu- was accounted for by any PRS ( < 1%). roticism. From the partial genetic correlation analysis, we Discussion: Previous analyses indicate that the genetic cor- found that the shared genetic architecture between depres- relation between MDD in CONVERGE and psychiatric disor- sion and neuroticism explained most of the genetic corre- ders in European samples is modest to moderate; trans- lation that depression has with attention deficit hyperactiv- ancestry differences may contribute to the current results ity disorder, anorexia, psychological distress, schizophrenia, as well. In addition, heterogeneity across individuals ex- age of first birth, pubertal growth, and college completion. hibiting SB – e.g., those experiencing a depressive episode, However, depression—independent of neuroticism—had spe- post-traumatic stress disorder, high levels of impulsivity, or cific genetic correlations with bipolar disorder, body mass no discernable psychiatric condition –likely corresponds to index, chronotype (“morningness”), and triglycerides. underlying genetic heterogeneity. Further research, both Discussion: Our results confirm that the majority of specific within and across ancestry groups, is necessary to clarify genetic variants associated with depression are shared with the extent to which diverse genetic risk factors contribute neuroticism. However, we identified several genetic associ- to SB liability under different conditions. ation signals and correlations that were specific to depression. While these findings do not support all the character- Disclosure: Nothing to disclose. istics that were historically used to distinguish neurotic and endogenous depression, they suggest that there may be sub- doi: 10.1016/j.euroneuro.2018.08.405 types of non-neuroticism-related depression, with specific genetic associations with bipolar disorder, metabolic traits, and sleep patterns. SU42 COMMONALITIES AND DIFFERENCES IN THE GENETIC Disclosure: Nothing to disclose. ARCHITECTURE OF NEUROTICISM AND DEPRESSION doi: 10.1016/j.euroneuro.2018.08.406

Mark Adams 1, David Howard 1, Michelle Luciano 1,

Toni Clarke 1, Gail Davies 1, William Hill 1, Daniel Smith 2,

Ian J. Deary 1, David Porteous 1, Andrew McIntosh 1 SU43 EXAMINING THE ROLE OF SEX HORMONES IN POST-

1 University of Edinburgh NATAL DEPRESSION AND MAJOR DEPRESSIVE DISOR-

2 University of Glasgow DER: POLYGENIC RISK SCORES AND HIPPOCAMPAL NEUROGENESIS Background: Historically, major depressive disorder had been classified into ‘neurotic’ and ‘endogenous’ forms. Demelza Smeeth, Timothy Powell, Sandrine Thuret ‘Neurotic depression’ was diagnosed in the presence of preexisting emotional instability. ‘Endogenous depression’, in King’s College London contrast, was characterised by melancholic symptoms, disrupted sleep, impaired appetite, diurnal variation of mood Background: Genetic variation accounts for up to 54% of and impaired cognition. We tested for depression subtypes postnatal depression (PND) liability and 40% of major de- using genome-wide summary statistics of depression and pressive disorder (MDD) liability. Alterations to sex hor- neuroticism to identify shared and unique genetic associ- mones have been associated with the pathophysiology of ations and trait correlates. depressive disorders and may partly explain the higher rates Methods: We performed a pairwise genome-wide associa- of MDD amongst females. However, few studies have consid- tion analysis using summary statistics on depression from ered whether genetic variants associated with sex hormone the Psychiatric Genomics Consortium and on neuroticism levels directly increase risk for depressive disorders. This from UK Biobank. Pairwise GWAS was conducted to cate- risk may be mediated by alterations in adult hippocampal gorize each genomic segment as being associated with de- neurogenesis (HN), a cellular process which has been associ- pression only, neuroticism only, both traits, or neither trait. ated with mood regulation. Here we consider: i. the effects We used MAGMA and FUMA to identify genes and GWAS of oestradiol, testosterone and prolactin on human HN, and catalogue results that were associated with depression but ii. whether polygenic risk for higher sex hormone levels di- not with neuroticism. We then used LD Score regression to rectly affect risk for MDD or PND. calculate genetic correlations among depression, neuroti- Methods: To better understand how sex hormones affect cism and other traits. We implemented a Bayesian model HN, human female hippocampal progenitor cells (HPCs) ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 24 Abstracts were cultured with biologically relevant concentrations of microstructure and locally-derived cortical metrics for a each hormone. Immunocytochemistry and high-throughput smaller subset (N = 2,966). We used standard linear regres- analysis were used to quantify a range of markers of cell sion models to examine interactive effects between SCZ- fate. To understand how polygenic risk scores (PRS) for PGR and MDD case/control status on all neuroimaging mea- sex hormones moderate risk, we used the PRSice software sures. and sex hormone genome-wide summary statistics from the Results: We observed significant SCZ-PGR by MDD inter- Tw i n s UK cohort (n = 2913). Our target dataset was the Eu- actions for mean cortical thickness (CT) of rostral ante- ropean RADIANT cohort consisting of 176 PND, 2772 MDD rior cingulate cortex (ACC; β= .191, q = .004) and fractional and 1588 control subjects. Sex and seven ancestry princi- anisotropy (FA) in parahippocampal cingulum ( β= .141, pal components were included as covariates in all logistic q = .039). These were driven by positive associations be- regression analyses. tween SCZ-PGR and CT/FA among MDD cases ( β= .098, Results: When examining the effect of sex hormones on p = .026; β= .148, p = .001), versus negative/zero associa- HPC fate, prolactin increased the proportion of Map2- tions among controls ( β= –.087, p = .002; β= –.002, p = .854). positive cells (N = 4, F(6,21) = 7.04, p = 0.0003) indicating Maximal case-control differences occurred at lower SCZ- an increase in neuronal differentiation, but had no effect PGR, with convergence at higher SCZ-PGR. on HPCs maintained in a proliferative state. Conversely, Discussion: While we demonstrated significant SCZ-PGR by oestradiol and testosterone had no effect on HPC differ- MDD interactions in rostral ACC and parahippocampal cin- entiation, but increased cell number (N = 3, F(6,14) = 3.42, gulum, these results were driven by greater CT/FA among p = 0.027 & F(5,11) = 5.378, p = 0.0096). Only the best-fit MDD cases at low SCZ-PGR. Such results could reflect com- PRS for oestradiol levels was associated with a depressive pensatory/protective features among these subjects, or im- disorder, specifically PND case-control status ( β = -1156.4, pairments in synaptic pruning. Either way, MDD with high SE = 423.7, uncorrected p = 0.006), where genetic risk for SCZ-PGR may represent a neurobiologically distinct form of lower levels predicted higher risk for PND. the disorder. Discussion: Here we provide evidence that genetic risk for higher plasma oestradiol may explain a small amount of the Disclosure: Nothing to disclose. variance in risk for PND, potentially lowering risk via its abil- doi: 10.1016/j.euroneuro.2018.08.408 ity to increase HPC number. Furthermore, we provide evidence that prolactin possesses neurogenic properties, but that genetic risk for higher prolactin does not influence risk for depressive disorders. This work suggests that the rela- SU45 tionship between sex hormones, HN and depression is com- IDENTIFICATION OF DISEASE-RELATED SNP IN A MDD plex, and that there may not be a clear-cut pathway for SUSCEPTIBILITY GENE LHPP aetiology or risk moderation. Jing Li Disclosure: Nothing to disclose. Institute of Basic Medical Sciences, Peking Union Medical doi: 10.1016/j.euroneuro.2018.08.407 College, Chinese Academy of Medical Sciences

Background: Depression is an affective disorder character- SU44 ized by a long-lasting depressed mood or marked loss of in-

STRATIFYING MAJOR DEPRESSIVE DISORDER BY POLY- terest or pleasure. There are ∼350 million patients world-

GENIC RISK FOR SCHIZOPHRENIA: DIFFERENCES IN wide. It has high clinical heterogeneity and lack of clear eti- UNDERLYING NEUROBIOLOGY ology. Genetic susceptibility plays an important role in the pathogenesis of depression. Our earlier genetic research, by Mathew Harris, Xueyi Shen, Simon Cox, Jude Gibson, low-coverage whole genome sequencing (EXL-WGS) identi- Mark Adams, Toni Clarke, Ian J. Deary, Stephen Lawrie, fied one loci rs35936514 located in the intron of LHPP gene. Andrew McIntosh, Heather Whalley Considering the rs35936514 may represent a genetic signal of causal SNPs, we resequenced the coding region of LHPP University of Edinburgh gene to find potential mutations. Methods: We resequenced the LHPP gene of 474 depression Background: Major depressive disorder (MDD) is a herita- patients and 640 health controls. Each of the seven exons ble, disabling psychiatric disorder, defined by the presence of LHPP gene was amplified by Polymerase chain reaction of an arbitrary number of symptoms. Such syndromal defini- (PCR) and examined by Sanger sequencing. tions likely group individuals with diverse aetiologias. MDD Results: Totally 21 SNPs was identified in our sequenc- shares symptoms, risk genes and neuroimaging findings with ing data. A missense mutation c.A281G is statistically sig- other disorders, such as schizophrenia (SCZ). We hypothe- nificant after correction (R = 5.6572, corrected p = 0.0428, sized that differences in neuroimaging measures between OR = 1.6142, 95%CI = 1.0157-2.5654). MDD cases and controls vary as a function of polygenic risk Discussion: LHPP (phospholysine phosphohistidine inorganic (PGR) for SCZ, indicating an MDD subtype. pyrophosphate phosphatase), a highly conserved phos- Methods: We assessed 7,536 UK Biobank subjects with ge- phatase in evolution, exists in the form of homologous dimer netic, clinical and neuroimaging data. Imaging measures and catalyzes pyrophosphoric acid hydrolysis with the help included subcortical volumes, measures of white matter of magnesium ions. The missense mutation p. Glu94Arg was ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 25 located within a highly conserved motif that belongs to HAD weighted median, MR Egger, and MR-PRESSO as sensitivity like supefamily. The original Glutamate is replaced by argi- analyses. nine. Glutamate is changed into arginine by a missense mu- Results: We found evidence for protective influences of tation. Since glutamate is an acidic amino acid and argi- accelerometer-based activity on depression (IVW odds ra- nine is a basic amino acid. Their characters vary widely. tio (OR) = 0.74 for MDD per 1 SD unit increase in aver- We start thinking whether this replacement affect the LHPP age acceleration, 95% confidence interval (CI) = 0.59-0.92, enzyme activity. According to the reports, LHPP has three p = .006) when using SNPs meeting the relaxed threshold main activities, including the hydrolysis of O-P bonds in PPI, (i.e., 10 versus only 2 GWS SNPs, which provided insuffi- the hydrolysis of N-P bonds in phosphorylated histidine, and cient data for follow-up analyses). In the other direction, the hydrolysis of N-P bonds in phosphorylated lysine. Based we found no evidence for negative influences of depression that, we will verify whether this misplaced mutation affect on accelerometer-based activity (IVW b = 0.04 change in av- these activities of LHPP in the subsequent experiments. On erage acceleration per positive depression status, 95% CI = - the other hand, we will continue to test some other samples 0.43-0.51, p = .87). Furthermore, we did not see evidence to verify the missense mutation in case of error judgment for causal influences between self-reported activity and de- for small sample size. pression, in either direction and regardless of SNP set. Discussion: We apply MR for the first time to examine causal Disclosure: Nothing to disclose. influences between physical activity and depression. Inter- estingly, we discover that SNPs associated with objectively doi: 10.1016/j.euroneuro.2018.08.409 measured—but not self-reported—physical activity tend to show opposite effects on depression. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being

SU46 more representative of actual movement. Our ﬁndings val-

USING MENDELIAN RANDOMIZATION TO TEST CAUSAL idate physical activity as a causal protective factor for de- BIDIRECTIONAL INFLUENCES BETWEEN PHYSICAL pression and point to the importance of objective measure- ACTIVITY AND DEPRESSION ments of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the no- 1 1 2 Karmel Choi , Chia-Yen Chen , Murray Stein , tion that enhancing physical activity is an effective preven- 3 4 5 Yann Klimentidis , Meg Wang , PGC MDD Working Group , tion strategy for depression.

Karestan Koenen 4, Jordan Smoller 6 Disclosure: Nothing to disclose.

1 Massachusetts General Hospital doi: 10.1016/j.euroneuro.2018.08.410 2 University of California, San Diego

3 University of Arizona

4 Harvard T. H . Chan School of Public Health

5 PGC SU47

6 Massachusetts General Hospital, Harvard Medical School RISK FOR SCHIZOPHRENIA IN INDIVIDUALS WITH EATING DISORDERS AND THEIR RELATIVES Background: Burgeoning evidence from randomized con- 1 1 2 trolled trials and prospective cohort studies suggests that Ruyue Zhang , Ralf Kuja-Halkola , Cynthia Bulik , 1 physical activity has protective effects on depression, point- Sarah Bergen ing to a potential modifiable target for prevention and treatment. However, it remains unclear whether this in- 1 Karolinska Institutet verse association is due to the protective effect of physical 2 University of North Carolina at Chapel Hill activity on depression, and/or depression’s negative impact on physical activity. Here, we used bidirectional two-sample Background: Eating disorders and schizophrenia are highly Mendelian randomization (MR) that leverages the random heritable psychiatric disorders with profound morbidity and assortment of genetic variants (i.e., SNPs) at birth to es- elevated mortality risks. Although they have few symptoms tablish instruments free of usual sources of environmental in common, they have substantial shared genetic risk. How- or genetic confounding, to test causal influences between ever, almost no research has been conducted into the co- physical activity and depression. aggregation of these disorders in individuals and families. Methods: For genetic instruments, we selected inde- Methods: To address this, we used the Swedish National pendent top SNPs associated with depression and two Registers to identify people diagnosed with anorexia ner- physical activity phenotypes—self-reported and objective vosa (AN) or other eating disorders (OED; bulimia nervosa, accelerometer-based—from the largest available, non- binge eating disorder and eating disorders not otherwise overlapping genome-wide association results. We used two specified) who were born between 1977 and 2003. We then sets of genetic instruments: (1) only SNPs previously re- used Cox regression to calculate the risk for schizophrenia ported as genome-wide significant (GWS; p < 5x10-8), and (2) in these individuals and their family members compared to top SNPs meeting a more relaxed threshold (p < 1x10-7). For individuals without eating disorders and their relatives. Sex each direction of influence, we combined SNP-exposure and and birth year were included as covariates. SNP-outcome effects using an inverse variance weighted Results: Individuals with AN or OED were more likely to also (IVW) approach, with other standard MR methods such as have schizophrenia than people without these diagnoses ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 26 Abstracts

(OR = 6), and risk differed by sex with women being about lated and four downregulated in the addicted mice group twice as likely as men to receive an additional diagnosis of compared to the resilient one. Gene network analysis re- schizophrenia. Both fathers and mothers of children with vealed that these microRNAs may regulate multiple genes OED had increased rates of schizophrenia, but no elevated that are important for brain functions. For example: PTEN, risk was shown for parents of children with AN. involved in synaptic plasticity and long-term potentiation or Discussion: These results suggest that individuals with FOXP1, which has a role in neuronal development, autism all types of eating disorders have increased risks for and intellectual disability. schizophrenia. Schizophrenia rates were also elevated for Discussion: We highlighted novel miRNAs that might have an the parents of people with OED but not AN. Whether sib- important role in the susceptibility to eating addiction. Fur- lings, grandparents, aunts, uncles and cousins exhibit in- ther studies are required to understand their contribution creased risk for schizophrenia will also be calculated and of- to the disorder. fer additional insights into the relationships between these disorders. Deeper analyses will explore whether family his- Disclosure: Nothing to disclose. tory and/or high genetic risk for schizophrenia inﬂuences doi: 10.1016/j.euroneuro.2018.08.412 eating disorder course, severity, and outcome.

Disclosure: Nothing to disclose. SU49 doi: 10.1016/j.euroneuro.2018.08.411 GENOME-WIDE ASSOCIATION META-ANALYSIS OF CO- CAINE DEPENDENCE IN SAMPLES WITH EUROPEAN ANCESTRY SU48 MIRNA PROFILING IN A MOUSE MODEL OF EATING Judit Cabana-Domínguez, Anu Shivalikanjli, ADDICTION Noèlia Fernàndez-Castillo, Bru Cormand

Judit Cabana-Domínguez 1, Laura Domingo 2, University of Barcelona, Centro Nacional de Investigación

Laura Pineda-Cirera 3, Aurelijus Burokas 2, Biomédica en Red de Enfermedades Raras (CIBERER), Insti-

Rafael Maldonado 2, Bru Cormand 1, Elena Martín-García 2, tuto de Salud Carlos III, Institut de Biomedicina de la Uni-

Noèlia Fernàndez-Castillo 1 versitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues de Llobregat

1 University of Barcelona, Centro Nacional de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Insti- Background: Cocaine dependence is a complex neuropsy- tuto de Salud Carlos III, Institut de Biomedicina de la Uni- chiatric disorder that is highly comorbid with other psychi- versitat de Barcelona (IBUB), Institut de Recerca Sant Joan atric traits. Association studies suggest that common ge- de Déu (IR-SJD), Esplugues de Llobregat, Catalonia netic variants contribute substantially to cocaine depen-

2 Universitat Pompeu Fabra dence susceptibility. In the present work we performed a

3 University of Barcelona, Institut de Biomedicina de la Uni- genome-wide association (GWAS) meta-analysis of cocaine versitat de Barcelona (IBUB), Institut de Recerca Sant Joan dependence. de Déu (IR-SJD), Esplugues de Llobregat Methods: Four cocaine dependence GWAS datasets were obtained from the dbGaP repository. For each dataset, quality Background: Increasing evidence supports the idea that control and imputation were performed using the ‘Ricopili’ energy-dense food (high in refined sugars and fats) is ad- PGC GWAS pipeline. Association analysis was run under the dictive and leads to some forms of obesity. Addiction is a additive logistic regression model with PLINK v1.9 and the chronically relapsing disorder characterized by compulsiv- first 10 principal components were included as covariates. ity in the face of adverse consequences, persistence to seek A total of 2,085 cases and 4,293 controls, all of them with the reward and high motivation to overconsume which is European ancestry, were meta-analyzed using an inverse- observed in only a subpopulation of individuals. MicroRNAs weighted fixed effects model implemented in the software are very abundant in the central nervous system and play METAL. LD Score regression (LDSC) and polygenic risk score an important role in neuronal plasticity, memory and learn- (PRS) analyses were used to identify shared genetic risk fac- ing that underlie addiction. Here, we aimed to investigate tors between cocaine dependence and comorbid conditions. changes in microRNA profiling in a mouse model of eating Results: Although no genome-wide significant findings were addiction. found in the SNP-based analysis, the gene-based analy- Methods: Genetically identical inbred mice were exposed sis identified HIST1H2BD as significantly associated with to a recently validated animal model of eating addiction, cocaine-dependence (10% FDR). This gene is located in and two extreme subpopulations related to the phenotypes a region of chromosome 6 that is enriched in histone- of vulnerability and resilience to addiction were considered. related genes, previously associated with schizophrenia Using smallRNA sequencing, we compared microRNA expres- (SCZ). The top associated SNPs of this region, rs806973 and sion levels of addicted and resilient animals in the nucleus rs56401801 (P = 3.14e-06 and 3.44e-06, respectively), are accumbens (NAc) and medial prefrontal cortex (mPFC), two eQTLs for different genes in multiple brain areas. Further- key areas of the brain’s reward circuitry. more, we performed LDSC analysis with comorbid condi- Results: We identified six miRNA genes that are differen- tions and found significant genetic correlations between co- tially expressed in mPFC (FDR 10%), two of them upregu- caine dependence and SCZ, attention deficit/hyperactivity ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 27 disorder (ADHD), major depressive disorder (MDD) and risk- ined how cognitive biases might mediate the association be- taking behavior. We also found that all tested phenotypes tween genes and psychopathology. can significantly predict cocaine dependence status by per- Results: The GWAS revealed no genome-wide significant hits forming a PRS analysis: SCZ (R2 = 2.28%; P = 1.21e-26), ADHD which was expected due to low power resulting from a small (R2 = 1.39%; P = 4.5e-17), risk-taking behavior (R2 = 0.60%; sample size. However, polygenic scores, including those for P = 2.7e-08), MDD (R2 = 1.21%; P = 4.35e-15), children’s ag- MDD, significantly predicted cognitive biases, and depres- gressive behavior (R2 = 0.3%; P = 8.8e-05) and antisocial be- sion and anxiety explaining up to 4% of the variance. Fur- havior (R2 = 1.33%; P = 2.2e-16). thermore, significant evidence for mediation was found sug- Discussion: To our knowledge, this is the largest reported gesting that cognitive biases may lie on a causal pathway cocaine dependence GWAS meta-analysis in European- from genes to psychopathology. Cross-lag mediation analysis ancestry individuals. Despite the small sample size, we further confirmed this for cognitive biases in interpretation identified suggestive associations in regions that may be re- and memory. lated to cocaine dependence. Furthermore, we found evi- Discussion: The lack of any significant hits from the dence for shared genetic risk factors between cocaine de- genome-wide analysis is likely the result of inadequate pendence and several comorbid psychiatric traits. power due to small sample size. However, findings regarding the polygenic scores suggest that genetic risk for MDD Disclosure: Nothing to disclose. explains individual differences in interpretation and memory bias in children. Furthermore, these biases appear to lie doi: 10.1016/j.euroneuro.2018.08.413 on a causal pathway between MDD risk and depression and anxiety symptoms in adolescence. Replication of these effects in further longitudinal studies is required. Nevertheless, these findings highlight cognitive

SU50 biases as important targets for treatments and interventions THE GENETICS OF COGNITIVE BIASES IN THE DE- for children at a high genetic risk of psychopathology. VELOPMENT OF PSYCHIATRIC DISORDERS Disclosure: Nothing to disclose.

John Vincent 1, Charlotte Booth 2, Annabel Songco 2, doi: 10.1016/j.euroneuro.2018.08.414 Sam Parson 2, Anne-Wil Kruijt 3, Maud Grol 2,

Desiree Spronk 2, Robert Keers 1, Elaine Fox 2

1 Queen Mary University of London

2 University of Oxford SU51

3 Stockholm University INTERACTIONS BETWEEN OBSTETRIC COMPLICATIONS AND GENETIC LOAD FOR PSYCHIATRIC DISORDERS Background: Cognitive biases in attention, memory and IMPACT PSYCHOPATHOLOGY IN ADULTHOOD interpretation have been associated with several psychopathologies including anxiety and major depressive dis- Viktoria-Eleni Gountouna, Joeri Meijsen, Jonathan Hafferty, order (MDD). Tw i n studies have shown that the same genes Archie Campbell, Caroline Hayward, David Porteous, that explain variation in cognitive biases also increase the Andrew McIntosh, Kristin Nicodemus risk of depression and anxiety in children. Cognitive biases may therefore represent an important University of Edinburgh intermediate phenotype that explains how genetic risk in childhood develops into psychopathology in adolescence Background: Both genetic and environmental inﬂuences and could therefore be a potential target for the preven- contribute to psychopathology, not always independently. tion of these disorders. Nevertheless, this hypothesis is yet We investigated the interaction between increased genetic to be tested using a genome-wide approach in a longitudinal liability for psychiatric disorders or related traits and ob- design. stetric complications (OCs), an early environmental factor The current study aims to assess the genetic overlap be- known to inﬂuence later mental health, in the Generation tween psychopathologies and cognitive biases and examine Scotland cohort. whether, and to what extent these cognitive biases mediate Methods: OCs were obtained using medical record linkage the relationship between genetic risk for, and an outcome and polygenic risk scores (PRS) were created using publicly of psychopathology using a longitudinal study design. available data (N = 2697). We used general linear models Methods: We obtained whole genome data from 959 indi- to test for interactions between OCs (birthweight, labor in- viduals tested at age 12 and 14 for a range of attention, duction, Caesarean section, use of forceps, gestational age memory and interpretation biases, as well as externalizing and neonatal care admission) and PRS for loneliness, ex- and internalizing disorders as part of the CogBIAS Longitudi- traversion, neuroticism, anxiety, major depression, bipolar nal Study at The University of Oxford. and autistic spectrum disorders (ASD), schizophrenia and A genome-wide association study (GWAS) was conducted psychiatric cross-disorder. Outcomes were measures of psy- to identify genes associated with cognitive biases. We then chopathology: General Health Questionnaire (GHQ), Schizo- tested whether polygenic scores of adult psychopatholo- typal Personality Questionnaire (SPQ), Mood Disorder Ques- gies were associated with cognitive biases. Finally, using tionnaire (MDQ) and personality (Eysenck Extraversion and a phenome-wide approach to inform analysis, we exam- Neuroticism). ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 28 Abstracts

Results: Significant interactions for the GHQ were observed quantitative trait loci (eQTL) databases, or chromatin in- between PRS for anxiety and birthweight (p = 0.004) and ASD teraction databases. and use of forceps (p = 0.002). In addition, we found signifi- Results: Our analyses revealed six genomic risk loci for ru- cant interactions for the MDQ between PRS for bipolar disor- mination, on chromosomes 2, 3, 5, and 13. SNPs on chro- der and gestational age (p = 0.001), for neuroticism between mosome 3 was found to regulate brain expression of SR- PRS for bipolar disorder and use of forceps (p = 0.003) and GAP3 and SETD5, genes important in intellectual disabil- for extraversion between PRS for anxiety and gestational ity. Moreover, this genomic risk locus has shown chromatin age (p = 0.003). All p-values reported are after Bonferroni interaction with promoter region of the oxytocin receptor correction. gene OXTR, which has been associated with many psychi- Discussion: This is to our knowledge the first study to atric phenotypes, such as autism, empathy, panic disorder, show that interactions between OCs and increased genetic and, most importantly, major depression, alcohol abuse and load for psychiatric disorders influence measures of psy- eating disorder symptoms, for which rumination denotes a chopathology and related psychological traits in adulthood. risk. Our genomic risk locus on chromosome 13 comprises These findings add to our understanding of the complex re- SNPs regulating brain expression of KCTD12, which gene has lationship between genetics and environment and highlight been related to bipolar depression and intrinsic excitability the potential impact of the early environment on personal- of hippocampal pyramidal neurons. This chromosome 13 risk ity and psychopathology in later life. locus also has shown chromatin interaction with promoter region of C13orf45 (LMO7DN) in hippocampus, dorsolateral Disclosure: Nothing to disclose. prefrontal cortex, and neural progenitor cells. Discussion: To conclude, our GWAS results on the endophe- doi: 10.1016/j.euroneuro.2018.08.415 notype of rumination can open new perspectives in revealing the common molecular underpinnings of several different mental disorders, hence they can fruitfully fuel drug SU52 target research and / or screening and disease prevention

GENOME-WIDE ASSOCIATION STUDY OF RUMINA- by biomarkers.

TIVE RESPONSE STYLE HIGHLIGHTS GENES PREVIOUSLY (The study was supported by: KTIA_NAP_13-1-2013-0001, ASSOCIATED WITH INTELLECTUAL DISABILITY OR KTIA_13_NAP-A-II/14, KTIA_NAP_13-2-2015-0001, 2017- RUMINATION-RELATED MENTAL DISORDERS 1.2.1-NKP-2017-00002 (Hungarian Brain Research Program); MTA-SE Neuropsychopharmacology and Neurochemistry 1 2 3 Nora Eszlari , Andras Millinghoffer , Peter Petschner , Research Group; Manchester Academic Health Sciences 4 1 5 Xenia Gonda , Daniel Baksa , John Francis William Deakin , Centre, OTKA 119866; ÚNKP-16-3, ÚNKP-17-3-III-SE-2, 2 3 1 Peter Antal , Gyorgy Bagdy , Gabriella Juhasz ÚNKP-17-4-I-SE-8 (New National Excellence Program of The Ministry of Human Capacities); Janos Bolyai Research

1 Semmelweis University Fellowship of the Hungarian Academy of Sciences.)

2 Budapest University of Technology and Economics

3 Hungarian Academy of Sciences, Semmelweis University Disclosure: Nothing to disclose.

4 Kutvolgyi Clinical Centre, Semmelweis University doi: 10.1016/j.euroneuro.2018.08.416 5 University of Manchester, Manchester Academic Health Sciences Centre

Background: Rumination, or in other words, ruminative re- SU53 sponse style, means a perseverative and passive mode of A CROSS-DIAGNOSTIC GWAS OF LONGITUDINAL EX- thinking about the person’s own depressed mood, and about ECUTIVE FUNCTION PROFILE SCORES its possible causes and consequences. It is not only a signiﬁ- 1 2 3 cant risk factor for major depression, but, since it has a 21- Urs Heilbronner , Bernadette Wendel , Monika Budde , 4 4 4 40% heritability, it is worth investigation by candidate gene Katrin Gade , Kristina Adorjan , Janos Kalman , 4 4 4 studies as an endophenotype, with the future aim of target- Fanny Senner , Till Andlauer , Ashley Comes , 4 4 2 ing molecular underpinnings of depression with preventive Eva Schulte , Sergi Papiol , Heike Bickeböller , 4 purposes. Thomas Schulze Methods: In the present genome-wide association study

(GWAS), we aimed to reveal candidate common genetic 1 Institute of Psychiatric Phenomics and Genomics, Medical variants in the background of rumination, measured by Center of the University of Munich the 10-item Ruminative Responses Scale, among 1825 Eu- 2 University Medical Center, Georg-August-University ropean white adults recruited in Manchester, United King- 3 Institute of Psychiatric Phenomics and Genomics, Univer- dom and Budapest, Hungary. Linear regression models sity Hospital, LMU Munich were run on rumination score in Plink v1.9 ( https://www. 4 Planck Institute of Psychiatry Munich cog-genomics.org/plink2 ), with each single nucleotide polymorphism (SNP) as predictor, controlling for gender, age and Background: Executive functions, i.e. cognition involving population structure. FUMA v1.3.1 ( http://fuma.ctglab.nl/ ) control and coordination of mental processes, are impaired was used to define genomic risk loci by SNPs with a sugges- in severe mental disorders such as bipolar disorder and tive significance level ( ≤1x10-5), and to map protein-coding schizophrenia. It has also been reported that psychiatric genes to SNPs of these loci, based on position, expression patients suffering from these disorders differ from healthy ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 29 controls in their ability to profit from practice incurred by where a large number of phenotypes (deep phenotyping) repeated test administration. were studied in each subject. Here, we use data of the longitudinal PsyCourse study, a Methods: Genome-Wide Association on 463 phenotypes study of patients from the affective-to-psychotic continuum from clinical and behavioral interview data, brain imaging (n = 1047) and healthy controls (n = 288), to research genetic structural MRI and DTI was performed on 754 Schizophrenia, underpinnings of patient individual differences in two core Bipolar, or Schizoaffective disorder cases, and 361 healthy aspects of executive functions: set-shifting and updating. controls. Genotypes were assessed using the Illumina Psy- Methods: Data were collected at four measurement points chChip microarray, followed by imputation for a total of 4.3 across a period of 1.5 years. Healthy controls were collected million common SNPs. to identify and correct for important phenotype variability Results: After Bonferroni correction, the volume of the and change over time. Temporal Horn of Left Lateral Ventricle (THLLV) was asso- Patients were genotyped with the Illumina PsychArray. ciated with SNPs of gene NRXN1 (P = 1.156E-11), and the We imputed common variants (MAF ≥0.01) using the 1000 Cavum Septum Pellucidum (CSP) was associated with SNPs Genomes Phase 3 reference panel. of gene LRP1B (P = 1.661E-11). Enlarged CSP is present in The Trail-Making-Test and the Verbal Digit Span Back- an important proportion of cases (26.29%, O.R. = 2.01). In- wards, a subtest from the Wechsler Intelligence Test for creased volume of the temporal horn was observed in 6% of Adults, are used as phenotypes of set-shifting and updating patients (O.R. = 3.49), and its presence combined with the capabilities, respectively. Both executive domains are in- NRXN1 risk allele gives a disease odds ratio of OR = 7.41, with vestigated using cognitive profile scores derived from data an attributable fraction in exposed of 86.4%. This feature is collected over the course of the study. These scores provide also associated with enlargement of other parts of the ven- a combined measure of both individual longitudinal change tricular system and reduction of some adjacent brain struc- and performance level. tures. We will perform a longitudinal genome-wide association Discussion: Enlarged CSP and THLLV are two biomarkers as- analysis, using both summary statistics addressing the pro- sociated with psychosis and with common SNPs. These re- files as well as longitudinal modelling via general linear sults lend molecular support to the neurodevelopmental hy- mixed models. This should enable us to gain further insights pothesis of Schizophrenia and related disorders and may in profile shapes and their dependence on specific disease constitute risk factors for psychosis. and genetic factors. Results: We will present results of this research at the Disclosure: Nothing to disclose. meeting. doi: 10.1016/j.euroneuro.2018.08.418 Discussion: We will present the discussion of our findings at the meeting.

Disclosure: Nothing to disclose. SU55 BALANCE AND GAIT ANALYSIS USING MICROSOFT doi: 10.1016/j.euroneuro.2018.08.417 KINECT IDENTIFIES GENES IMPACTING LOCOMOTION AND AUTISM LIABILITY

Kevin Vervier, Leo Brueggeman, Jacob Michaelson SU54

DEEP PHENOTYPING GENOME-WIDE ASSOCIATION University of Iowa STUDY IDENTIFIES GENETIC MARKERS ASSOCIATED

WITH BRAIN VENTRICULAR ENLARGEMENT AS NEU- Background: While the core clinical phenotype of autism RODEVELOPMENTAL BIOMARKERS OF PSYCHOSIS always involves deﬁcits in social communication and restricted and repetitive behaviors, there are also a wide va- 1 2 2 Ney Alliey , Rebecca Shafee , Jaya Padmanabhan , riety of comorbidities that contribute to its immensely het- 2 3 1 Neeraj Tandon , Tamar A Grey , Danielle Rubin , erogeneous presentation. One of these domains of comor- 4 5 6 Brett A. Clementz , J Sweeney , Godfrey D. Pearlson , bidity is in disorders of movement and gross motor coordi- 2 5 1 Matcheri S. Keshavan , C Tamminga , Sarah Keedy , nation. Despite this known relationship, little is understood 1 Elliot Gershon about the genetic overlap in susceptibility to movement disorders and autism. A better understanding of this relation-

1 University of Chicago ship will contribute to a more reﬁned parsing of patient sub-

2 Harvard Medical School groups, which in turn will lead to more effective clinical tri-

3 Massachusetts Institute of Technology als.

4 University of Georgia Methods: Here, we propose an affordable digital phenotyp-

5 UT Southwestern ing solution, consisting of a single Microsoft Kinect cam-

6 Yale School of Medicine, Olin Research Center era to record gait in two balance activities: standard walk and heel-toe balancing while walking exercise. Among the Background: In order to explore the genetic components outputs of the Kinect camera is a 25-point skeleton of of major psychoses, the Bipolar and Schizophrenia Network the research participant tracked at 30 frames per second for Intermediate Phenotypes (B-SNIP) collected a sample of in 3-dimensional space. Our study of neurodevelopmen- individuals with psychotic disorders and healthy controls, tal conditions, devGenes, includes nearly 600 gait profiles ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 30 Abstracts for ASD-affected and unaffected individuals. We converted Methods: We analyzed DNA methylation in the promoter re- these movement profiles into the frequency-domain using a gion of MORC1 in a cohort of Caucasian adults with (n = 76) Fourier transform. Random forests were then used to clas- and without (n = 76) experience of early life adversity as sify walking profiles as affected or unaffected. This machine assessed by the Childhood Trauma Questionnaire. 50% of learning approach allowed us to assign semi-quantitative the participants in each group had a current or lifetime di- scores to devGenes participants that described the extent agnosis of moderate to severe major depressive disorder, to which their gait resembled affected individuals. Perfor- whereas the other 50% had never experienced any psychi- mance of the classifier was good, with an area under ROC atric disorder. High accuracy methylation measurements via curve of 0.744 and an out-of-sample accuracy of 66%. Using targeted bisulfite sequencing (HAM-TBS) were used to assess these scores as a quantitative trait, we mapped the genetic a region spanning 57 CpG sites in the MORC1 promoter. Influ- determinants of ASD-related gait abnormalities via genotyp- ence of methylation quantitative trait loci (mQTLs) was as- ing with the PsychArray. sessed via genotyping of relevant single nucleotide polymor- Results: Through this analysis, we were able to prioritize phisms. Further, we will study interacting effects of early genes harboring genetic burden related to locomotion. A life stress, DNA methylation and major depressive disorder follow-up analysis revealed that these candidate genes were on self-reported stress reactivity as assessed by the stress enriched for known autism genes, and specifically for synap- reactivity scale (SRS). tic pathways. Of particular interest was an association with Results: Results will be presented at the congress. We hy- the gene DMD (the causal factor of Duchenne Muscular Dys- pothesize that MORC1 serves as a biomarker of early life trophy), potentially broadening the role of this gene to a adversity in adults and that this effect may be specifically subclinical locomotion phenotype in the context of autism. linking ELA and depression later in life. Further, we hypoth- Discussion: This work illustrates the promise of using ob- esize that there is an interacting gene-ELA effect on MORC1 jective, semi-quantitative measures as a trait to facilitate promoter methylation and vulnerability to depression. mapping of genetic risk factors that ultimately lead to a bet- Discussion: Our results will provide valuable information ter understanding of comorbidities in autism, such as motor about the validity of MORC1 methylation as blood-based coordination deficits. marker of early life stress in adults and its potential role in the development of major depressive disorder. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.419 doi: 10.1016/j.euroneuro.2018.08.420

SU56 SU57 EPIGENETIC REGULATION OF THE NOVEL EARLY INCREASED BDNF METHYLATION IN SALIVA, BUT NOT LIFE ADVERSITY RESPONSIVE GENE MORC1 IN MAJOR BLOOD, OF PATIENTS WITH BORDERLINE PERSONALITY DEPRESSIVE DISORDER DISORDER

Mara Thomas 1, Vanessa Nieratschker 2, Nadine Provençal 3, Vanessa Nieratschker 1, Mara Thomas 2, Nora Knoblich 1,

Andressa Coope dos Santos Botezelli 3 Annalena Wallisch 1, Katarzyna Glowacz 1,

Friederike Gundel 1, Julia Becker-Sadzio 1,

1 IMPRS for Cognitive and Systems Neuroscience Christof Brueckmann 1

2 University Hospital of Tuebingen

3 Simon Fraser University Burnaby 1 University of Tuebingen

2 IMPRS for Cognitive and Systems Neuroscience Background: Early life adversity (ELA) is a risk factor for the development of psychiatric disorders later in life, among Background: The importance of epigenetic alterations in them major depressive disorder (MDD). It is believed that psychiatric disorders is increasingly acknowledged and the the increased susceptibility to MDD is caused by maladap- use of DNA methylation patterns as markers of disease and tation to the early stressful environment, potentially lead- therapy response is a topic of ongoing investigation. Re- ing to a disturbed stress response. It has been proposed cent studies suggest that patients suffering from Border- that DNA methylation, an epigenetic modification that in- line Personality Disorder (BPD), display differential DNA fluences gene expression, may be one mechanism by which methylation of various genes relevant for neuropsychiatric early experiences are translated into permanent changes in conditions. Among those is the gene encoding the brain- cellular function. A recent genome-wide methylation anal- derived neurotrophic factor (BDNF). Studies report differ- ysis identified MORC1 to be differentially methylated in re- ential BDNF methylation in blood, but only little is known sponse to exposure to different early life stressors in three about BDNF methylation levels in tissues other than that. different species (human, rhesus monkey, rat), at different However, recent evidence indicates that saliva might be a ages (birth, childhood, adulthood) and in different tissues better suited surrogate measure than blood for the study of (blood, brain). MORC1 is an epigenetic regulator protein DNA methylation in psychiatric disorders. that has in the meanwhile been implicated with the devel- Methods: 41 BPD patients and 41 healthy controls were in- opment of MDD via genetic association studies as well as cluded in the study. BPD patients were diagnosed accord- genetic animal models of psychiatric disease. ing to the IPDE and met at least five diagnostic criteria of ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 31

BPD. 26 BPD patients completed a 12-week program of Di- Background: We previously observed an association be- alectical Behaviour Therapy (DBT). DNA methylation status tween DDR1 genetic variants and schizophrenia [1]. Also we of the BDNF IV promoter in whole blood and saliva sam- have reported that DDR1 is a myelin protein [2] and an in- ples was analyzed by pyrosequencing. The pyrosequencing creased expression of DDR1 isoform c in postmortem brains assay contained six CpG sites, but only four sites passed from schizophrenic patients [3]. DNA methylation at spe- pyrosequencing quality control and were used for further cific CpG sites is an important regulator of myelin genes [4]. analysis. Statistical analysis was performed with SPSS (IBM, Compelling evidence shows that life event stressing factors Version 26). Group mean comparisons were performed using are able to modify gene methylation patterns [5]. two-sided student’s t-test. Cohen’s effect size d was calcu- Here we aimed to show that life event stressing factors lated from the z-score. Differences in percentages between modify the pattern of DDR1 methylation in early interven- groups were assessed with the Chi-Square-Test. Bivariate tion psychotic patients (PP). correlation analysis was performed using Pearson’s correla- Methods: We selected 60 patients attended at the Early tion coefficient and 95% percentile bootstrapping was per- intervention Program with a schizophrenia spectrum disor- formed. der diagnostic according to DSMV criteria, and 40 controls Results: In saliva samples, DNA methylation was signif- matched by sex and age. icantly higher in BPD patients than in healthy controls Stress variables were measured using Childhood Trauma at all four analyzed CpG sites within the BDNF promoter Questionnaire (CTQ), Holmes–Rahe Stress Scale (HRSS) In- (p < 0.001 for all sites). Further, the average methylation ventory and Perceived Stress Scale (PSS). Neutrophil to lym- level calculated from all analyzed sites was higher in BPD phocyte rate (NLR) and C reactive protein (CRP) were used patients than in healthy controls (M = 6.9 %, SE = 0.19 vs. as inflammatory markers. Severity of depressive and psy- M = 4.3 %, SE = 0.20, M = Mean, SE = Standard Error). This dif- chotic symptoms were measured by Hamilton Depression ference, −2.6 %, 95% CI [ −3.163, −2.061] was significant rating scale and PANSS respectively. Each dose of antipsy- (t(80) = −9.431, p-value = 1.26 x 10–14) and represented a chotic was transformed into chlorpromazine and diazepam large effect (Cohen´ s d = 2.1). In DNA isolated from whole equivalent. Levels of methylation at 5 regions (45 CpG is- blood, BDNF methylation levels did not differ significantly lands) were measured in peripheral blood DNA using Massar- between BPD patients and healthy controls neither for sin- ray EpiTYPER technologyR (Agena Biosciences). gle CpG sites, nor for the average calculated from all sites After a bivariate analysis between dependent (methyla- (patient average 9.0 % vs- healthy controls average 8.9 %). tion) and independent variables (all the rest) was conducted We further compared BDNF IV promoter methylation of sin- to explore associations between variables we carried out gle CpG sites and the average calculated from all sites in a linear regression analysis using CpG island as dependent saliva and blood samples of individual patients and controls variable and participant group (patient or control), CTQ di- and did not find any significant correlation. mensions, HR, PSS, NLR, PCR and benzodiazepine equiva- Following psychotherapeutic intervention (N = 26 pa- lents as independent variables. tients), salivary DNA methylation at the BDNF IV promoter Results: PPs (sex ratio 1:1) had a mean age of 24.7 ±5.4 decreased at all analyzed CpG sites, though the effect was years and controls (sex ratio 1:1) 24.6 ±5.4 years. Sex, significant only for CpG 1, CpG 3 and the average calcu- age, psychotic symptoms (PANSS), depression and chlorpro- lated from all sites, where BDNF methylation decreased mazine equivalents associations with methylation did not from 7.2 % to 6.5 % (mean difference = -0.7 %, SE = 0.33, pass the significance filter for multiple correlations. The lin- 95% CI [-1.370,-0.019], t(25) = -2.118), p-value = 0.044, Co- ear regression analysis carried out to measure which vari- hen’s d = 0.4). ables associate with the methylation level at each CpG DDR1 Discussion: Our results speak in favor of the recently postu- island studied showed that: 1/ Methylation at CpG AS5_16 lated hypothesis that saliva is a better surrogate tissue for inside the DDR1-AS1 gene which is located upstream the the use in psychiatric studies than blood is. Particularly in- promoter region of DDR1, associates with benzodiazepine teresting is our finding of significantly decreasing BDNF IV equivalent dose and physical neglect, but is not different methylation levels following DBT, since this points towards between patients and controls; 2/ Methylation at CpGs 1_3, the usability of saliva BDNF methylation as a marker for 1_5, 1_7, is statistically different between patients and con- therapy response. trols and highly associated to NLR; 3/ Methylation at CpG 2_2 and 2_5 was different between patients and controls Disclosure: Nothing to disclose. but not associated to NLR. Stress variables (CTQ, HRSS and PSS) show an indirect association (negative B and β values) doi: 10.1016/j.euroneuro.2018.08.421 with methylation levels. That is, the higher the score in the stress item the lower the methylation level. Conversely, the inflammation NLR parameter showed a direct relationship SU58 with CpG methylation levels. STRESS VARIABLES AND METHYLATION OF THE DDR1 Discussion: We show for the first time that DDR1 CpG GENE IN EARLY INTERVENTION PSYCHOTIC PATIENTS methylation levels are increased in PPs compared to controls. In some regions the methylation levels are in part ex- Elisabet Vilella, Lorena Moreno, Ángel Cabezas, plained by stress and inflammation biomarkers but in op- Vanessa Sánchez-Gistau, Alfonso Gutierrez-Zotes, posite directions. Region 1 has a high association with in- Gerard Muntané, Lourdes Martorell, Elisabet Vilella flammation, but region 2, which is also different between patients and controls is not associated with inflammatory Hospital Universitari Institut Pere Mata markers. Our results suggest that DDR1 methylation levels ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 32 Abstracts could be used as a PPs biomarker, but further studies are the promoter region of KCNAB3 gene was hypermethylated needed to confirm the present results. on HRC_B compared to HRC_F (Mean Beta FC = 0.055; Min adjusted p-value within DMR = 1.29 x 10-23). Comparing Disclosure: Nothing to disclose. HRC_B to controls, we observed that the 3 CpGs within KC- NAB3 region were hypomethylated in HRC_B. We found the doi: 10.1016/j.euroneuro.2018.08.422 same pattern in the follow-up: all CpGs were hypomethylated in HRC_F compared to controls. No methylation levels were associated to age and sex.

SU59 Discussion: The KCNAB3 gene encodes for a member of the

DNA METHYLATION ASSOCIATED TO PSYCHOPATHOL- potassium channel, voltage-gated, shaker related subfam- OGY IN CHILDREN AND ADOLESCENTS: DETECTING ily. The mRNA is expressed in some brain regions and the DIFFERENTIALLY METHYLATED REGIONS protein is strongly expressed in the brain, shows a weaker expression in the heart but seems absent in other tissues. Al- 1 1 1 Leticia Spindola , Marcos Santoro , Pedro Pan , though we found a hypermethylation in HRC_B compared to 1 1 Fernanda Talarico , Carolina Muniz Carvalho , HRC_F, all CpGs were hypomethylated in HRC subjects com- 2 2 Giovanni Salum Junior , Luis Augusto Rohde , pared to controls in both time-points. Moreover, methyla- 3 4 Euripedes Constantino Miguel , Michael March , tion levels were not associated to age, suggesting that there 4 4 1 Patrick Sleiman , Renata Pellegrino , Rodrigo Bressan , is a difference in KCNAB3 methylation between children be- 1 4 1 Vanessa Ota , Hakon Hakonarson , Sintia Belangero fore the developed high psychopathology and controls. Our results have identiﬁed a differentially methylated region in

1 Federal University of Sao Paulo blood that might be a risk marker for psychopathology in

2 Hospital de Clínicas de Porto Alegre children and adolescents.

3 University of Sao Paulo

4 Children’s Hospital of Philadelphia Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.423 Background: Psychiatric disorders are genetically complex traits, and little is known about the causal genes involved their pathogenesis, and how their function is regulated. The SU60 study of epigenetics processes will help to better understand the role of genetic variation in health and disease. Al- GENOME-WIDE DNA METHYLATION INVESTIGATION though performing a probe-wise methylation analysis is use- OF SYNTHETIC GLUCOCORTICOID EXPOSURE WITHIN ful and informative, knowing whether several proximal CpGs HUMAN BUCCAL SAMPLES are concordantly differentially methylated could provide in- 1 1 1 sights into different phenotypes. In the present study, we Patricia Braun , Benjamin Hing , Mai Tanaka-Sahker , 1 1 1 aimed to identify differentially methylated regions (DMRs) Aubrey Chan , Yasunori Nagahama , Lindsey Gaul , 1 1 1 associated with psychopathology using subjects from a large Jonathan Heinzman , Kumi Yuki , Liesl Close , 1 1 1 prospective community school-based study in Brazil, the Brian Dlouhy , Hiroto Kawasaki , Kyle Stein , 2 1 High Risk Cohort (HRC) for Psychiatric Disorders. For this James Potash , Gen Shinozaki purpose, we compared DNA methylation in children and adolescents before (baseline) and after (3 years of follow- 1 University of Iowa Carver College of Medicine up) develop high psychopathology. Furthermore, to con- 2 Johns Hopkins firm DMRs findings, we compared the methylation levels of CpGs within DMR between HRC subjects and healthy con- Background: Glucocorticoids play a major role in regulating trols paired by age and sex. the stress response, and an imbalance of glucocorticoids has Methods: The HRC has clinical and genetic measures in been implicated in stress-related disorders. Within mouse two different time-points. In both points, psychopathology models, CpGs across the genome have been shown to be dif- was assessed using Child Behavior Checklist (CBCL). For the ferentially methylated in response to glucocorticoid treat- present study, we selected 24 subjects with CBCL score ment, and using the Infinium 27K array, it was shown that < 30 at the baseline (HRC_B) that increased these score humans given synthetic glucocorticoids had DNA methyla- more than 16 (mean = 29, SD = 9) after 3 years of follow-up tion (DNAm) changes in blood. However, further investiga- (HRC_F). Moreover, we selected 24 healthy controls paired tion of the extent to which glucocorticoids affect DNAm by age and sex with HRC_B subjects and compared methyla- across a larger proportion of the genome is needed. tion levels of CpGs within DMRs. We used the same criteria Methods: Buccal samples were collected before and after to select other 24 healthy controls to compare to HRC_F synthetic glucocorticoid treatment in the context of oral subjects. To check for possible confounding, we verified if surgery. This included 30 minor tooth extraction surgery methylation levels within DMRs were associated to age and patients who received 10 mg of dexamethasone. Genome- sex. The methylation data was generated using the Infinium wide DNAm was assessed with the Infinium HumanMethyla- Methylation EPIC BeadChip. To find DMRs, DMRcate package tionEPIC array. Data were processed and analyzed with the was used. R packages Minfi and RnBeads. Results: Comparing time-points, we have found 1 DMR span- Results: Five CpGs showed genome-wide significant change ning 3 DNA methylation sites. This DMR overlap KCNAB3 in DNAm that was > 10%. These differentially methylated promoter area on chromosome 17. We have found that CpGs were in or nearest the following genes: ZNF438, ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 33

KLHDC10, miR-544 or CRABP1, DPH5, and WDFY2. Us- quantified in the samples at over 850,000 sites on the ing previously published datasets of human blood gene genome using the Illumina EPIC array. We then carried out expression changes following dexamethasone exposure, a two epigenome-wide association studies (EWASs) to iden- significant proportion of genes with FDR-adjusted significant tify (i) differentially methylated CpG positions and regions CpGs were also differentially expressed. A pathway analysis associated with the deletion (ii) to compare the genome- of the genes with FDR-adjusted significant CpGs revealed wide methylation profile of 22q11.2DS individuals with and significant enrichment of olfactory transduction, pentose without SCZ. Next, we performed a weighted gene co- and glucuronate interconversions, ascorbate and aldarate methylation network analysis (WGCNA) in subjects with metabolism, and steroid hormone biosynthesis pathways. In 22q11.2DS and we examined the association between the a replication cohort of patients with treatment refractory identified modules and a wide-range of clinical manifesta- epilepsy, brain, blood, buccal, and saliva samples were tions related to 22q11DS. obtained before and after dexamethasone treatment. A Results: We found 486 differentially methylated positions portion of the FDR-adjusted significant CpGs in the discov- (DMPs) P-value < 6.31e-08 and 26 differentially methylated ery cohort were also nominally significant in the replication regions (DMRs) associated with 22q11.2DS. Several identi- cohort (13 CpGs in blood, 5 in buccal tissue, 58 in saliva, fied DMPs and DMRs mapped to the deleted region on chro- and 6 in brain), and one of the CpGs that replicated in mosome 22 (for example, COMT, DGRC5, ARVCF). The within saliva also withstood correction for multiple testing. 22q11DS analysis identified 2 hypomethylated DMRs map- Discussion: In conclusion, high-dose synthetic glucocorti- ping to RUFY1 and NBR2 genes which were associated with coid administration in the setting of oral surgery was sig- SCZ diagnosis. Co-methylation analysis revealed discrete nificantly associated with DNAm changes within buccal sam- modules of co-methylated loci associated with cleft palate ples. These findings are consistent with prior findings of an and hypocalcaemia in the 22q11DS individuals. influence of glucocorticoids on DNAm in humans. Discussion: This is, to our knowledge, the most extensive study of DNA methylation in association with 22q11DS. We Disclosure: Nothing to disclose. present robust evidence for cis and trans effects of the 22q11 deletion on DNA methylation. Many of the DMPs and doi: 10.1016/j.euroneuro.2018.08.424 DMRs associated with the deletion mapped to the COMT gene. However, no significant changes in the methylation of the COMT gene in association with psychotic symptoms

SU61 were found. Altered mRNA expression of the RUFY1 gene, METHYLOMIC ANALYSIS OF SCHIZOPHRENIA IN 22Q11.2 a within 22q11DS SCZ-associated DMR, has been previously DELETION SYNDROME observed in early-onset SCZ.

Ehsan Pishva 1, Therese van Amelsvoort 2, Eilis Hannon 3, Disclosure: Nothing to disclose.

Laurens JM Evers 2, Jonathan Mill 1, Emma Dempster 1 doi: 10.1016/j.euroneuro.2018.08.425

1 University of Exeter

2 Maastricht University

3 University of Exeter Medical School SU62 THE ROLE OF ENVIRONMENTAL STRESS AND DNA Background: Central nervous system (CNS) manifesta- METHYLATION IN THE LONGITUDINAL COURSE OF tions of 22q11.2 Deletion Syndrome (22q11.2DS) are BIPOLAR DISORDER highly diverse including intellectual disabilities, attention- deﬁcit hyperactivity and anxiety disorders, autism, and Ashley Comes 1, Kristina Adorjan 2, Till Andlauer 3, schizophrenia (SCZ). Up to date, 22q11.2DS is the Monika Budde 2, Franziska Degenhardt 4, strongest molecular genetic link with SCZ. While catechol- Andreas J. Forstner 4, Katrin Gade 5, Urs Heilbronner 2,

Omethyltransferase (COMT), a well-studied candidate gene Janos Kalman 6, Ivan Kondofersky 7, Sergi Papiol 2, for SCZ, maps to the deleted region on chromosome 22, no Fanny Senner 2, Sugirthan Sivalingam 4, Peter Falkai 8, evidence for association between polymorphisms in COMT Thomas Schulze 2 and SCZ has been found in individuals with 22q11.2DS. More- over, the hemizygosity of this region itself cannot fully ex- 1 Institute of Psychiatric Phenomics and Genomics plain the increased risk to SCZ in 22q11.2 deletion carriers 2 Institute of Psychiatric Phenomics and Genomics, Univer- due to variable penetrance. Therefore, other genetic, en- sity Hospital, LMU Munich vironmental or stochastic factors might contribute in such 3 Max Planck Institute of Psychiatry phenotype variation. In this study we investigated the role 4 Life & Brain Center, University of Bonn of DNA methylation in the phenotype heterogeneity in indi- 5 University Medical Center Goettingen viduals with 22q11.2DS. 6 Institute of Psychiatric Phenomics and Genomics, Univer- Methods: Whole blood derived DNA Samples were obtained sity Hospital, LMU Munich, International Max Planck Re- from 64 individuals from a Dutch cohort of 22q11.2DS (37 search School for Translational Psychiatry (IMPRS-TP) developed SCZ and 27 with no symptoms of psychosis) indi- 7 Institute of Computational Biology, Helmholtz Center Mu- viduals. We also included 162 age and gender-matched indi- nich, German Research Center for Environmental Health viduals with no CNV (65 was diagnosed with ﬁrst episode (GmbH) psychosis and 97 healthy controls). DNA methylation was 8 University Hospital, LMU Munich ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 34 Abstracts

Background: Stressful life events in either early stages of phenomenon is complex, heterogeneous and its contributing development or adulthood can have a profound influence factors remain unclear. The molecular pathology of suicide on the course of affective disorders. However, the molecu- remains poorly understood. It has been hypothesized that lar mechanisms allowing these stressors to bring about phe- regulatory genomic processes are involved. Recent studies notypic effects is not completely understood. Recently, em- have started to examine the role of epigenetic processes in- phasis has been placed on long-term alterations in gene excluding DNA Methylation. Nevertheless, to date, few studies pression mediated by epigenetic modifications. Specifically, have examined DNA methylation differences changes in the DNA methylation has been proposed as an adaptive mech- brains of suicide completers and non-has focused in Latino anism by which the interaction between gene and environ- population. The aim of the study is to describe the suicide ment is integrated at the cellular level, influencing pheno- methylation variation in cortical brain samples. typic expression. Methods: In this study, genome-wide patterns of DNA Methods: We explored signatures of DNA methylation as- methylation were assessed in suicide completers (n = 38) sociated with stressful life events (i.e. childhood trauma and compared with sudden-death controls (n = 13) using tis- based on the Childhood Trauma Screener and stressful life sue from Brodmann Area 9 brain region. Analyses focused events in the last 6 months based on the Life Events Ques- on identifying differentially methylated positions (DMP) and tionnaire) in 96 bipolar patients from the longitudinal Psy- methylated regions (DMRs) using the Infinium HumanMethy- Course study. Whole blood samples from two time points lation450 BeadChip. All samples passed stringent quality- (baseline and 1-year follow-up) were used to measure DNA control measures. Microarray preprocessing, Quantile nor- methylation using the Infinium methylationEPIC beadchips malization and background correction were performed us- from Illumina. First, we conducted an epigenome-wide asso- ing minfi R package. Statistical Analyses for DMPs and DMRs ciation study (EWAS), modeling the effect of both childhood were performed using R statistical package limma and DMR- trauma and the impact of stressful life events in the last cate, respectively. six months on DNA methylation. Second, we interrogated Results: We identified 92 DMPs and 14 DMRs, the top 10 variation in DNA methylation in the vicinity of candidate most significative genes were; TMEM68, TGS1, TCP11L1, genes previously implicated in the stress response (BDNF, IER3IP1, SNX5, ANKH, MORN4, TMEM14A and B3GALT4-001 OXTR, IL6, and FKBP5). Third, an investigation of differen- and RPS18-008, B3GALT4-002 located in the chr6:33245585- tially methylated regions (DMRs) was performed. 33246488. We also identificated the most enriched genes Results: In the analysis of differential methylation, a single networks implicating biological processes relevant to suici- CpG was significantly associated with stressful life events dality, including nervous system development, mitochondria in the last six months (cg15212455; gene symbol POU6F2; function, inflammation process and immune system. FDR = 0.022). Hypothesis-driven analyses of four candidate Discussion: Our data suggest that there are changes in DNA genes regarding the stress response revealed a significant methylation associated with suicide that may offer novel effect of the interaction between childhood trauma and insights. stressful life events on DNA methylation for a CpG probe annotated to BDNF (cg09505801; FDR = 0.016). Investiga- Disclosure: Nothing to disclose. tion of DMRs identified one region consisting of five CpGs doi: 10.1016/j.euroneuro.2018.08.427 in chr3:146,262,331-146,262,434 that significantly correlated with baseline stressful life events scores (overlapping PLSRC-1 promoters; min. FDR = 6.8x10-16).

Discussion: Preliminary ﬁndings from this exploratory study SU64 support a role of epigenetic changes associated with stress- EARLY EXPERIENCES OF THREAT, BUT NOT DEPRI- ful life events for bipolar patients. Future studies are VATION, ARE ASSOCIATED WITH ACCELERATED EPIGE- needed with larger sample sizes to replicate these ﬁndings NETIC AGING IN CHILDREN AND ADOLESCENTS on DNA methylation.

Jennifer Sumner 1, Natalie Colich 2, Monica Uddin 3,

Disclosure: Nothing to disclose. Don Armstrong 3, Katie McLaughlin 2 doi: 10.1016/j.euroneuro.2018.08.426 1 Columbia University Medical Center

2 University of Washington

3 University of Illinois Urbana-Champaign SU63

DNA METHYLOMIC PROFILING OF PREFRONTAL CORTEX Background: Recent conceptual models argue that early- SAMPLES FROM COMPLETED SUICIDE CASES life adversity (ELA) accelerates development, which may contribute to poor mental and physical health outcomes. Ev- Ana Romero-Pimentel, Said Munoz-Montero, idence for accelerated development in youth comes primar- Mirna Morales-Marin, Humberto Nicolini, Claudia Rangel ily from neuroimaging studies of circuits involved in emotional processing and learning. Further, ELA encompasses a National Institute of Genomic Medicine INMEGEN wide range of experiences that do not have identical developmental consequences. Thus, it remains unclear whether Background: Suicide represents a global health challenge any ELA is associated with a more global biological metric of because the rates are increasing among the world, the ma- accelerated development and whether this pattern emerges jority occurring in low and middle-income countries. This following speciﬁc adversity types. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 35

Methods: In 247 children and adolescents aged 8-16 years confirmation of diagnosis using the Diagnostic Interview with wide variability in ELA exposure, we evaluated the hy- for Psychosis. The Positive And Negative Symptom Scale pothesis that early environments characterized by threat, (PANSS) evaluated current symptoms in the case partici- but not deprivation, would be associated with acceler- pants. The Childhood Trauma Questionnaire and the Stress- ated development on a global biological aging metric: DNA ful Life Events scale were administered to all participants. methylation (DNAm) age relative to chronological age. We DNA was extracted from peripheral whole blood samples. also examined whether accelerated DNAm age relative to Genomic data was assayed using the HumanCoreExome Psy- chronological age explained associations of ELA with psy- chChip (Illumina, San Diego), and DNA methylomic data was chopathology, namely depression and externalizing behav- assayed using the Infinium HumanMethylation 450K Bead- iors. Youth and caregivers reported on ELA exposure and Chip (Illumina, San Diego). Epigenetic age acceleration was psychopathology, and youth provided saliva samples for calculated using the epigenetic clock developed by Steve DNAm. Horvath. Results: Exposure to threat-related ELA (e.g., violence) was Results: We find no association between epigenetic age associated with accelerated DNAm age (ß= 0.17, p = .042), acceleration and psychotic diagnoses. However, marginal but exposure to deprivation (e.g., neglect, food insecurity) support for epigenetic age acceleration was associated was not (ß= 0.10, p = .260). Older DNAm age was related with trauma exposure (t = 1.86, p = 0.06), which was attenu- to greater depressive symptoms (ß= 0.26, p = .004), and a ated when including standardized Imipramine and Chlorpro- significant indirect effect of threat exposure on depressive mazine dosages in the model. There was also evidence of symptoms was observed through DNAm age [0.045, (95% association between epigenetic age acceleration and neg- CI:0.001–0.125)]. ative symptoms in clinical cases from the PANSS (t = 3.05, Discussion: Early experiences of threat and violence were p = 0.003), independent of schizophrenia or bipolar diagno- associated with accelerated development with respect to sis when standardized medication dosages were included in epigenetic age, whereas early experiences of deprivation the model. Additional findings in relation to structural and were not. Advanced epigenetic aging may be one mecha- cognitive changes will be presented. nism linking early threat exposure with risk for depressive Discussion: The strongest association with peripheral DNA symptoms. Our findings shed light on how ELA, particularly epigenetic age acceleration was revealed for current neg- threat-related experiences, may get under the skin to con- ative symptoms in the clinical cases, regardless of diagno- tribute to negative health outcomes. sis. This could reflect severity of psychosis, and potentially variation within individuals with a history of psychosis. The Disclosure: Nothing to disclose. attenuation of associations with childhood trauma when accounting for medication dosages suggests that these clinical doi: 10.1016/j.euroneuro.2018.08.428 factors should be controlled as potential confounds in future methylation analyses of psychosis samples. SU65 Disclosure: Nothing to disclose. IMAGING GENETICS IN PSYCHOSIS STUDY: EPIGE- NETIC AGE ACCELERATION, TRAUMA, AND PSYCHOSIS doi: 10.1016/j.euroneuro.2018.08.429 OUTCOMES

SU66 Sarah Cohen-Woods 1, Oliver Watkeys 2, Nina Teroganova 3, OPEN BOARD Yann Quide 3, Janice Fullerton 2, Murray Cairns 4,

Melissa Green 3 Disclosure: Nothing to disclose. 1 Flinders University, South Australia doi: 10.1016/j.euroneuro.2018.08.430

2 Neuroscience Research Australia

3 University of New South Wales

4 University of Newcastle SU67 POLYGENIC RISK SCORES DERIVED FROM A TOURETTE Background: Schizophrenia (SZ) and bipolar disorder (BD) SYNDROME GWAS PREDICT PRESENCE OF TICS IN share cognitive and brain abnormalities, polygenic vulnera- THE AVON LONGITUDINAL STUDY OF PARENTS AND bility, and common environmental risk factors such as child- CHILDREN (ALSPAC) COHORT hood maltreatment. Childhood maltreatment has been associated with signiﬁcant alterations in structure, function, Mohamed Abdulkadir 1, Carol Mathews 2, Jeremiah Scharf 3, and connectivity of the brain, as well as with advanced epi- Dongmei Yu 4, Jay Tischﬁeld 5, Gary Heiman 5, PJ Hoekstra 1, genetic age. Epigenetic processes (such as DNA methylation) Andrea Dietrich 6 function to regulate gene expression and may be important mediators on the path between childhood maltreatment and 1 University Medical Center Groningen psychosis. 2 University of Florida

Methods: The Imaging Genetics in Psychosis (IGP) co- 3 Massachusetts General Hospital/Harvard Medical School hort includes 240 individuals (n = 80 Schizophrenia/ 4 Massachussetts General Hospital

Schizoaffective, 80 bipolar cases, 80 healthy controls) who 5 Rutgers, The State University of New Jersey have completed clinical, cognitive, imaging, genetic, and 6 University of Groningen, University Medical Center DNA methylation assessments. Clinical measures include Groningen ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 36 Abstracts

Background: Tourette syndrome (TS) is a complex polygenic ministered the Edinburgh Postnatal Depression Scale (EPDS), neuropsychiatric disorder. The authors investigated the role Clinician-Administered Rating Scale for Mania (CARS-M) and of polygenic risk scores (PRS) derived from a TS genome- the Positive and Negative Symptom Scale (PANSS, for psy- wide association study (GWAS) in relation to the occurrence chosis) and drew blood for RBC folate/genotype analysis. of tics and associated traits in a general population cohort. We used linear regression to investigate the effect of the in- Methods: Using the most recent TS GWAS (N cases = 4,819; teraction between RBC folate and genotype on the highest N controls = 9,488) as the discovery sample, PRS were cal- EPDS and CARS-M scores, and logistic regression to explore culated in ALSPAC participants (N = 8,941). Regression anal- the effect of the interaction on PANSS scores above/below yses were used to assess whether PRS predicted the pres- cut-off. ence and number of tics, and symptom severity of obsessive- Results: There was no significant interaction effect be- compulsive (OCD), attention-deficit/hyperactivity (ADHD), tween RBC folate and MTHFR genotype on highest EPDS and autism spectrum disorder (ASD) in ALSPAC participants. (p = 0.19), CARS-M (p = 0.09), or PANSS (p = 0.14). There was Results: Following correction for multiple testing for the also no difference between genotypes for EPDS CARS-M or number of P-value thresholds (10,921), the PRS significantly PANSS (all p > 0.05) controlling for RBC folate, and no rela- predicted presence (P = 0.005) and number of tics (P = 0.04) tionship between RBC folate on its own and any of the scales in the ALSPAC cohort. The TS based PRS did not predict (all p > 0.05). severity of OCD, ADHD, and ASD. Discussion: Our data do not support a relationship between Discussion: The authors found a significant polygenic com- MTHFR C677T polymorphisms and folate in risk for postpar- ponent of tics occurring in a general population cohort tum psychopathology, at least in the context of food fortifi- based on PRS derived from a GWAS of individuals with a TS cation/supplement use. diagnosis. This supports the notion that tics along a spectrum from non-clinical to clinical symptom levels share a Disclosure: Nothing to disclose. similar genetic background. doi: 10.1016/j.euroneuro.2018.08.432

Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.431 SU69 PERIPHERAL MITOCHONDRIAL DNA COPY NUMBER IS INCREASED IN MAJOR DEPRESSIVE DISORDER SU68

NO ASSOCIATION OF MTHFR C677T VARIANTS IN Jae Kyunng Chung 1, Soo Young Lee 2, Hee Yeon Jung 3,

POSTPARTUM PSYCHOPATHOLOGY: A PROSPECTIVE Eun-Jeong Joo 4, Soon Ae Kim 3 STUDY OF AT-RISK WOMEN

1 Eumsung-Somang Hospital 1 1 1 Jehannine Austin , Emily Morris , Catriona Hippman , 2 School of Medicine, Eulji University 1 1 1 Caitlin Slomp , Angela Inglis , Prescilla Carrion , 3 SMG-SNU Boramae Medical Center, Seoul National Univer- 1 1 2 Rolan Batallones , Heather Andrighetti , Arianne Albert , sity College of Medicine 1 1 Colin Ross , Roger Dyer 4 Eulji University, School of Medicine

1 University of British Columbia Background: Mitochondrial dysfunction has been suggested 2 BC Women’s Hospital as a promising pathophysiology of depression. Mitochondrial DNA (mtDNA) copy number is considered as a biomarker Background: Postpartum mental illnesses (PPMI) are urgent for mitochondrial dysfunction. It is also suggested that DNA health concerns, but their etiology is not well understood. methylation of genetic region such as the D-loop region Low red blood cell (RBC) folate has been associated with of mitochondria DNA and peroxisome-proliferator-activated psychiatric disorders, and demands for folate increase dra- receptor γ co-activator-1 α (PPARGC1A) gene related to mi- matically during pregnancy, with one study suggesting that tochondria biogenesis may have a regulatory role for mtDNA perinatal folic acid supplementation can improve maternal copy number change. In this study, we compared mtDNA depression symptomatology. The MTHFR C677T variant in- copy numbers between mood disorder patients and controls fluences folate metabolism, and some studies have impli- in peripheral blood and investigated DNA methylation ratio cated it in psychiatric disorders. Taken together, this sug- in the D-loop region and PPARGC1A. gests a strong rationale for exploring the interaction be- Methods: One hundred eighteen patients with major detween MTHFR C677T and RBC folate in PPMI. Objective: To pressive disorder and 116 sex and age matched healthy con- conduct a prospective longitudinal study to explore the re- trols were investigated. The relative mtDNA copy number lationship between MTHFR C677T genotype, RBC folate lev- in peripheral blood cells was measured using quantitative els, and PPMI (depression, mania, and psychosis) in women polymerase chain reaction and the DNA methylation ratio with a history of mood or psychotic disorders. Hypothesis: In was measured using methylation-specific PCR after bisulfite the first three months postpartum, TT homozygous women conversion. would have increased symptoms of depression, mania, and Results: The relative mtDNA copy number was significantly psychosis, compared to CC homozygotes. higher in patients than controls ((p < .0001). In the pa- Methods: We recruited 365 pregnant women (psychiatric tients group, the metDNA/unmetDNA ratio was decreased history confirmed by the Structured Clinical Interview for in PPARGC1A promoter (p < .0001), but there are no differ- the DSM-IV (SCID-IV)). At 3 postpartum timepoints, we ad- ences in mitochondrial D-loop region. Increase of mtDNA ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 37 copy number was strongly associated with decrease of DNA SU71 methylation status in PPARGC1A promoter (p < 0.05) but was MICROBIOTA FEATURES IN PARTICIPANTS WITH SEVER- not associated with DNA methylation status of mitochon- ITY OF DEPRESSION AMONG THE BIPOLAR DISORDER drial D-loop region. AND HEALTHY CONTROLS Discussion: The elevated mtDNA copy number and decreased methylation ratio at the promoter of PPARGC1A in Li-Chung Chuang 1, Yu-Chu Ella Chung 2, Wei-Liang Shih 3, the patients with major depressive disorder suggest not only Po-Hsiu Kuo 4 the role of mitochondrial dysfunction in depression but also the involvement of epigenetic control mechanism for this 1 Cardinal Tien Junior College of Health mitochondrial dysfunction. 2 College of Public Health, National Taiwan University

3 Institute of Epidemiology and Preventive Medicine, Col- Disclosure: Nothing to disclose. lege of Public Health, National Taiwan University doi: 10.1016/j.euroneuro.2018.08.433 4 Institute of Epidemiology and Preventive Medicine, Na- tional Taiwan University

SU70 Background: Depression episode in the bipolar disorder rep- ANTIDEPRESSANT RESPONSE IN MAJOR DEPRESSIVE resents the function weakening in the most patients. In- DISORDER AND RARE VARIANTS stead of mania episode, several recent longitudinal studies indicated depression being the hallmark for bipolar disor-

Ma-Li Wong 1, Mauricio Arcos-Burgos 2, Julio Licinio 1 der, demonstrating that depressive episodes may play the dominant role in the illness course. Recent research has sug-

1 State University of New York Upstate Medical University gested the gut microbiota could assist in understanding and

2 International Institute of Translational Medicine, Univer- be treating depression. In the present study, we observed sity of Rosario the microbiota features for the severity of depression in the bipolar disorder and healthy control. Background: Approximately 12% of Americans are currently Methods: We recruited 23 patients with bipolar disorder and taking antidepressants; thus, the ability to predict antide- 37 healthy controls, and the self-reported Beck Depression pressant drug response may have significant public health Inventory (BDI) was used to examine the severity of de- impact. Rare genetic variants are thought to contribute up pression. The BDI score more than 14 was used as a cut-off to 40% of functional variability in genes relevant to drug ac- point for depression. The fecal samples were examined by tion. We investigated the contribution of rare functional ge- Illumina Miniseq or Miseq platform for 16s rRNA sequenc- netic variants to antidepressant drug response by performing of microbiota features. Three approaches were applied ing whole genome screening and performing rare functional to test associations between depression and microbiota, in- variant analysis. cluding Linear discriminant analysis effect size (LEfSe), cor- Methods: We obtained whole exome genotyping data in relation analysis and random forest. The area under the Mexican-Americans individuals who met DSM-IV criteria receiver operating characteristic curve was used to assess of major depressive disorder and completed 8 weeks of the discrimination capability of the microbiota features for double-blind treatment with desipramine or fluoxetine in depression. a prospective randomized double-blind pharmacogenetics Results: In the LEfSe approach, the abundance of Novosph- trial. Hamilton Depression Rating Scale was used to deter- ingobium significantly increased in the participants with mine the primary treatment outcome. depression. The abundances of class Alphaproteobacteria, Results: Data from remitters and non-responders were ana- Megasphaera, Candidatus Portiera, Odoribacter, and Aero- lyzed using regression- and permutation-based kernel-based coccaceae were significantly different in the participants adaptive cluster (KBAC) analysis. We identified rare variants with depression in the correlation analysis. Random forest in several genes significantly associated with treatment re- algorithm revealed the top 5 bacteria of index mean de- mission (FDR < 0.05), and their pathway analysis were en- crease in accuracy for classification, including Novosphin- riched for sensory transduction, regulation of response to gobium, Blautia, Odoribacter, Sutterella, and Leuconostoc. cytokine stimulus, and meiotic cell cycle process. The abundance of Blautia was with discriminability for the Discussion: Our results support the involvement of rare severity of depression, and the area under the receiver op- functional variants in antidepressant drug response, and erating characteristic curve was 0.7513 (0.6028–0.8998). enriched pathways were in sensory, immune mediation and Discussion: In conclusion, our study indicated the associ- growth processes. ation between the severity of depression and the microbiota features among the patients with bipolar disorder and Disclosure: Nothing to disclose. healthy participants. doi: 10.1016/j.euroneuro.2018.08.434 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.435 ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 38 Abstracts

SU72 disorder-speciﬁc differences were observed at the tran- RNA-SEQUENCING OF THE SUBGENUAL ANTERIOR script level. Integration of eQTL and GWAS data implicated CINGULATE CORTEX HIGHLIGHTS TRANSCRIPT-LEVEL many genes, some of which showed clear brain-region speci- EXPRESSION DIFFERENCES BETWEEN MAJOR PSYCHI- ﬁcity. ATRIC DISORDERS Disclosure: Nothing to disclose. 1 1 1 2 Nirmala Akula , Robin Kramer , Qing Xu , Kory Johnson , doi: 10.1016/j.euroneuro.2018.08.436

Stefano Marenco 1, Pavan Auluck 1, Jose Apud 1,

Harker Rhodes 1, Brent Harris 1, Barbara K. Lipska 1,

Francis J. McMahon 1 SU73 POLYGENIC RISK SCORES FOR CALLOUS-UNEMOTIONAL

1 NIMH/NIH TRAITS ARE LINKED TO BRAIN STRUCTURAL CONNEC-

2 NINDS/NIH TIVITY: RESULTS FROM THE NEUROIMAGE-COHORT

Background: The subgenual anterior cingulate cortex Hyun Ruisch 1, JC Glennon 2, A Dietrich 1, JK Buitelaar 2,

(sgACC) has been implicated in both mood disorders and PJ Hoekstra 1 schizophrenia, but gene expression in this brain region has been little studied. Here we report the first large-scale 1 University Medical Center Groningen study of the sgACC transcriptome in major psychiatric dis- 2 Donders Institute for Brain, Cognition and Behaviour, Ni- orders. jmegen Methods: A total of 200 tissue samples were obtained post- mortem from sgACC of people diagnosed with bipolar disor- Background: Callous-unemotional (CU) traits describe po- der (BD, n = 39), major depression (MDD, n = 54), schizophre- tential psychopathic traits in youngsters with conduct prob- nia (SCZ, n = 46), or no mental illness (controls, n = 61). lems and are assumed to result from both complex genetics Stranded, paired-end sequencing of high quality RNA (RIN and environmental risk factors. In the current study we in- ³6) was performed on the Illumina HiSeq 2500. The resulting vestigated whether genetic overlap exists between aggres- 125bp reads were mapped to the reference genome (hg38) sive traits in the population and CU-traits in our clinical using HISAT2. Gene-level and transcript-level analyses were sample, and whether genetic liability for CU-traits relates performed using HTSeq and StringTie, respectively. DESeq2 to structural connectivity in the brain. was used for quality control, normalization, and differen- Methods: Our sample consisted of 780 subjects from the tial gene expression, with correction for known covariates. NeuroIMAGE-study, which is a Dutch follow-up of the IMAGE- Matrix eQTL was used to discover the eQTLs, which were project, and contains genotype, MRI and phenotypic data. then combined with SNPs identified by published GWAS us- First, we computed polygenic risk scores (PRS) based on a ing SMR. SMR results were compared with those from other pediatric-aggression GWAS, across multiple gene-sets and brain regions reported by GTex and Common Mind Consor- SNP P-value thresholds in relation to callous, uncaring tium (CMC). and unemotional subscores of the Inventory of Callous- Results: Of the 21 billion total reads obtained, 98M reads Unemotional traits. Subsequently, identified best-fit PRS per sample mapped to the reference genome and 70M reads were analyzed in relation to brain fractional anisotropy (FA), were properly paired, providing about 3-fold greater se- radial diffusivity (RD) and mode of anisotropy (MO) using quencing depth than previous studies. A total of 67, 53, and Tract-Based Spatial Statistics with threshold-free cluster en- 11 genes were differentially expressed at FDR < 10% in BD, hancement. Correction for multiple hypotheses was per- SCZ, and MDD, respectively, but absolute log2 fold-change formed using permutation-based testing. values were all < 0.5. Many of the same genes were differ- Results: Best-fit PRS explained 1.09% of variance in cal- entially expressed in multiple disorders (mean overlap 42%). lous scores (P = 5.37E-3, glutamate-set PRS), 1.84% of vari- Compared to controls, the overlapping genes showed a con- ance in uncaring scores (P = 2.28E-4, genome-wide PRS), and sistent direction of differential expression in cases, with a up to 1.55% of variance in unemotional scores (P = 8.57E-4, significant positive correlation in fold-change values across glutamate-, dopamine- and neuroendocrine-set PRS). Best- all 3 disorders. Transcript-level analysis identified 336, 680, fit PRS related to brain MO (peak P = 7.20E-3, genome-wide and 304 transcripts differentially expressed at FDR < 10% in PRS) and FA (peak P = 1.86E-2, dopamine-set PRS) in multi- BD, SCZ, and MDD, respectively, and many absolute log2 ple, predominantly right hemisphere clusters across differ- fold-changes exceeded 1. For some genes, multiple distinct ent white matter tracts. transcripts were differentially expressed in the same disor- Discussion: Our results showed genetic overlap between ag- der, but for other genes some of the same transcripts were gressive traits in the population and CU-traits in our sam- differentially expressed in multiple disorders. The mean ple. In addition to genome-wide PRS, genetic liability for overlap of differentially-expressed transcripts across disor- CU-traits emerged from glutamatergic, dopaminergic and ders was only 18%. At FDR < 10%, a total of 370 genes, 62 neuroendocrine gene-sets, and was linked to structural con- genes and 7 genes were implicated by SMR in SCZ, BD and nectivity across multiple nerve tracts, suggesting involve- MDD, respectively. ment of different biological pathways and white matter mi- Discussion: To our knowledge, this is the largest and deep- crostructural abnormalities. est study of the sgACC transcriptome in human brain. Differ- ential gene expression was modest, with substantial over- Disclosure: Nothing to disclose. lap across disorders. Greater differential expression and doi: 10.1016/j.euroneuro.2018.08.437 ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 39

SU74 Discussion: Some of the phenotypic variance of LGI is THE POTENTIAL OF LOCAL GYRIFICATION INDEX shared with ICV, area, and thickness. These relationships ap- AS A NEUROPHENOTYPE pear to be largely environmental in nature, suggesting that they may be driven, at least in part, by methodological fac-

Samuel Mathias 1, Emma Knowles 2, Joanne Curran 3, tors (e.g., imprecision or bias in the estimation of subsets

Laura Almasy 4, Ravi Duggirala 3, Rene Olvera 5, of metrics in certain cortical regions) rather than biological

John Blangero 6, David Glahn 7 ones. Indeed, a signiﬁcant proportion of the genetic variance of LGI is not shared with the other metrics, suggesting

1 Yale School of Medicine that it captures some unique genetic signal. The results sug-

2 Yale University gest that LGI is a useful neurophenotype. However, future

3 University of Texas Rio Grande Valley studies, including those using LGI as an allied phenotype of

4 Children’s Hospital of Philadelphia psychiatric disorders, should probably take care to control

5 University of Texas Health Science Center San Antonio for other aspects of global and local cerebral morphology.

6 University of Texas Rio Grande Valley School of Medicine

7 Yale University and Olin Neuropsychiatric Research Center Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.438 Background: Cortical surface area and thickness are two dominant neurological phenotypes (neurophenotypes) in imaging genetics. Both measures are generated from mod- SU75 els comprising thousands of points along the surface of the ASSOCIATIONS BETWEEN POLYGENIC RISK FOR LOW cerebral cortex. Both are heritable, independent from one CIRCADIAN AMPLITUDE AND RISK TAKING BEHAVIOUR another at a given locus, and are differentially associated AND BRAIN STRUCTURE IN THE UK BIOBANK COHORT with cognitive abilities and psychiatric disorders. Recently, interest has grown in local gyriﬁcation index (LGI)—another Laura Lyall 1, Amy Ferguson 1, Rona Strawbridge 1, heritable surface-based metric which quantiﬁes the com- Joey Ward 1, Cathy Wyse 2, Donald Lyall 1, Breda Cullen 1, plexity of cortical folding at a given locus. LGI correlates Nicholas Graham 1, Keira Johnston 1, Daniel Mackay 1, with general cognitive ability and may dissociate individu- Mark Bailey 1, Jonathan Cavanagh 1, Jill Pell 1, Daniel Smith 1 als with some psychiatric disorders from healthy controls.

However, a thorough investigation of the potential of LGI 1 University of Glasgow as a neurophenotype is lacking. For instance, it is unclear 2 Royal College of Surgeons in Ireland whether the genetic factors influencing LGI are distinct from those influencing surface area and/or thickness at any given point on the cortex, or even those influencing total Background: Disrupted circadian rhythmicity and greater intracranial volume (ICV). risk taking behaviour are common features of mood disor-

Methods: We calculated area, thickness, and LGI at 20,484 ders. Bipolar disorder and major depressive disorder are as- cortical surface points (vertices) via T1-weighted magnetic sociated with reduced brain white matter tract integrity and resonance images of 1,443 individuals from extended pedi- reduced volumes of several cortical and subcortical brain grees (the Genetics of Brain Structure and Function [GOBS] structures compared to healthy controls. Genetic contribu- cohort; 836 female; age range 18-85 years). We estimated tions to these brain structural differences may overlap with the narrow-sense heritability of each metric at each vertex, genetic contributions to common risk factors for mood dis- with and without ICV as a nuisance covariate. For LGI, we order, including circadian disruption and risk taking. additionally estimated heritability with local (i.e., at the Methods: We conducted GWAS of low relative amplitude same vertex) area and thickness as covariates. We also esti- (RA), an accelerometry-derived objective measure of cir- mated phenotypic, genetic, and environmental correlations cadian rhythmicity, and of self-reported risk taking (“Do between area, thickness, and LGI at each vertex. you consider yourself a risk taker?”) in 71,500 and 328,339

Results: LGI was at least moderately heritable at al- participants of the UK Biobank, respectively. Polygenic risk most every vertex (mean heritability = 0.48; interquar- scores (PRS) for low RA and risk taking were generated for tile range = 0.42-0.54). Heritability of LGI was reduced distinct subsamples (not used in the GWAS) with available = = very slightly by controlling for ICV, but remained mod- MRI data (n 4,882 for RA; n 9,249 for risk taking). For erate at most vertices (mean = 0.46; interquartile low RA, associations between top and bottom PRS quartiles range = 0.40-0.52). By contrast, controlling for ICV drasti- and general components of common metrics of white matter cally reduced the heritability of area. Phenotypically, LGI integrity, derived using principal component analysis, were was not wholly independent from either area or thickness. examined (fractional anisotropy (FA); mean diffusivity (MD),

LGI tended to correlate most strongly with either area or intracellular volume fraction (ICVF) and orientation disper- thickness on a region-dependent basis. Despite all three sion index (ODI)). For risk taking, we examined associations metrics being heritable, environmental correlations be- between the top vs. bottom PRS quintile and general com- tween the metrics tended to be much stronger than the ponents of FA and MD as well as total tissue volumes and corresponding genetic correlations. LGI remained heritable volumes of ten cortical/subcortical regions that have previ- at most vertices when ICV, local area, and local thickness ously been linked to risk taking.

(as well as their interactions) were included as covariates Results: There were no signiﬁcant associations between

(mean heritability = 0.43; interquartile range = 0.39-0.48). polygenic risk for low RA and general components of measures of white matter integrity (FA, MD, ICVF, ODI) at any ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 40 Abstracts

PRS threshold. At 3 of 5 PRS thresholds, higher PRS for risk sular ( β = .371, pcorr = .005) medial orbitofrontal ( β = .417, taking was associated with greater white matter tract MD pcorr = .006), middle temporal ( β = .287, p = .045), rostral (reflecting poorer integrity), and at 2 of 5 thresholds, with anterior cingulate ( β = .266, p = .045) and IFG ( β = .512, smaller middle frontal gyrus volume. pcorr = .009) parcels. Discussion: We provide evidence that genetic propensity Discussion: Our findings extend previous studies reporting towards risk taking behaviour is associated with structural associations between BW and adult cortical morphology. brain differences. The middle frontal gyrus has been linked They provide evidence of a potential causal effect of BW to inhibitory control, and poorer white matter integrity to as indexed by genetic variants, on several measures of cor- risk taking behaviour and impulsivity: the current findings tical volume and surface area. The current MR results may suggest these associations are linked to by genetic propen- therefore also have relevance for links between increased sity for risk taking. risk of psychiatric and cognitive impairment in individuals with lower BW. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.439 doi: 10.1016/j.euroneuro.2018.08.440

SU76 EXPLORING THE RELATIONSHIP OF BIRTH WEIGHT SU77 ON CORTICAL BRAIN STRUCTURE IN UK BIOBANK USING BRAIN CORTICAL TRAJECTORIES, POLYGENIC RISK GENETIC INSTRUMENTS AND ENVIRONMENTAL INTERACTIONS IN A PROSPEC- TIVE LONGITUDINAL STUDY OF YOUNG PEOPLE AT-RISK Emma Neilson, Toni Clarke, Xueyi Shen, Simon Cox, OF BIPOLAR DISORDER Masoud Shirali, David Howard, Jude Gibson, Mark Adams,

Mathew Harris, Gail Davies, Ian J. Deary, James Boardman, Janice Fullerton 1, Gloria Roberts 2, Bronwyn Overs 1,

Stephen Lawrie, Andrew McIntosh, Heather Whalley Rhoshel K. Lenroot 3, Michael Breakspear 4,

Andrew Frankland 3, Melvin McInnis 5, Anne Glowinski 6,

University of Edinburgh Holly Wilcox 7, Emma Stapp 8, Leslie Hulvershorn 9,

Kelly Benke 10, Peter Schofield 1, John Nurnberger 9, 3 Background: Differences in the brain’s cortical organization Philip B. Mitchell are linked to common psychiatric disorders and differences in cognitive ability. Low birth weight (BW, < 2.5kg) is asso- 1 Neuroscience Research Australia ciated with alterations in cortical brain structure, reduced 2 University of New South Wales cognitive ability and psychiatric problems; suggesting that 3 School of Psychiatry, University of New South Wales somatic fetal growth may be an important determinant of 4 QIMR Berghofer brain structure and function in later life. However, the re- 5 University of Michigan lationship between BW within the normal range and adult 6 Washington University School of Medicine brain structure in the general population is little under- 7 Johns Hopkins University stood, including whether a causal relationship exists. We 8 National Institute of Mental Health therefore sought to test if there is a causal relationship be- 9 Indiana University School of Medicine tween BW and brain cortical morphology in a general adult 10 Johns Hopkins Bloomberg School of Public Health population using Mendelian Randomization (MR). Methods: The current sample included 1,680 individuals Background: ‘High-risk’ (HR) prospective studies of young from the first release of brain imaging data from UK people at increased risk of Bipolar Disorder (BD) are crucial Biobank. Linear mixed effects models were first used to test for identifying risk profiles that underlie the development for associations between BW and global and localized re- of psychopathology. Environmental exposures may interact gions of brain cortical volume, surface area and thickness. with preexisting genetic vulnerabilities, to affect brain mat- Secondly, to test for causal relationships between BW and uration and/or development of psychopathology. The Aus- cortical metric phenotypes we used a Tw o - s a m p l e MR frame- tralian prospective BD HR study has rich phenotyping over work, applying the inverse-variance weighted method. 8 years, including annual clinical assessments, neuroimag- Results: BW was significantly and positively associated ing and genetic data. The sister study, with participants with global cortical volume ( β = .104, p = 2.86 ×−07) and recruited from four Universities in USA, used identical re- surface area ( β = .100, p = 3.58 ×−07), but not thickness cruitment criteria and clinical assessments, allowing joint ( β = −.054, p = .097). The strength of effects was regionally genetic and clinical data analyses. heterogeneous across the cortical mantle; including frontal, Methods: Participants were aged 12-30 years, in two groups: temporal and insular regions ( β range = .037 − .069, pcorr 1) children/siblings of a proband with BD (type-I or -II) who range = .037 - .010). had not yet developed BD (HR); and 2) controls (CON) with Using birth-weight associated SNPs as proxies for life- no family history of major mental illness. Peripheral blood time exposure to low birth weight, MR indicated significant DNA was genotyped (Aus-US combined cohort n = 392 HR, 239 causal links between lower BW and decreased cortical vol- CON, 80 young-BD), and polygenic risk scores (PRS) calcu- ume of the insular lobe ( β = .346, pcorr = .009), global sur- lated based on Psychiatric Genomics Consortium BD-GWAS. face area ( β = .281, p = .009), and surface areas of the in- Genome-wide methylation was assessed at baseline in 214 ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 41

Australian subjects, and biological age acceleration calcu- Background: Obsessive-compulsive disorder (OCD) is a com- lated using the Horvath calculator. T1-weighted magnetic mon debilitating developmental neuropsychiatric disorder resonance images (MRI) were acquired on the Australian with a genetic risk component, yet identification of high- sample at baseline (n = 170HR, 126 CON, plus 68BD), and 75% confidence risk genes has been challenging. We performed were re-scanned ∼2.1 years later. MRI scans were processed whole-exome sequencing in 222 OCD parent-child trios and using Freesurfer v5.3.0. For baseline analysis, vertex-wise found strong evidence for the contribution of de novo likely- cortical thickness and volume measures were analyzed in gene-disrupting and predicted damaging missense variants a General Linear Model (GLM) to examine effects of group (RR 1.52, p = 0.0005) to OCD risk, identifying CHD8 and and BD-PRS, including relevant covariates. For longitudinal SCUBE1 as high-confidence recurrently mutated genes. analysis of cortical change over time, Linear Mixed Effects Methods: To extract additional information about possible analyses were performed. enriched pathways, biological processes, and potential can- Results: 35% of Australian subjects (n = 63) have now de- didate risk genes, we performed an exploratory gene-set veloped psychopathology since baseline, including thresh- network analysis of all 103 genes carrying at least one de old BD-I or -II (n = 14, 7.7%), and subthreshold BD (n = 29, novo damaging variant in our OCD trios using three separate 16%). HR subjects have higher mean BD-PRS than controls. methods. GeneMANIA and its Cytoscape plug-in were used Traumatic stress interacts with BD-PRS to increase risk for to identify and visualize the resulting protein-protein inter- suicide attempts, independent of demographics, group sta- action (PPI) network, and the CentiScaPe plugin was used to tus, and mood and substance use disorders (interaction analyze the topological parameters of the network. A sec- p = 0.041). Familial risk (group) is associated with thicker ond method, GeNets was used taking advantage of InWeb cortex at baseline in several regions, including the inferior PPI information and 853 expertly curated pathways from the frontal gyrus. We find widespread cortical areas in which Molecular Signatures Database. Finally, Ingenuity was used stress exposure or BD-PRS interacts with age, such that the to “validate” the top expressed biological pathways found thickest cortex was found in the youngest individuals with by GeneMANIA and GeNets. the highest PRS scores in the HR group, but a thinner cor- Results: Starting from 103 seed genes, we obtained a Gene- tex in controls. A repeated measures analysis found strik- MANIA PPI network of shared functional relationships among ing differences in rates of cortical thinning over time across 98 genes more directly connected than expected by chance large sections of the cortex: HR subjects, but not controls, (p value = 0.021), with at the least one connection and a to- showed cortical thinning in a number of right lateralized tal of 835 gene-gene interactions. The LRBA gene was found frontal regions (inferior frontal gyrus, lateral orbitofrontal to be highly connected and classified as a significant hub in cortex, superior frontal gyrus, and rostral middle frontal the directed network (p = 0.046). Topological analysis clas- gyrus). Biological age acceleration does not significantly dif- sified SEC24B, DOCK5, AP1G1 and LRBA as key connector fer in this sub-sample of HR and CON, nor with broadly- genes. Among these, AP1G1 had lower missense and loss-of- defined conversion to BD. function mutation rates than expected based on the ExAC Discussion: Clear clinical and neurobiological differences database. The GeneNets network was also more connected are observable in BD HR subjects, before they develop BD. than by chance (p < 2e-03) and the most significant genes in- Significant interactions between age, polygenic risk and en- cluded LDB3, STARD13, TLN2, GOLGA3, CTCF, SEC24B and vironmental risk factors, indicate that effects of BD risk CHD8. Among these, CTCF, TLN2 and CHD8 are mutation- factors on cortical development may follow a complex tra- intolerant, further supporting their candidacy for OCD risk. jectory. Evidence of widespread accelerated thinning of the The most significant pathway was negative regulation of frontal cortex over time in HR suggests that the frontal cor- fibroblast growth factor receptor signaling (p = 9.98e-06). tical thinning observed in established BD appears to be de- Finally, Ingenuity identified the granulocyte-macrophage veloping early, even before BD manifests. colony-stimulating factor, renin-angiotensin signaling (RAS) system, and neurotrophin/TRK signaling pathway as addi- Disclosure: Nothing to disclose. tional significant pathways. Discussion: PPI analyses confirmed CHD8 as a high- doi: 10.1016/j.euroneuro.2018.08.441 confidence OCD risk gene. Although SCUBE1 was not identified by the PPI analysis, it is part of the EGF family and interacts directly with LRBA that was highly connected in the network and plays an important role in immune response de- SU78 velopment. Finally, most of the resulting key network genes PROTEIN-PROTEIN INTERACTION (PPI) NETWORK based on their network topology are also known ASD risk ANALYSES OF DE NOVO VARIATION IN OBSESSIVE- genes and are known to participate in brain development

COMPULSIVE DISORDER REVEAL OVERLAP WITH and immunological processes. AUTISM RISK GENES Disclosure: Nothing to disclose.

Carolina Cappi 1, Euripedes Constantino Miguel 2,

Dalila Pinto 1, Thomas Fernandez 3 doi: 10.1016/j.euroneuro.2018.08.442

1 Icahn School of Medicine at Mount Sinai

2 University of Sao Paulo

3 Yale University School of Medicine ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 42 Abstracts

SU79 SU80 GENETIC PATHWAYS INVOLVED IN THE SEVERITY OPEN BOARD OF OBSESSIVE COMPULSIVE DISORDER: A FUNCTIONAL GENOMICS APPROACH SU81 OPEN BOARD María Alemany-Navarro 1, Raquel Cruz 2, Eva Real 3,

Cinto Segalàs 3, Sara Bertolín-Triquell 4, 3 2 José Manuel Menchón , Angel Carracedo , SU82 4 Maria Del Pino Alonso AN ALGORITHM TO IDENTIFY PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDERS IN BIOVU US- 1 Instituto de Investigación Biomédica de Bellvitge ING NATURAL LANGUAGE PROCESSING, ICD- CODE

(Barcelona) AND MEDICATION ADMINISTRATION RECORDS IN THE 2 Santiago de Compostela University SYNTHETIC DERIVATIVE 3 Instituto de Investigación Biomédica de Bellvitge, Hospi- talet de Llobregat, Barcelona 1 2 2 4 Takahiro Soda , Evonne McArthur , Patrick McGuire , Hospital Universitari de Bellvitge Angela Maxwell-Horn 2, Celestial Jones-Paris 2,

Angelica Soto-Freita 2, James Sutcliffe 3, James Crowley 1,

Background: Different evidences exist about the genetic Lea Davis 2 risk for Obsessive Compulsive Disorder (OCD) from Genome- wide studies (Stewart, 2013; Matthiesen, 2015). However, 1 University of North Carolina at Chapel Hill no studies look into the genomic base of the severity of 2 Vanderbilt University Medical Center the disorder. Nowadays, the dimensional -as opposed to 3 Vanderbilt University categorical- nature of the psychiatric disorders has been assumed (APA,2013). Knowing more about the genetic bases Background: Obsessive-compulsive disorder (OCD) is a com- of the severity of OCD, in addition to OCD risk, would allow mon psychiatric disorder with a lifetime prevalence of 2.3% developing more personalized treatments as well as preven- and an annual prevalence of 1.2%. It causes a high burden tion strategies for OCD patients. of society. Additionally, patients commonly start to experi- Methods: Three-hundred and seven patients diagnosed ence symptoms from childhood, with a mean age of onset for OCD were genotyped with the Infinium PsychArray at 19 years of age. Despite this disorder burden, OCD’s eti- from Illumina. The severity of the disorder was evaluated ology is unknown and existing treatments are suboptimal. through the Yale-Brown Obsessive-Compulsive Scale (Good- In order to improve clinical outcomes and to reduce mor- man, 1989). Individual variant analyses were carried out for bidity and societal costs, we need a better understanding of single nucleotide polymorphisms (SNPs). Enrichment analy- the causal mechanisms implicated in OCD. Initial genome- ses were executed for rare and normal variants (minor allele wide association studies (GWAS) for OCD were underpow- frequency = 0.000000001 to 0.05) for those genes with a p- ered, but clearly indicated that OCD is a complex genetic value < 0.001. trait and that increased sample size will yield significant Results: At the variant level, one single nucleotide polymor- loci. The worldwide genotyped sample size for OCD cases is phism (SNP) was found to be associated with YBOCS score lagging behind other psychiatric disorders, despite the fact at GWAS significance level (2,08x10-08) under additive and that OCD is prevalent and a major source of disability. dominant models: rs9955055, an intronic variant next to Methods: Clinical data were obtained from the Synthetic RPL31P9 (147 bp) and near from DSEL gene (368 kb). The Derivative (SD), which is a de-identified electronic medi- most enriched genetic pathways were rich in splice variants cal record (EMR) data warehouse that contains clinical in- (enrichment score = 1.59; FDR = 6.55x10-4) or involved in al- formation extracted from heath records of over 2.2 mil- ternative splicing (enrichment score = 1.39; FDR = 0.006). lion individuals in a searchable form covering the past Discussion: Given the proximity of rs9955055 to RPL31P9 20 years. Available data types include (but are not lim- and DSEL genes, the functional roles of these genes could be ited to)structured data including: ICD9, ICD10, PheWAS, involved in the severity of OCD. In line with this, RPL31P9 CPT codes, administered medications, laboratory values, has been associated to Mood Disorders and non-response vitals as well as unstructured data including clinical com- to serotonine-reuptake inhibitors (Li, 2016). DSEL gene is munications (including discharge summaries, H + P, progress a CpG-associated gene within a region linked to Bipolar Dis- notes, other communication between care providers, or be- order (Goossens, 2003). tween providers and patient, clinical reports including those Regarding the results from pathway analyses, a dysfunc- from radiology, pathology, rehabilitation), problem lists, tional splicing has been observed in other neuropsychiatric and family history). A combination of ICD9/10 codes, medi- disorders such as Schizophrenia, affective disorders, sub- cation administration history, history of treatment/ diagno- stance abuse disorders or neurodevelopmental disorders sis as ascertained by natural language processing was used (Glatt et al.; 2011). Our results suggest that an altered splic- to identify roughly 1500 samples within BioVU (Vanderbilt ing could be in the base for OCD severity. University’s biobank). These samples were genotyped and

Disclosure: Nothing to disclose. imputed for comparison to other available genotypes of patients with OCD. doi: 10.1016/j.euroneuro.2018.08.443 ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 43

Results: The heritability estimates, polygenic risk scores, metric by estimating the mean and variance of the factor and comparison between this sample set and existing OCD score distributions in each study site and diagnostic group. sample sets is ongoing and will be presented. Results: We demonstrate that alignment is a ﬂexible, scal- Discussion: Recent studies (C-Y Chen et al 2018) have able method to create valid phenotype scores using differ- demonstrated that EHR based automated phenotyping to be ent instruments across different sites. Using this approach, an efﬁcient method of collecting samples for inclusion into we were able to create factor scores for mania, depres- GWAS studies for psychiatric disorders. Our method demon- sion and psychotic symptom dimensions and transform those strates that this method is applicable to obsessive compul- scores to a common metric across study sites and diagnostic sive disorders as well. groups. After alignment, differences in factor scores across groups can be easily assessed and used to demonstrate the Disclosure: Nothing to disclose. validity of the approach. Discussion: We show that the alignment method is a doi: 10.1016/j.euroneuro.2018.08.446 valid approach to create phenotype dimension scores using symptom-level data derived from a variety of clinical instruments measured in different samples. We are now evaluat-

SU83 ing the heritability of these phenotypes and examining their

PHENOTYPE HARMONIZATION METHOD IN THE WHOLE relationship with genetic variability. GENOME SEQUENCING FOR PSYCHIATRIC DISORDERS CONSORTIUM Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.447 Whole Genome Sequencing for Psychiatric Disorders

Consortium 1, Nelson Freimer 1, Annabel Vreeker 2

1 University of California, Los Angeles SU84

2 UMC Utrecht FAMILIAL INFLUENCES ON NEUROTICISM IN UK BIOBANK

1 1 Background: Severe psychiatric disorders, including Rosa Cheesman , Jonathan Coleman , 2 1 schizophrenia and bipolar disorder, are clinically het- Genevieve Morneau-Vaillancourt , Kirstin Purves , 1 1 3 erogeneous with overlapping symptoms and substantially Christopher Rayner , Gerome Breen , Thalia Eley shared genetic risk. Discovering causal genetic variants contributing to these disorders has proven difficult, de- 1 King’s College London spite the identification of numerous loci associated with 2 Laval University them. Phenotypic imprecision likely contributes to this 3 Institute of Psychiatry, Psychology & Neuroscience, King’s difficulty, leading to growing interest in assaying specific College London clinical symptoms and dimensional traits that may be associated with disease risk across diagnostic categories. The Background: A key mechanism by which genes can come to NIMH Whole Genome Sequencing for Psychiatric Disorders shape our experiences is genotype-environment correlation, (WGSPD) Consortium is analyzing such measures in individ- or genetic influence on exposure to environments. In other uals affected by severe psychiatric disorders for whom it words, the environmental influences affecting an individual has obtained whole genome sequencing data. As phenotype are not independent of their own behaviour. Recently, ge- definition and assessments vary across languages, cultures, nomic methods have yielded evidence that common genetic sites and instruments, the WGSPD has harmonized diagnos- variants influence experiences of psychopathology-related tic, symptom-level data, to enable combination of measures environments in adulthood such as life events. However, we across studies as a prelude to genetic association analyses. can now go further in unpicking genetic and environmental Here, we describe adaptation of a recently developed influences on individual differences in experiences. factor analytic technique for test equating (Alignment; Methods: The UK Biobank sample includes family mem- Asparouhov & Muthén, 2014) to calculate factor scores for bers with different degrees of relatedness (23,197 couples, use in cross-study genetic analyses. 22,665 siblings, 6273 parent-offspring pairs in the full sam- Methods: The WGSPD includes ∼20,000 cases across mul- ple). This offers an opportunity to estimate the extent that tiple diagnostic categories, drawn from several countries environments are influenced not only by common SNPs but worldwide. Across the different participating sites, there by kin genetic effects, family environment, sibling environ- is great variation in used clinical diagnostic instruments. ment and couple environment. This study separates these For the current analyses, we included individuals with familial sources of individual differences in experiences of schizophrenia, schizo-affective disorder, bipolar disorder psychopathology-related environments: substance use, so- and major depressive disorder. We used symptom-level data cial deprivation, and trauma. We employ GREML-KIN, a from six major clinical instruments (SCID, OPCRIT, CASH, DI- quantitative genetic mixed-model method that makes use PAD, DIGS and MINI) to create factor scores for mania, de- of matrices of genomic and environmental relatedness. pression and psychosis. After identifying harmonized item Results: N/A: analyses underway. sets, we used item response theory (Embretson & Reise, Discussion: This research contributes to a body of evidence 2013) to calculate factor scores within each study site and supporting a move away from a passive model of imposed diagnostic group. Lastly, we adapted the alignment method environmental influences, and the environment as just a to place factor scores from the six instruments on a common residual element. As well as quantifying the contribution ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 44 Abstracts of specific domains of ‘missing environments’, we address ditive and 0.017 in recessive models). This latter result sur- the ‘missing heritability’ problem: exploiting the high LD vived correction for lifetime depression and was replicated in family members to quantify the effects of variants not in both population subsamples. tagged in GWAS of unrelated individuals, e.g. rare variants, Discussion: Our results suggest that CLOCK rs10462028 CNVs, and structural variants. These findings shed new light might alter migraine risk in the presence of financial on why people differ in their exposure to risk factors for difficulties, a chronic persistent stress factor. Further psychiatric disorder. investigation of potential roles of circadian genes in the pathophysiology of migraine, especially in patients Disclosure: Nothing to disclose. with serious life stressors, may provide new treatment strategies. (The study was supported by: KTIA_NAP_13- doi: 10.1016/j.euroneuro.2018.08.448 1-2013-0001, KTIA_13_NAP-A-II/14, KTIA_NAP_13-2-2015- 0001, 2017-1.2.1-NKP-2017-00002 (Hungarian Brain Re- search Program); MTA-SE Neuropsychopharmacology and

SU85 Neurochemistry Research Group; ÚNKP-16-3, ÚNKP-17-3-III- CLOCK CLICKS WITH FINANCIAL STRESS BEHIND MI- SE-2, ÚNKP-17-4-I-SE-8 (New National Excellence Program GRAINE of The Ministry of Human Capacities); Janos Bolyai Research Fellowship of the Hungarian Academy of Sciences.)

Daniel Baksa 1, Xenia Gonda 2, Nora Eszlari 1,

Peter Petschner 3, Gyorgy Bagdy 3, Gabriella Juhasz 4 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.449 1 Semmelweis University

2 Kutvolgyi Clinical Centre, Semmelweis University

3 Hungarian Academy of Sciences, Semmelweis University

4 Semmelweis University, University of Manchester SU86 GENETIC INFLUENCES ON EIGHT PSYCHIATRIC DIS-

Background: Mood disorders have previously been con- ORDERS BASED ON FAMILY DATA OF 4,408,646 FULL nected to circadian dysregulation and are also frequently AND HALF SIBLINGS, AND GENETIC DATA OF 333,748 comorbid with migraine. CLOCK gene is a central compo- CASES AND CONTROLS nent in the main circadian clock mechanism working as 1 2 2 a transciptional activator, and the rs10462028 tagSNP of Tinca Polderman , Erik Petterson , Henrik Larsson , 3 1 CLOCK has been connected to bipolar disorder, a disease Patrick Sullivan , Danielle Posthuma with known comorbidity with migraine. The effects of circadian genes on common migraine have not been tested 1 VU University Amsterdam yet and recent meta-analyses of migraine GWASs have not 2 Karolinska Institutet Stockholm identified any circadian genes as a susceptibility gene of mi- 3 University of North Carolina at Chapel Hill graine. However, environmental factors including stress and their interaction with genes are also important elements to Background: Most studies underline the contribution of address in migraine research. In our present study our goal heritable factors for psychiatric disorders. However, heri- was to test the main effect of rs10462028 and its interac- tability estimates depend on the population under study, tions with stress factors on migraine. diagnostic instruments, and study designs that each has Methods: 2349 subjects (69.3% females) were recruited its inherent assumptions, strengths and biases. We aim to from Manchester (n = 1350) and Budapest (n = 999) (aged test the homogeneity in heritability estimates between two between 18 and 60). 27.6% was defined to show mi- powerful, and state of the art study designs for eight psy- graine symptoms according to the ID-Migraine Question- chiatric disorders. naire. The following stress factors were used: childhood ad- Methods: We assessed heritability based on data of Swedish versity (Childhood Trauma Questionnaire), recent negative siblings (N = 4,408,646 full and maternal half siblings) and life events (List of Threatening Experiences) and financial based on summary data of eight samples with measured difficulties (from our validated background questionnaire). genotypes (N = 125,533 cases and 208,215 controls). All data The main effect of rs10462028 and the SNP x stress factors were based on standard diagnostic criteria. Eight psychi- interaction effects were tested on migraine using logistic re- atric disorders were studied: 1) alcohol dependence, 2) gression models with additive, dominant and recessive mod- anorexia nervosa, 3) ADHD, 4) autism spectrum disorder, 5) els in the total population and in both subpopulations. All bipolar disorder, 6) major depressive disorder, 7) obsessive- statistical models were adjusted for population, gender and compulsive disorder, and 8) schizophrenia. age, and confounding effect of lifetime depression (derived Results: Heritability estimates from sibling data varied from from our background questionnaire) was also tested. Sta- 0.30 for Major Depression to 0.80 for ADHD. The estimates tistical analyses were made using PLINK 1.9 and IBM SPSS based on the measured genotypes were lower, ranging from Statistics 23. 0.10 for AD to 0.28 for OCD. The largest discrepancy be- Results: CLOCK rs10462028 showed no main genetic effect tween sibling-based and genotype-based estimates was ob- on migraine. Childhood maltreatment and recent negative served for OCD which is probably due to the fact that the life events showed no significant interaction with the SNP. genotype sample is heavily ascertained from highly multi- Only financial difficulties were found to have a significant plex families and early age of onset cases and consists thus interaction with rs10462028 on migraine (pFDR = 0.025 in ad- of the most severe and genetically loaded cases. Genotype- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 45 based estimates correlated positively (0.19) with sibling- highlight the need for further large-scale genetic analyses based estimates. When removing OCD from the data this and, in parallel, continued pharmacovigilance for patients correlation increased to 0.50. currently treated with PCSK9 inhibitors. Discussion: Heritability estimates for eight psychiatric conditions converge across sibling-based and genotype-based Disclosure: Nothing to disclose. study designs and are comparable to estimates based on doi: 10.1016/j.euroneuro.2018.08.451 previously reported survey measures in twin studies, suggesting that heritability estimates are robust across different tools and designs. The findings also highlight large dif- SU88 ferences in genetic and environmental influences between psychiatric disorders, providing future directions for etio- THE EXTERNALIZING CONSORTIUM: A NEW EFFORT logical psychiatric research. TO IDENTIFY GENES INVOLVED IN A SPECTRUM OF PSYCHIATRIC AND SUBSTANCE USE DISORDERS CHAR- Disclosure: Nothing to disclose. ACTERIZED BY BEHAVIORAL UNDERCONTROL doi: 10.1016/j.euroneuro.2018.08.450 Danielle Dick 1, Philipp Koellinger 2, Paige Harden 3,

Richard Karlsson Linnér 2, Travis Mallard 3, Ronald de

Vlaming 2, Andrew Grotzinger 3, Peter Barr 1,

SU87 Elliot Tucker-Drob 3, Irwin Waldman 4, Arpana Agrawal 5,

PCSK9 GENETIC VARIANTS, LIFE-LONG LOWERING Abraham Palmer 6 OF LOW-DENSITY LIPOPROTEIN CHOLESTEROL, AND

COGNITIVE ABILITIES 1 Virginia Commonwealth University

2 VU Amsterdam

Donald Lyall 1, Joey Ward 1, Maciej Banach 2, 3 University of Texas at Austin

George Davey Smith 3, Jason Gill 1, Jill Pell 1, 4 Emory University

Michael Holmes 4, Naveed Sattar 1 5 Washington University School of Medicine

6 University of California San Diego

1 University of Glasgow

2 Medical University of Lodz Background: The “externalizing spectrum” is a constel-

3 University of Bristol lation of co-morbid disorders and behaviors that involve

4 University of Oxford under-controlled or impulsive action. It encompasses multiple clinical diagnoses across development, including at- Background: PCSK9 inhibitors lower low-density lipoprotein tention deficit hyperactivity disorder (ADHD), conduct dis- (LDL) cholesterol and are efficacious at reducing risk of order, oppositional defiant disorder, antisocial personality vascular disease, however questions remain about poten- disorder, alcohol use disorders, and other substance use dis- tial adverse effects on cognitive function. We examined the orders. Considered together, externalizing disorders impose association of LDL cholesterol-lowering genetic variants in an enormous public health burden. Multiple twin and fam- PCSK9, with continuous measures of cognitive ability in UK ily studies have found that much of the genetic influence Biobank. on any one externalizing disorder is broadly shared with Methods: Six independent SNPs in PCSK9 scaled to a other externalizing spectrum disorders, and with personal- 50mg/dL lower LDL cholesterol were used in up to 337,348 ity traits that are characterized by behavioral disinhibition individuals from UK Biobank who completed tests of cogni- (e.g., Krueger et al., 2002; Hicks et al, 2004). For example, tive ability: fluid reasoning, reaction time, trial making test as much as 65% of the heritability of alcohol dependence A/B and digit symbol coding. Associations were adjusted for is suggested to operate via a general externalizing disposi- age, sex, GWAS array, and 10 principal components (as pro- tion, rather than via genes specific to alcohol dependence vided by UK Biobank). (Kendler et al., 2003). This shared, latent factor underlying Results: The scaled PCSK9 allele score was associated with a externalizing disorders and traits is highly heritable. lower risk of coronary heart disease (odds ratio 0.73; 95% CI: Methods: Capitalizing on the known genetic overlap be- 0.60 to 0.90, P = 0.003). The scaled PCSK9 allele score nom- tween externalizing traits and disorders, we have launched inally associated with worse log reaction time (0.04 stan- a new consortium that employs genome-wide association dard deviations per 50mg/dL lower; 95%CI: 0.00 to 0.08; studies (GWAS) of externalizing phenotypes, with the goals P = 0.038). Although no strong associations of the PCSK9 al- of (a) estimating the genetic structure underlying exter- lele score were identified with any cognitive trait, the im- nalizing phenotypes, (b) identifying genes involved in the precision around the estimates meant that we could not ex- shared underlying liability to externalizing versus genes clude a similar magnitude of effect of genetic inhibition of unique to specific phenotypes, (c) boosting statistical power PCSK9 to that seen with established risk factors, including for GWAS of specific externalizing phenotypes that are cur- APOE e4 or smoking history, for any of the individual cog- rently available in only relatively small samples, and (d) nitive traits. Point estimates for the PCSK9 allele score and understanding the extent to which genetic associations ob- cognitive traits were all on the harmful side of unity. served with individual outcomes are operating through a Discussion: Using currently available data in UK Biobank, general predisposition to externalizing behavior. we are not able to rule out meaningful associations of Results: We will present results from applying Genomic SEM, PCSK9 genetic variants with cognitive traits. These data a new multivariate method, which applies structural equa- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 46 Abstracts tion modeling to summary statistics from genetically cor- Results: APOE ε4 allele carriers had significantly higher related traits. With the method we perform exploratory behavior problem scores than non-carriers, and adverse and confirmatory factor analyses, allowing for sample over- associations with PAHs and NO2 were stronger or limited to lap. Our initial analyses include GWAS summary statistics ε4 carriers for behavior problem scores (P-interaction 0.03 for addictive behaviors (n ∼ 157,000), ADHD (n ∼ 53,000), and 0.04), caudate volume (P-interaction 0.04 and 0.03), alcohol consumption (n ∼ 414,000), antisocial behavior (n and inattentiveness trajectories (P-interaction 0.15 and ∼ 16,000), childhood aggression (n ∼ 19,000), lifetime 0.08, respectively). Patterns of associations with the same cannabis use (n ∼ 32,000), impulsivity (N ∼ 20,000) and outcomes were similar for EC. several risk behaviors (n ∼ 370,000 – 405,000). We present Discussion: PAHs, EC, and NO2 were associated with higher results from these initial analyses and our planned future behavior problem scores, smaller reductions in inattentive- directions. ness over time, and smaller caudate volume in APOE ε4 al- Discussion: We will conclude with details about the Exter- lele carriers in our study population, while corresponding nalizing Consortium, in order to invite groups to participate associations were weak or absent among ε4 non-carriers. in the next wave of analyses. These findings support a potential role of APOE in biological mechanisms that may contribute to associations be- Disclosure: Nothing to disclose. tween air pollution and neurobehavioral outcomes in children. Replication in other population settings is needed to doi: 10.1016/j.euroneuro.2018.08.452 establish the potential role of APOE gene in neurobiological susceptibility to air pollution. SU89 Disclosure: Nothing to disclose. TRAFFIC-RELATED AIR POLLUTION, APOE ε 4 STA- TUS, AND NEURODEVELOPMENTAL OUTCOMES AMONG doi: 10.1016/j.euroneuro.2018.08.453 SCHOOL CHILDREN ENROLLED IN THE BREATHE PROJECT (CATALONIA, SPAIN) SU90

Silvia Alemany 1, Natàlia Vilor-Tejedor 1, USING MEDICATION DATA TO DEFINE PSYCHIATRIC

Raquel García-Esteban 1, Mariona Bustamante 1, PHENOTYPES AND RECRUIT LARGE SAMPLES FOR

Payam Dadvand 1, Mikel Esnaola 1, Marion Mortamais 1, GWAS

Joan Forns 1, Barend van Drooge 1, Mar Alvárez-Pedrerol 1,

Joan Grimalt 2, Ioar Rivas 2, Xavier Querol 2, Jesús Pujol 3, Nick Martin, Sarah Medland

Jordi Sunyer 1 Queensland Institute of Medical Research

1 Barcelona Institute for Global Health

2 Institute of Environmental Assessment and Water Re- Background: It has become abundantly clear that the key to search (IDAEA-CSIC) progress in psychiatric genetics is large samples for GWAS.

3 Hospital del Mar How to collect these quickly and cheaply? Methods: We are using data from the Australian Pharma- Background: Traffic-related air pollution is emerging as a ceutical Benefit Scheme (which centrally registers 99% of all risk factor for Alzheimer’s disease (AD) and impaired brain prescriptions) to ascertain cases through their prescription development. Individual differences in vulnerability to air information. pollution may involve the ε4 allele of Apolipoprotein E Results: So far, we have collected DNA from > 15,000 people (APOE) gene, the primary genetic risk factor for AD. We aim with > 4 prescriptions for SSRIs of whom 93% report depres- to analyze whether the association between traffic air pollu- sion as a first diagnosis; 60% also report anxiety. We have tion and neurodevelopmental outcomes is modified by APOE also found > 2000 ADHD cases through prescriptions for Ri- ε4 status in children. talin etc. Methods: Data on parent-reported behavior problems (to- Discussion: This year we are launching recruitment of bipo- tal difficulties scores, Strengths and Difficulties Question- lar cases via lithium prescriptions and schizophrenia via naire), teacher-reported attention-deficit hyperactivity dis- clozapine. We have applied for funding to extend this model order (ADHD) symptom scores, cognitive performance tra- to alcoholism [acamprosate, naltrexone] and Alzheimer’s jectories (computerized tests of inattentiveness and work- disease [memantine]. ing memory repeated 2–4 times during January 2012–March 2013), and APOE genotypes were obtained for 1,667 children Disclosure: Nothing to disclose. aged 7–11 years attending 39 schools in or near Barcelona. doi: 10.1016/j.euroneuro.2018.08.454 Basal ganglia volume (putamen, caudate, and globus pal- lidum) was measured in 163 of the children by MRI (October 2012–April 2014.) Average annual outdoor polycyclic aro- matic hydrocarbons (PAHs), elemental carbon (EC), and ni- trogen dioxide (NO2) concentrations were estimated based on measurements at each school (two 1-week campaigns conducted 6 months apart in 2012). ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 47

SU91 Results: Preliminary analyses in the Netherlands Tw i n Reg- THE VALUE OF POLYGENIC RISK SCORES IN PRE- ister showed the strongest genetic associations in the ex- DICTING THE TRANSITION FROM CHILDHOOD AND pected directions with schizophrenia, MDD, neuroticism and ADOLESCENT PSYCHIATRIC SYMPTOMS INTO CHRONIC wellbeing, although not always signiﬁcant. Especially ADHD ADULT PSYCHOPATHOLOGY was negatively associated with the educational attainment PRS.

Christel M. Middeldorp 1, Omowonuola Akingbuwa 2, Discussion: The results show how childhood, adolescent and

Marjo-Riitta Jarvelin 3, Paul Lichtenstein 4, adult psychiatric symptoms are inﬂuenced by overlapping

Sebastian Lundstrom 5, Ralf Kuja-Halkola 4, Marcus Munafo 6, genetic factors explaining persistence of symptoms from

Robert Plomin 7, Kaili Rimfeld 7, Hannah Sallis 6, childhood into adulthood. Adding polygenic risk scores to

Henning Tiemeier 8, Eivind Ystrom 9, Meike Bartels 2 models predicting which children are at high risk for chronic symptoms may improve prediction.

1 Child Health Research Centre, University of Queensland Disclosure: Nothing to disclose. 2 Vrije Universiteit Amsterdam

3 Imperial College London doi: 10.1016/j.euroneuro.2018.08.455

4 Karolinska Institutet

5 University of Gothenburg

6 University of Bristol SU92 7 King’s College London GENERAL COMMON POLYGENIC RISK IN PSYCHIATRIC 8 Erasmus MC DISORDERS 9 Norwegian Institute of Public Health

Arija Jansen 1, Tinca Polderman 1, Philip Jansen 1, Background: Adult psychiatric disorders can be preceded Danielle Posthuma 1, Frank Verhulst 2, Gwen Dieleman 2 by a broad range of childhood psychiatric symptoms. Schizophrenia, for example, is associated to anxious, de- 1 VU University Amsterdam pressive, behavioural and ADHD symptoms in childhood. A 2 Erasmus Medical Centre critical need to be able to provide targeted treatment is the ability to identify the children at highest risk for this Background: Neurodevelopmental disorders such as autism unfavorable trajectory. Earlier polygenic risk score analyses spectrum disorder (ASD), attention deficit/hyperactivity in the Netherlands Tw i n Register (NTR), the Avon Longitudi- disorder (ADHD), major depressive disorder (MDD) and anx- nal Study of Parents and Children (ALSPAC) and Generation iety disorders (AD) are at least partly, heritable. These dis- R have suggested that the association with schizophrenia is orders each have a unique genetic architecture consisting due to shared genetic risk factors. Fewer studies have inves- of common and rare genetic variants. Recent research pro- tigated the association with Major Depressive Disorder and poses the existence of a general genetic underlying psy- Bipolar disorder, as fewer genetic variants were identified chopathology factor with in addition a unique set of genetic for these disorders. For other adult traits associated with risk variants resulting in a specific psychiatric disorder. We adult psychiatric disorders, such as wellbeing and neuroti- aim to investigate this common genetic signal by exploring cism, genetic overlap with childhood psychopathology has the joint genetic contribution of five psychiatric disorders, not been analysed yet. Given the large increase in genetic and Insomnia to a clinical diagnosis in a unique clinical child variants associated with adult psychopathology and associ- and adolescent sample (N = 1591). ated traits, together with the large increase in available Methods: We calculated polygenic risk scores (PRS) for genotypes in individuals with longitudinal data on psychi- ADHD, ASD, Schizophrenia (SCZ), MDD, anti-social behav- atric symptoms from birth or childhood, it is timely to test ior (ASB) and insomnia (INS) for individuals with a psy- genetic associations, and, if present, to test whether these chiatric disorder in a clinical child and adolescent sample associations vary with age. (total N = 1591), and for an adult control sample (N = 943). Methods: Polygenic risk scores (PRS) will be based on The clinical sample is overrepresented with ADHD (N = 449), the most recent results from Genome-Wide Association ASD (N = 428) and AD (N = 305). Other diagnoses vary from Meta-Analyses for schizophrenia, depression, bipolar disor- Anorexia Nervosa, to TIC disorder, to depression and dis- der, wellbeing, neuroticism, BMI, height, educational at- ruptive behavior. We tested all PRS jointly, representing a tainment and insomnia. The associations with internaliz- common genetic signal, with logistic regression analyses for ing, ADHD and social problems measured between age 7 an association with disorder status. Follow-up analyses ex- and age 18 will be analyzed in the cohorts participating plored the specific contributions per PRS. in the CAPICE consortium: ALSPAC, Child and Adolescent Results: With our common variant model that included all Tw i n Study in Sweden (CATSS), Generation R, NTR, Norwe- PRS we observed an explained variance of 3,8% (Nagelkerke gian Mother and Child Cohort Study (MoBa), Northern Fin- R2 = 0.038). Inspection of the single contributions showed land Birth Cohort (NFBC), Tw i n s Early Development Study that MDD (R2 = 0.021), and ADHD (R2 = 0.014) showed the (TEDS) and Tw i n Study of Child and Adolescent Development largest effects, while ASB (R2 = 0.006), ASD (R2 = 0.001), (TCHAD), total N = ∼40,000. Meta-regression analyses will INS (R2 = 0.001) and SCZ (R2 = 0.01) showed small contri- show whether associations depend on age and type of psy- butions. chiatric symptoms in the children. Discussion: This is the first study that explored the joint and single genetic effects of five psychiatric disorders, and ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 48 Abstracts

Insomnia in a large clinical sample of children and adoles- psychopathology factor and MDD PRS with a speciﬁc emo- cents. Interestingly, our results indicate that the ADHD and tional problems factor but only at age 13 years, not at age MDD PRS explain the largest part of the variance between 7 years. We found no clear associations for ASD PRS. our cases and controls. Given the large group of ASD cases Discussion: Our results suggest that schizophrenia and ADHD in our clinical sample we also expected a substantial effect genetic risk may contribute to pleiotropy at least partly of the ASD PRS but the explained variance by this PRS was via association with a ‘general psychopathology’ factor in limited. This might be due to the relatively small sample childhood, whereas genetic liability for MDD appears to size of the discovery sample on which this PRS is based. The contribute to a speciﬁc emotional factor indexing depres- MDD PRS is based on a large discovery sample (N = 59.851 sion and anxiety symptoms. This further suggests that while cases), however, this is also the case for the INS and SCZ the phenotypic structure of psychopathology is stable from PRS (respectively N = 386.533 cases and N = 40.675 cases) of childhood to early adolescence, there may be developmen- which the genetic effect was small. tal changes in the genetic architecture of psychopathology.

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.456 doi: 10.1016/j.euroneuro.2018.08.457

SU93 SU94 THE CONTRIBUTION OF PSYCHIATRIC RISK ALLELES INVESTIGATING THE GENETIC ARCHITECTURE OF TO A GENERAL LIABILITY TO PSYCHOPATHOLOGY IN PSYCHIATRIC DISORDERS AND THEIR MEDICAL COMOR- EARLY LIFE: INVESTIGATING ONE EXPLANATION FOR BIDITY FROM A DEVELOPMENTAL PERSPECTIVE PLEIOTROPY

Alison Merikangas 1, Rachel Kember 2, Monica Calkins 2,

Lucy Riglin 1, Stephan Collishaw 1, Ajay K. Thapar 1, Kosha Ruparel 2, Ruben Gur 2, Raquel E. Gur 2, Laura Almasy 1

Beate Leppert 2, Joanna Martin 1, Alexander Richards 1,

Richard Anney 1, George Davey Smith 2, Kate Tilling 2, 1 Children’s Hospital of Philadelphia

Evie Stergiakouli 2, Michael O’Donovan 1, Anita Thapar 1 2 University of Pennsylvania

1 Cardiff University Background: Mental disorders are a leading cause of dis-

2 MRC Integrative Epidemiology Unit at the University of ability worldwide. One of the major sources of disability is Bristol comorbidity between mental and physical conditions, which has been documented in both clinical and community sam- Background: Molecular genetic studies provide evidence ples of both adults and youth. Previous work on the Chil- of shared genetic risks across different psychiatric disor- dren’s Hospital of Philadelphia (CHOP)/University of Penn- ders. Using factor analyses, phenotypic overlaps between sylvania Philadelphia Neurodevelopmental Cohort (PNC) has different disorders have been found to be best explained demonstrated pervasive comorbidity between physical and both by a latent factor that reflects general liability to mental disorders in youth. Shared genetic etiology between psychopathology, as well as by specific factors represent- some seemingly disparate mental and physical disorders has ing constructs such as emotional/internalizing and behav- been identified. Establishing the loci underlying this comor- ioral/externalizing problems. In this study we examine the bidity across development may provide insight into etiology structure of psychopathology in childhood and early adoles- and identify key pathways for treatment of both disorders. cence in a population-based birth cohort, including autistic Methods: The sample included 9498 youth ages 8 and ADHD symptoms as well as emotional and behavioral to 21 years from the PNC identified through pedi- items that have been used in previous studies. We tested atric clinics in the CHOP health care network (mean the hypothesis that common psychiatric risk alleles, indexed age = 14.2; female = 51.7%; European American = 55.8%; by polygenic risk scores (PRS), are associated with a gen- African American = 32.9%; Other Ancestry = 11.4%). Measures eral psychopathology factor, providing an explanation for were as follows: physical condition based on electronic pleiotropy across disorders. medical records and interview data on 42 physical con- Methods: We used data from a UK, prospective, population- ditions of 14 organ systems/specialties, mental disorders based cohort (ALSPAC). The sample included individuals were assessed with an abbreviated version of the structured with data on psychopathology at ages 7 (N = 8161) and 13 Kiddie-Schedule for Affective Disorders and Schizophrenia years (N = 7017). Given the young age of the cohort, symp- (K-SADS) psychiatric diagnostic interview, alcohol and other toms were parent-reported. PRS were derived from the substance use were assessed with the Minnesota Tw i n and largest available published genome-wide association studies Family Study computerized substance use assessment or of schizophrenia, major depressive disorder (MDD), autism the K-SADS substance screener, and participants were geno- spectrum disorder (ASD) and attention-deficit/hyperactivity typed and standard quality control measures employed. disorder (ADHD). Patterns of medical/psychiatric comorbidity across devel- Results: ADHD PRS were associated with a general psy- opment were established with traditional regression tech- chopathology factor at ages 7 and 13 and also with a niques, and empirically based phenotype groups were cal- specific neurodevelopmental problems factor at age 7 culated using latent variable analysis. SNP-based heritabil- years. Schizophrenia PRS were associated with the general ities were calculated to estimate the degree of influence ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 49 of common genetic variation on the established subtypes, p = 0.027). The polyenvironmental adversity score also sig- and polygenic risk scores were calculated for disorders to nificantly predicted psychopathology burden (beta = 1.25, establish if SNPs associated with medical conditions predict 95%CI 0.75-1.76, p < 0.001). Family history and polyenviron- psychiatric phenotypes, and vice versa. mental adversity jointly explained 16% of variance in youth Results: Models adjusted for sociodemographic correlates, psychopathology burden. other physical and mental disorders, and false discovery re- Discussion: Psychiatric family history and cumulative expo- vealed broad patterns of associations between neurodevel- sure to adversity can be combined to powerfully predict psy- opmental disorders with behavior disorders and attention chopathology. deficit/ hyperactivity disorder (ADHD); neurologic/central nervous system conditions with mood disorders and ADHD; Disclosure: Nothing to disclose. and autoimmune/ inflammatory conditions with mood dis- doi: 10.1016/j.euroneuro.2018.08.459 orders. Discussion: To our knowledge, our study is the first to examine the genetic architecture underlying comorbid medical/mental conditions in a large diverse sample of children. SU96 Our findings show strong overlap between physical and men- PHARMACOGENETICS MAY IMPROVE THE SAFETY tal conditions and the specific patterns of comorbidity have PROFILE OF ANTIPSYCHOTIC TREATMENTS important implications for etiology. Prospective tracking of 1 2 cross-disorder morbidity will be important to establish more MJ Arranz , Alex Gonzalez-Rodriguez , 3 4 effective mechanisms for prevention and intervention since Josefina Perez-Blanco , Rafael Penadés , 3 1 5 the order of onset cannot be determined from these data. Blanca Gutierrez , Ibañez Laura , Barbara Arias ,

Mercè Brunet 4, Jorge Cervilla Ballesteros 3,

Disclosure: Nothing to disclose. Juliana Salazar 6, Rosa Catalan Campos 4 doi: 10.1016/j.euroneuro.2018.08.458 1 Fundacio Mutua Terrassa - Hospital Universitari Mutua Ter- rassa

2 Parc Taulí University Hospital, Sabadell

SU95 3 University of Granada

TRANSDIAGNOSTIC FAMILY HISTORY OF MENTAL ILL- 4 Hospital Clinic, Barcelona

NESS, EXPOSURE TO ENVIRONMENTAL ADVERSITY, AND 5 Universitat de Barcelona/Institut de Biomedicina de la PSYCHOPATHOLOGY IN YOUTH Universitat de Barcelona (IBUB)

6 Hospital de la Santa Creu i Sant Pau, Barcelona

Alyson Zwicker 1, Vladislav Drobinin 1, Emily Howes Vallis 1, 1 2 3 Lynn Mackenzie , Jill Cumby , Lukas Propper , Background: Antipsychotic drugs fail to achieve adequate 3 3 1 Sabina Abidi , Alexa Bagnell , Barbara Pavlova , response in 30-50% of treated patients and about 50% of 1 1 Martin Alda , Rudolf Uher them develop severe and lasting side-effects. Treatment failure results in poorer prognosis with devastating reper-

1 Dalhousie University cussions for the patients, caretakers and broader society.

2 Nova Scotia Health Authority Hypothesis: Growing evidence indicates that genetic fac-

3 Dalhousie University/Nova Scotia Health Authority tors in Cytochrome P450 (CYP) enzymes play a critical role in determining the clinical outcome of antipsychotic treat- Background: Family history of mental illness strongly pre- ment. The adjustment of clinical doses according to the CYP dicts psychopathology. Exposure to adversity, such as child- genetic profile of patients may improve the safety and effi- hood maltreatment, bullying, or poverty also contributes to cacy of antipsychotic treatments. OBJECTIVES: The aim of risk. However, each individual form of exposure is typically this study was to evaluate the clinical benefits of a pharma- studied in isolation. We aimed to examine whether a cumu- cogenetic intervention for the personalization of antipsy- lative measure of multiple adversities adds to family history chotic treatment in predicting youth psychopathology. Methods: Pharmacogenetic information in key CYP polymor- Methods: We assessed family history of mental illness and phisms was used to adjust clinical doses in a group of pa- exposure to environmental adversity in a cohort of 323 tients who started or switched treatment with antipsychotic youth aged 8-26 years. We calculated family history scores drugs (PharmG + , N = 123), and their results were compared as the proportion of relatives affected with mood or psy- with those of a group of patients treated following existing chotic disorders weighted by biological relatedness. We con- clinical guides (PharmG-, N = 167). structed polyenvironmental adversity scores as mean of 10 Results: Patients who had their antipsychotic dose ad- indicators: physical, sexual, and emotional abuse, neglect, justed according to key polymorphisms (PharmG + ) had a exposure to violence, bullying, parents’ education, income, bigger reduction in side-effects than those treated as usual and home ownership status. We defined psychopathology (PharmG-), although the difference was not statistically sig- burden as sum of affective lability, anxiety, psychotic symp- nificant (p > 0.05 for all comparisons). However, clearer dif- toms, and basic symptoms. ferences were observed in the subgroup of patients car- Results: Transdiagnostic family history of mood and psy- rying CYP functional variants. PharmG + patients treated chotic disorders significantly predicted psychopathology with CYP2D6 substrates that were carriers of CYP2D6 UMs burden in children and youth (beta = 0.66, 95%CI 0.08-1.24, or PMs variants showed a significantly higher improve- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 50 Abstracts ment in global, psychic and other UKU side-effects than Results: A total of 648 participants who reported SI at base- their PharmG- counterparts (p = 0.02, p = 0.05 and p = 0.01, line were available for analysis. Among these SI patients, respectively). PharmG + clozapine treated patients with preliminary congruency was scored for 67 patients, of which CYP1A2 or CYP2C19 UM and PMs variants also showed higher 23 received congruent medication at V2 and 44 did not. reductions in UKU scores than PharmG- clozapine patients in We examined whether receiving congruent medications re- general. However, those differences were not statistically solved SI. Our preliminary analysis did not detect a statis- significant. tically significant association between medication congru- Discussion: Our results suggest that pharmacogenetic in- ency and the resolution of SI (p = 0.89). terventions may improve the safety of antipsychotic treat- Discussion: This exploratory analysis did not show a ma- ments by reducing associated side-effects. This interven- jor effect of pharmacogenetic testing on suicidal ideation. tion may be particularly useful when considering treatment However, our analysis is currently limited by the small sam- with antipsychotics with one major metabolic pathway, and ple size and naturalistic design of the study. We expect to therefore more susceptible to be affected by functional have full congruency information for all 648 participants in variants of CYP metabolizing enzymes. our final analysis. Larger prospective randomized controlled studies will identify the contribution of pharmacogenetic Disclosure: Nothing to disclose. testing in SI. doi: 10.1016/j.euroneuro.2018.08.460 Disclosure: Patent applications - Patent, Self.

doi: 10.1016/j.euroneuro.2018.08.461

SU97 EFFECT OF PHARMACOGENETICS-GUIDED ANTIDE- SU98 PRESSANT TREATMENT ON SUICIDAL IDEATION CONVERGENT ANALYSIS OF SEQUENCING AND MI- CROARRAY DATA SUGGEST THE INVOLVEMENT OF

Sheraz Cheema 1, Anashe Shahmirian 1, Gwyneth Zai 2, MIRNAS AND THEIR TARGET MRNAS IN RESPONSE TO

Arun Tiwari 1, Deanna Herbert 1, Nicole Braganza 1, LITHIUM TREATMENT IN BIPOLAR DISORDER

Sajid Shaikh 1, Maria Tampakeras 1, Natalie Freeman 1,

Clement Zai 1, James L. Kennedy 1 Alessio Squassina 1, Claudia Pisanu 1,

Eleni Merkouri Papadima 1, Carla Melis 1, Stefano Calza 2,

1 Centre for Addiction and Mental Health Donatella Congiu 1, Annalisa Loizedda 3, Nicola Orrù 4,

2 Centre for Addiction and Mental Health, University of Giovanni Severino 1, Raffaella Ardau 5, Caterina Chillotti 5,

Toronto Sandro Orrù 4, Carlo Carcassi 4, Maria Del Zompo 1

Background: Pharmacogenetic-guided treatment is be- 1 University of Cagliari ing increasingly considered for improving psychiatric drug 2 University of Brescia treatment. The effect of pharmacogenetic guidance on sui- 3 Consiglio Nazionale delle Ricerche (C.N.R.), Istituto di cidal ideation (SI) has not yet been investigated. Ricerca Genetica e Biomedica (I.R.G.B.)

Methods: To test the feasibility and utility of pharmaco- 4 Medical Genetics, R. Binaghi Hospital, ASSL Cagliari, ATS genetic testing, we conducted a multi-year study and pro- Sardegna vided pharmacogenetics-based guidance to clinicians in pre- 5 University Hospital of Cagliari scribing antidepressant and antipsychotic medications. This study, IMPACT, was cross-diagnostic and naturalistic, and in- Background: After more than 60 years of use, lithium (Li) cluded patients referred by primary-care physicians, allied is still a first line treatment for bipolar disorder (BD). Clin- health professionals, and psychiatrists. The IMPACT study ical trials have shown that Li is effective in at least 60% uses a combinatorial pharmacogenomics test GeneSight (As- of patients but its use is characterized by high interindivid- surex Health), which tests for variants in six liver en- ual variability and important side effects. These features zyme genes (CYP1A2, CYP2D6, CYP3A4, CYP2C9, CYP2C19, have stimulated intensive research to identify genetic and CYP2B6) and two serotonin genes (HTR2A, SLC6A4). The pa- molecular predictors of response and disentangle its com- tients are assessed for symptom severity and side effects at plex biological mechanisms. Genetic studies have so far ex- baseline and eight weeks. plained only a small proportion of the observed variability, As part of an interim analysis for the IMPACT study, we suggesting that factors other than DNA variants could be selected participants with Beck Depression Inventory (BDI) implicated. Recent findings have shown that Li interferes scores of at least 20 at baseline, and medication information with the expression of microRNAs (miRNA) and their tar- available for their baseline (V0) and eight-week follow-up geted genes, suggesting that non-coding RNAs could play a (V2) visits. We divided the patients into two groups: patients role in modulating its clinical efficacy. whose physicians considered the genetic information that Methods: We used next generation sequencing (NGS) to in- was provided in prescribing were classified as ‘congruent’ vestigate genome wide miRNAs expression in lymphoblas- group compared to patients whose medications were not toid cell liens (LCLs) derived from BD patients character- guided by the GeneSight report (‘non-congruent’). In this ized as excellent responders (ER, n = 12) and non-responders pilot analysis, we included only patients of self-reported Eu- (NR, n = 12) to Li with the “Retrospective Criteria of Long- ropean ancestry. Term Treatment Response in Research Subjects with Bipo- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 51

lar Disorder” (Alda scale). These data were matched with 3 Inserm U955, Psychiatrie Translationnelle, Université genome wide expression data obtained from the same LCLs. Paris Est, Fondation FondaMental

The lists of miRNAs and mRNA differentially expressed be- 4 AP-HP, Hôpital H. Mondor –A. Chenevier, Plateforme de tween ER and NR were analyzed with MiRComb to identify Ressources Biologiques, Créteil couples of miRNA/mRNA inversely and significantly corre- 5 Commissariat àl’Energie Atomique, Institut Génomique, lated. This analysis was integrated with results from miRNA Centre National de Génotypage, Evry target prediction performed using 7 different databases. 6 Inserm U955, Psychiatrie Translationnelle, Université Results: In total, 24 miRNAs were significantly differentially Paris Est, Fondation FondaMental, AP-HP, Hôpital H. Mon- expressed in ER vs NR and significantly, inversely corre- dor –A. Chenevier, Pôle de Psychiatrie, Créteil lated with genes showing significant differential expression between the two groups (FDR q < 0.05). The 24 miRNAs Background: Despite nearly fifty years of pharmacological were involved in 146 negative correlations which included research, the treatment of schizophrenia remains a chal- 125 unique genes. Tw o miRNAs (miR-320a and miR-155-3p) lenge and clinical outcomes are still far from optimal. One were selected for qRT-PCR validation based on the strength of the major shortcomings in the current treatment of and p values of the correlations with mRNAs. Both miR- schizophrenia is that we have no valid criteria in clinical NAs were successfully validated. miR-320a and miR-155-30 practice to predict who will respond to antipsychotic treat- were inversely correlated with 24 and 19 genes predicted ment and how long the treatment should be maintained by at least 1 database respectively. Four genes for miR-320a before changing therapeutic strategy. The identification of and three genes for miR-155-3p were selected for valida- blood-based biological markers of drug response with a good tion. CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regu- sensitivity and specificity would enable physicians to use lator of G Protein Signaling 16) for miR-320a and SP4 (Sp4 these tests prior to choosing the antipsychotic treatment Transcription Factor) for miR-155-3p were successfully vali- and therefore help the practitioner in his daily clinical prac- dated. miRNA mimic experiments for functional analysis of tice. the miRNA/mRNA interactions identified are currently on- Methods: Through a European consortium on Optimization going. of Treatment and Management of Schizophrenia in Europe Discussion: miR-320a was previously suggested to be in- (OPTiMiSE), we investigated treatment response in 188 involved in major depression, Alzheimer disease and demen- dividuals with first episode psychoses. Using RNA sequenc- tia. Its target gene CAPN1 is involved in dendritic branching, ing, we characterized changes in gene expression after 4- spine density, and hippocampal long-term potentiation, and week treatment with amisulpride according to treatment has been reported to be hypermethylated in the prefrontal outcome. In addition, we genotyped subjects with DNA ar- cortex of schizophrenia patients. RGS16 encodes for an in- ray to identify eQTLs, and used this eQTLs to propose a poly- dispensable protein for the circadian regulation of cAMP genic score to predict treatment outcome. in the superchiasmatic nucleus. Circadian genes have been Results: Out of the 16,264 genes expressed in peripheral strongly suggested to be involved in BD and in Li response. blood mononuclear cells, we showed an enrichment in dif- miR-155-3p is involved in processes related to the immune ferentially expressed genes in subjects who will be in remis- system. Its target gene SP4 codifies for a transcription fac- sion after 4-week amilsupride treatment, when compared tor involved in the development of the hippocampus. It has with non-remitted patients. We thus demonstrated that 10% been associated with schizophrenia, major depression, and of differentially expressed genes had a change in the ex- BD in several studies, and its encoded protein was shown pression level, which was correlated with clinical outcome. to be stabilized by Li in rat cerebellar granule neurons. We identified many eQTLs that may explain transcriptional Our data suggest that miRNAs and their targeted genes in- variations between responders and non-responders to treat- volved in key processes of neuronal functioning and circa- ment. The combination of these eQTLs in a polygenic score dian rhythm might be involved in Li response in BD. allowed the prediction of clinical improvement with an accuracy of 0.7 on the discovery sample of 135 individuals and Disclosure: Nothing to disclose. 0.6 on an independent sample of 129 subjects. doi: 10.1016/j.euroneuro.2018.08.462 Discussion: We demonstrated here that amisulpride treatment affects gene expression in peripheral blood mononuclear cells, mainly in patients who will be in remission after four-week treatment, and that gene expression was as- SU99 sociated with symptom improvement. We also showed that

COMBINING DIFFERENTIAL GENE EXPRESSION ANALYSIS combining transcription and genetic data might help in the

AND GENETIC DATA TO PREDICT TREATMENT RESPONSE identiﬁcation of biological signature to predict treatment IN FIRST-EPISODE PSYCHOSIS response in ﬁrst episode psychosis.

Stephane Jamain 1, Réjane Troudet 2, Wafa Bel Haj Ali 3, Disclosure: Nothing to disclose.

Caroline Barau 4, Anne Boland-Auge 5, doi: 10.1016/j.euroneuro.2018.08.463 Jean-François Deleuze 5, Marion Leboyer 6, OPTiMiSE Consortium

1 Inserm U955, Psychiatrie Translationnelle

2 Inserm U955, Psychiatrie Translationnelle, Université Paris Est ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 52 Abstracts

SU100 HIST1H2BK, HIST1H2BD and ZNF322) and 40 methylation INTEGRATIVE ANALYSIS OF OMICS SUMMARY DATA probes were associated with Li-quant + SCZ through the TO IDENTIFY GENES ASSOCIATED WITH LITHIUM RE- same SNP (rs2237234). SPONSE AND RELATED PHENOTYPES IN PATIENTS WITH Discussion: This study points toward functionally relevant BIPOLAR DISORDER genes whose expression or methylation levels are associated with a shared predisposition to lithium response and

Claudia Pisanu 1, Nirmala Akula 2, Consortium on Lithium SCZ. NMB encodes a bombesin-like peptide whose receptor

Genetics, Maria Del Zompo 1, Alessio Squassina 1, is highly expressed in various brain regions and has been

Francis J. McMahon 2 suggested, among other functions, to be a potential therapeutic target in memory and anxiety disorders. Although

1 University of Cagliari the results were signiﬁcant only in blood, this might be due

2 National Institute of Mental Health, National Institute of to the more limited sample sizes of publicly available brain

Health eQTL data, compared to peripheral blood. Further analyses on larger eQTL and mQTL datasets will be needed to validate and extend these results. Background: Summary-data-based mendelian randomization (SMR) is a novel approach that integrates genome-wide Disclosure: Nothing to disclose. association (GWA) data with expression (eQTL) or methylation (mQTL) quantitative trait locus data to identify genes whose expression/methylation levels are associated with a References complex trait due to a shared genetic variant ( 1,2 ). Using Hou, et al., 2016. Lancet. data from the International Consortium on Lithium Genet- International Consortium on Lithium Genetics, 2018. JAMA Psych. ics (ConLiGen, 3) and the Psychiatric Genomics Consortium Wu, et al., 2018. Nat Commun. (PGC), we applied SMR to pinpoint functionally relevant Zhu, et al., 2016. Nat Genet. genes involved in lithium response in patients with bipolar disorder (BD) as well as in shared heritability between doi: 10.1016/j.euroneuro.2018.08.464 lithium response and susceptibility to schizophrenia (SCZ), reported previously ( 4 ). Methods: We applied the SMR method to 1) ConLiGen only SU101 [GWA results for > 2,000 Caucasian BD patients character- EVALUATION OF GLUTAMATE RECEPTOR GENE (GRID2, ized for lithium response on both a categorical (Li-categ) GRIK2) VARIANTS IN OBSESSIVE-COMPULSIVE DISOR- + and a quantitative (Li-quant) scale], and 2) ConLiGen PGC DER RISK, SYMPTOM SEVERITY, AND ANTIDEPRESSANT

2 SCZ summary statistics (36,989 cases and 113,075 con- TREATMENT RESPONSE trols). We used the Bioconductor package ASSET, which provides meta-analysis statistics as well as the "best subset" Amanda Lisoway 1, Gwyneth Zai 2, Vanessa F. Goncalves 1, of studies contributing to the signal, to identify SNPs rele- Clement Zai 1, Arun K. Tiwari 1, Karen Wigg 3, vant for both lithium response and SCZ. In order to evalu- James L. Kennedy 1, Margaret (Peggy) Richter 3 ate the association between genes and lithium response or lithium response + SCZ in different tissues, we used eQTL 1 Centre for Addiction and Mental Health data from: 1) two large studies conducted on peripheral 2 Centre for Addiction and Mental Health, University of blood; 2) a meta-analysis of 13 brain regions from GTEx V7, Toronto corrected for sample overlap with the SMR Meta-analysis 3 Sunnybrook Health Sciences Centre of cis-eQTL in Correlated Samples (MeCS) method; and 3) post-mortem dorsolateral prefrontal cortex (DLPFC) sam- Background: Convergent evidence increasingly supports ab- ples from the CommonMind Consortium. mQTL summary normalities in glutamate signaling to play an important role data from peripheral blood were obtained from a meta- in the pathophysiology and treatment response of obsessive- analysis of the Brisbane Systems Genetics Study (BSGS) and compulsive disorder (OCD). In fact, genes within the gluta- the Lothian Birth Cohorts (LBC) data (2). mate system have consistently appeared among the top hits Results: No gene was found to be associated with lithium in genetic studies of OCD risk and treatment response. In- response in the ConLiGen only dataset after correc- terestingly, a recent meta-analysis of two consortia level tion for multiple testing. ASSET identified 2,816 and genome-wide association studies (GWAS) of OCD reported 3,208 SNPs for which both SCZ and Li-categ or Li-quant, polymorphisms within the glutamate ionotropic receptor respectively, contributed to the signal. SMR showed that delta type subunit 2 (GRID2) and the glutamate ionotropic the same SNP (rs2002375) was significantly associated with receptor kainate type subunit 2 (GRIK2) genes to be among the Li-categ + SCZ trait, blood expression (P = 6.44E-09), the top hits associated with the disorder. As a result, we at- and blood methylation levels (p < 2.1E-10) of Neuromedin tempted to replicate these findings by investigating GRID2 B (NMB). In DLPFC, expression levels of three pseudo- and GRIK2 single-nucleotide polymorphisms (SNPs), or tag genes located on chr 15 were significantly associated SNPs, in a well-characterized sample of OCD patients. We with the Li-categ + SCZ trait (CSPG4P11, rs142959789, hypothesized that GRID2 and GRIK2 SNPs would be associ- pSMR = 4.33E-08; CSPG4P12, rs35677834, pSMR = 6.09E-08, ated with OCD when compared to the general population. and GOLGA2P7, rs12906983, pSMR = 7.34E-08). Blood ex- We also investigated associations with OCD symptom sever- pression of five genes located on chr 6 (BTN2A1, BTN3A2, ity and with antidepressant treatment response. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 53

Methods: OCD patients of European Caucasian ancestry 3 Mental Health Care Organization North-Holland North, (n = 150) were selected from a large retrospective sample Heerhugowaard collected in Toronto, Ontario, Canada. Quality control pro- 4 The University of Liverpool cedures, genotype extraction from the Illumina Human610- 5 Karolinska Institutet

Quadv1_B SNP array, and statistical analyses were per- 6 Mental Health Services Rivierduinen formed using PLINK1.9 and Rv3.3.2. OCD symptom severity 7 St Jansdal Hospital was evaluated using the Yale-Brown Obsessive Compulsive 8 University of Eastern Finland, Niuvanniemi Hospital

Scale (Y-BOCS) and patients were naturalistically treated 9 School of Health Sciences, University of Iceland, Landspi- with up to six different SRIs, including ﬁve selective SRIs tali University Hospital

(ﬂuoxetine, ﬂuvoxamine, sertraline, paroxetine, and citalo- 10 Centre for Addiction and Mental Health pram) and one SRI (clomipramine). Each medication trial 11 King’s College London was evaluated retrospectively for response and was rated 12 University of North Carolina at Chapel Hill categorically as either responder or non-responder using the 13 Central Institute of Mental Health

Clinical Global Impression – Improvement (CGI-I) scale. A Eu- 14 deCODE genetics ropean Caucasian comparison sample was selected from The 15 Institute of Psychiatry, Psychology & Neuroscience, King’s 1000 Genomes Project Consortium (EUR, n = 503). Pearson’s College London chi squared or Fisher’s exact test was used to investigate the relationship between the GRID2 and GRIK2 variant genotype Background: The atypical antipsychotic drug clozapine is distributions and the 1000 Genomes sample, as well as SRI the only effective drug for treatment-resistant schizophre- response, while linear regression was used to investigate the nia, but also bears the risk of inducing severe adverse effect of genotypes on symptom severity. drug responses including neutropenia and agranulocytosis. Results: A significant difference in genotype distributions Agranulocytosis and neutropenia occur in about 1% and 3% between our OCD sample and the 1000 Genomes compar- of treated individuals. The aetiology is largely unknown, but ison sample was observed for GRIK2 rs2852615 (X2 = 6.12, there is evidence for contributing genetic factors. p < 0.05). The minor T allele was more frequent in OCD pa- The Clozapine-Induced Agranulocytosis Consortium tients than in the comparison sample. Furthermore, OCD (CIAC) identified two independent loci in the major his- symptom severity was also associated with rs2852615. Pa- tocompatibility complex genome-wide associated with tients with the TT genotype reported more severe OCD clozapine-induced agranulocytosis: A single amino acid in symptoms than either the CC or CT genotypes (p < 0.05). HLA-DQB1 (126Q) (OR = 0.19, P = 4.7E −14) and an amino However, these glutamate gene variants were not associ- acid change in HLA-B (158T) (OR = 3.3, P = 6.4E −10). ated with antidepressant response (p > 0.05). A meta-analysis of CIAC and CLOZUK identified a Discussion: Our targeted study provides further evidence genome-wide association with rs149104283 (OR = 4.32, in support of a role for the glutamate GRIK2 gene in OCD P = 1.79E −08), located in the intergenic region between risk and symptom severity. While our preliminary results transcripts of SLCO1B3 and SLCO1B7. were not significant for antidepressant response, our phar- We sought to confirm previous findings and to identify macogenetic data sample size was limited at the time of novel variants by performing the largest meta-analysis to this analysis. Our work is continuing to add coverage of date including individuals of European ancestry. additional glutamate system genes, a larger sample size, Methods: The CRESTAR project aimed at the development as well as additional pharmacogenetic antidepressant re- of pharmacogenetic biomarkers for schizophrenia and col- sponse variables. lected individuals from sites of Finland, Germany, Iceland, the Netherlands and the UK. We combined genome-wide as- Disclosure: Nothing to disclose. sociation summary statistics of CIAC, CLOZUK and CRESTAR doi: 10.1016/j.euroneuro.2018.08.465 and performed a meta-analysis. Moreover, we imputed HLA alleles, amino acid changes and SNPs and performed a meta- analysis of CIAC and CRESTAR. This CRESTAR project was funded by the European Union’s Seventh Framework Programme for research, technologi-

SU102 cal development and demonstration under grant agreement

META-ANALYSIS OF CLOZAPINE-ASSOCIATED NEU- #279227. TROPENIA AND AGRANULOCYTOSIS Results: The genome-wide association analysis revealed 9 genome-wide hits in 2 independent regions, confirm- 1 2 1 2 Bettina Konte , J.T. Walters , I. Giegling , S. Legge , ing the most associated marker from CIAC and the meta- 2 3 4 5 A.F. Pardiñas , D. Cohen , M. Pirmohamed , J. Tiihonen , analysis of CIAC and CLOZUK. The first marker rs149104283 1 6 7 A.M. Hartmann , J.P. Bogers , J. van der Weide , K. van (OR = 3.96, P = 6.38E-09) is located in the intergenic re- 7 8 8 der Weide , A. Putkonen , E. Repo-Tiihonen , gion between SLCO1B3 and SLCO1B7. The second marker 8 4 9 9 T. Hallikainen , E. Silva , O. Ingimarsson , E. Sigurdsson , rs41549217 (OR = 3.96, P = 1.57E-08) is located in HLA-B. 10 11 12 James L. Kennedy , Gerome Breen , Patrick Sullivan , Analysis of imputed HLA variants identified 17 13 14 15 Marcella Rietschel , Hreinn Stefansson , D.A. Collier , genome-wide hits in 3 independent regions. Tw o 2 1 Michael O’Donovan , Dan Rujescu markers, HLA_DRB1_1601 (OR = 0.15, P = 9.55E-18) and SNP_B_31431998 (OR = 3.29, P = 5.85E-11), are in linkage

1 Martin-Luther-University Halle-Wittenberg disequilibrium to the variants genome-wide associated

2 Cardiff University ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 54 Abstracts in CIAC. We further identified a novel independent SNP, Using network analysis, we identified fifteen modules of co- rs3129891 (OR = 1.87, P = 2.92E-08), located 2kb downstream expressed genes which show a striking shift in module con- to HLA-DRA. nectivity in response to the drug. These modules show over- Discussion: Our study gives further evidence for the im- representation of key GO terms, implicating processes such plication of a variant located in the intergenic region be- as calcium ion transport, cell-cell signaling, G-protein cou- tween members of a family of hepatic transporter genes pled receptor activity, ribosomal activity, and the regulation (SLCO1B3 and SLCO1B7) previously implicated in docetaxel- of transcription. induced neutropenia. Moreover, our study gives further ev- Discussion: Our study highlights the utility of zebrafish as idence for the contribution of the HLA region. We found a model for assessing the molecular consequences of an- genome-wide associated variants in three independent re- tipsychotic medications. Our data show marked behavioural gions: HLA-DQB1/DRB1, HLA-B and HLA-DRA. This suggests effects induced by clozapine and significant transcriptomic the implication of immune function as contributing process alterations in important functional pathways in the brain. to this severe adverse drug response. Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.467 doi: 10.1016/j.euroneuro.2018.08.466

SU103 A ZEBRAFISH MODEL OF CLOZAPINE EXPOSURE: SU104 DRUG-INDUCED TRANSCRIPTOMIC CHANGES IN THE GESTATIONAL INFLUENZA INCREASES THE RISKS OF BRAIN PSYCHOSIS IN ADULTS

Joana Viana 1, Nick Wildman 2, Eilis Hannon 3, Lin He 1, Lei Cai 2

Audrey Farbos 1, Paul O’Neill 1, Karen Moore 1, 1 4 2 Konrad Paszkiewicz , Ronny van Aerle , Gregory Paull , 1 Shanghai Jiao Tong University 2 1 Eduarda Santos , Jonathan Mill 2 Bio-X Institutes, Shanghai Jiao Tong University

1 University of Exeter Background: Psychotic disorders are complex and caused 2 University of Exeter School of Biosciences by interplay of genetic and environmental factors. Influenza 3 University of Exeter Medical School is a common infectious disease in humans, and it has been 4 Centre for Environment, Fisheries and Aquaculture Sci- suggested that maternal influenza is an estimated risk factor ence (CEFAS) for psychotic disorders, especially for schizophrenia. Methods: In view of conflicting results of this association in Background: Schizophrenia (SZ) is a severe neuropsychi- literature, we performed the strict meta-analysis to exam- atric disorder characterized by episodic psychosis and al- ine whether maternal influenza is a risk factor for psychosis tered cognitive function. About 20% of SZ patients are resis- in the children. Four ecological studies and three birth co- tant to the commonly-prescribed antipsychotic medications hort studies were included in our meta-analysis. used to treat disease symptoms. Clozapine is an atypical Results: It has been observed that the Risk Ratio (RR) of antipsychotic drug often prescribed to treatment-resistant maternal influenza on psychosis is 1.062 (95% Confidence In- SZ patients, although the functional pathways mediating its terval (CI) = 1.004-1.123) for the analysis of ecological stud- action are not well understood. Importantly, 40-70% of pa- ies and the RR is 1.564(95%CI = 1.051-2.324) for the analysis tients treated with clozapine show an inadequate response of birth cohort studies. Furthermore, a survey of pregnant and there are sever side-effects. Understanding the molec- women and fetus’ health in Nanjing of China indicated that ular pathways involved in antipsychotic response will help only 1.5% of women received the influenza vaccine before in the development of new improved therapeutics that act pregnancy, 0.4% received it during pregnancy, and 5.1% were on pathogenicity rather than just treating the acute mani- willing to receive the influenza vaccine if necessary. festations of SZ. Discussion: These results showed that gestational influenza Methods: We exposed wild type zebrafish to two doses of could increase mental disorders risks in adult offspring be- clozapine and performed RNA-seq analysis in the brain of sides its established harms for gravidas. Results suggest it these animals to identify transcriptional changes occurring might be effective to increase attention to gravidas to pro- in response to clozapine. Weighted gene co-expression net- tect them from influenza infection through encouragement work analysis was performed to identify modules of co- of vaccinations. expressed genes sensitive to clozapine exposure and pathway analysis was employed to identify over-representation Disclosure: Nothing to disclose. of gene ontology (GO) terms in each of the clozapine doi: 10.1016/j.euroneuro.2018.08.468 exposure-associated modules. Results: We identified five genes showing significant gene expression changes in response to clozapine, including odc1, a gene previously implicated in SZ which shows changes in expression during brain development, angptl4 and slc16a9b. ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 55

SU105 Discussion: Our results suggest that clinically-relevant do- BRAIN CELL TYPE-SPECIFIC POLYGENIC RISK IN mains of SCZ might be inﬂuenced by cell-type differential SCHIZOPHRENIA: INFLUENCE ON CLINICAL PHENO- polygenic risk. Our study will be extended with longitudi- TYPES nal analyses given the availability of follow-up data in these SCZ samples. Taken together, our results suggest that dif-

Sergi Papiol 1, Nirmal Raman Kannaiyan 2, Kristina Adorjan 1, ferent brain cell types may have distinct roles in the clinical

Monika Budde 1, Ashley Comes 1, Katrin Gade 1, expression of SCZ.

Urs Heilbronner 1, Janos Kalman 1, Eva Schulte 1, Funding: this research was funded by the Deutsche

Fanny Senner 1, Richard Musil 2, Alkomiet Hasan 2, Forschungsgemeinschaft (Clinical Research Group 241,

Moritz Rossner 3, Peter Falkai 2, Thomas G. Schulze 1 Grant number SCHU 1603/4-1 & SCHU 1603/5-1; PsyCourse, Grant number SCHU 1603/7-1); Lisa-Oehler-Foundation.

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

2 Ludwig Maximillian University, Munich doi: 10.1016/j.euroneuro.2018.08.469

3 Ludwig Maximillian University, Munich, Max Planck Insti- tute of Experimental Medicine, Goettingen SU106

Background: Genome-wide association studies (GWAS) have IS GENETIC LIABILITY TO SCHIZOPHRENIA MAPPING just started to shed light on the polygenic architecture of TO THE PSYCHOSIS CONTINUUM MODEL? schizophrenia (SCZ) (Ripke et al., 2014; Pardiñas et al., 2018). Polygenic risk scores (PRS) summarize the joint risk Evangelos Vassos 1, Diana Prata 2, Vishal Bhavsar 1, effect of such common risk variants. However, little is Gerome Breen 1, Marta Di Forti 1, Matthew Kempton 1, known about the biological processes, cellular pathways Robin Murray 1, Matthew Hotopf 1, Philip McGuire 1, and/or cell types underlying such a polygenic risk. A recent Cathryn Lewis 1 study has been able to map genomic SCZ risk loci onto specific brain cell types (Skene et al., 2018). Here we lever- 1 King’s College London age the cell type-specific expression profiles derived from 2 iMM Lisboa this single-cell RNAseq study and from our own experimental work using primary cells (Sharma et al., 2015) to generate cell type-specific PRS in our sample of SCZ patients. Background: Genetic studies of binary outcomes, such as

Subsequently we have analyzed the association of these PRS mental disorders, are based on the liability threshold model with the rich clinical information available in our sample. (LTM), in which a large number of genetic risk factors

Methods: The sample under analysis consists of 700 are summed to yield an overall ’liability’ score. The ob-

SCZ (or schizoaffective) patients of German origin served outcome is determined by whether the latent score

(KFO241/PsyCourse, Exercise II, RESIS & RIE cohorts). All is smaller or larger than the threshold. Polygenic risk scores these patients were genotyped using the Infinium PsychAr- (PRS) can give an aggregate measure of the genetic liabil- ray Bead ¬Chip (Illumina®) and imputed using the stan- ity and the PRS for schizophrenia, given its high predictive dard SHAPEIT2/IMPUTE2 pipeline. Cell type-specific gene- ability, would be ideal to test subthreshold expression of the sets definition: 1) the 5% most specifically expressed genes liability, if the outcome could be presented as a continuous in each mouse brain cell type as published in the aforemen- or ordinal variable. Our hypothesis is that genetic liability tioned single-cell RNAseq study (Skene et al., 2018); 2) by to schizophrenia is associated with a gradient of psychosis high-throughput RNAseq or deep proteomic analyses of pri- expression, from ‘mild’ psychosis phenotypes to fully diag- mary mouse brain cells differentiated in vitro into differ- nosed schizophrenia. ent cell types (Sharma et al., 2015). PLINK 1.90 (Chang et Methods: For this analysis we used European individuals al., 2015), SPSS and R were used for PRS calculation and from three samples recruited in South London. The first data manipulation/analysis. The most recent SCZ GWAS was is a clinical sample of first episode psychosis and controls = used as discovery sample for these calculations (Pardiñas (GAP, N 333), the second was a sample of individuals at et al., 2018). The association of cell type-specific risk pro- high risk of psychosis with two years prospective follow up = file scores with relevant clinical variables (psychopathology, to establish conversion to psychosis (OASIS, N 108) and the cognition, functioning) was studied using linear models. third, a sample of general population assessed with the Psy-

Results: Our preliminary analyses show that psychopathol- chosis Screening Questionnaire (PSQ) for lifetime psychotic = ogy (PANSS positive score) in our sample of SCZ patients symptoms (SELCoH, N 322). All samples had genome-wide might be inﬂuenced by polygenic risk associated to Neural genotyping and PRS was estimated using PGC2 schizophrenia

Progenitors cell type (P = 0.006, R2 = 0.9%). Results also sug- summary results as the reference panel. gest that the risk derived from Hypothalamic Dopaminergic Results: We observed a gradient of PRS for schizophrenia

Neurons (HDN) is associated with the overall functioning of in the different groups we analyzed with the lowest PRS in these patients as measured by GAF. The genetic risk asso- controls, followed by general population individuals who re- ciated to HDN also seems to influence cognitive functions ported psychotic symptoms, followed by people with at risk measured by Trail-Making-Test-A (TMT-A) and TMT-B tests, mental state who did not convert to psychosis and the high- although the full SCZ PRS shows the best results in TMT-B est PRS was observed in cases with first episode psychosis = analyses (P = 0.008, R2 = 1%). (overall regression p 9.3E-10). To ensure that our results were not driven by the two extremes (cases and controls) ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 56 Abstracts we repeated the analysis excluding the controls (p = 0.009) I: n = 606 males, II: n = 320 males, III: n = 503 females) and and excluding the GAP case-control sample (p = 0.002). in 2 general population samples from Spain (replication Discussion: Our results show that genetic liability for IV: n = 336; V: n = 229; both genders) pre-adult risk expo- schizophrenia, as measured by the PRS, is associated with a sure, comprising urbanicity, migration, physical and sex- gradient of psychosis phenotypes, supporting the psychosis ual abuse as primary, and cannabis or alcohol as secondary continuum model. It is noteworthy that people from the hits. As proxies of violent aggression, highly intercorre- general population with non-clinical psychotic symptoms lated measures were applied as available: (1) violent ag- and, more remarkably, individuals with at risk mental state gression severity score (VASS) based on questionnaires, in- who do not convert to psychosis have an intermediate ge- terviews and charts; (2) conviction for bodily injury, sex- netic risk to schizophrenia, higher than controls and lower ual assault, murder, or forensic history; (3) psychopathy than cases. and aggression-hostility scores. To check for differential methylation patterns of 134 extreme group individuals re- Disclosure: Nothing to disclose. garding environmental hits ( ≤1 vs. ≥3 risk factors), whole blood-derived DNA was analyzed by Infinium HumanMethy- doi: 10.1016/j.euroneuro.2018.08.470 lation450K. Moreover, histone deacetylase 1 (HDAC1) mRNA levels in peripheral blood mononuclear cells (PBMCs) available from 142 male extreme group subjects ( ≤1 vs. ≥3 risk

SU107 factors) were determined. MULTIPLE ENVIRONMENTAL HITS BEFORE ADULTHOOD Results: All environmental hits were by themselves PREDICT VIOLENT AGGRESSION marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted 1 1 1 Marina Mitjans , Jan Seidel , Martin Begemann , violent aggression (odds ratio 10.5). This accumulation ef- 1 1 1 Fabian Bockhop , Anna Seelbach , Vikas Bansal , fect was documented premorbid for schizophrenic individ- 1 2 Janina Wesolowski , Jorge Moya-Higueras , uals and likewise seen in healthy samples. An epigenome- 3 3 4 Manuel Ignacio Ibáñez , Generós Ortet , Lourdes Fañanás , wide association scan to detect differential methylation of 5 6 4 Luise Poustka , Jürgen L. Müller , Bárbara Arias , blood-derived DNA of selected extreme group individuals 7 Hannelore Ehrenreich yielded overall negative results. Conversely, determination in PBMCs of HDAC1 mRNA as ‘umbrella mediator’ of epige-

1 Max Planck Institute of Experimental Medicine, Göttingen netic processes revealed an increase in the high-risk group,

2 University of Lleida, Instituto de Salud Carlos III, Centro suggesting lasting epigenetic alterations. de Investigación Biomédica en Red de Salud Mental (CIBER- Discussion: Together, we provide sound evidence of SAM) a disease-independent unfortunate relationship between

3 Universitat Jaume I, Instituto de Salud Carlos III, Centro well-deﬁned pre-adult environmental hits and violent ag- de Investigación Biomédica en Red de Salud Mental (CIBER- gression, calling for more efﬁcient prevention. SAM) Acknowledgements: Max Planck Society, DFG (CNMPB), EX-

4 Universitat de Barcelona; Institut de Biomedicina de la TRABRAIN EU-FP7, N-RENNT, EU-AIMS, CIBERSAM; Instituto Universitat de Barcelona (IBUB); Instituto de Salud Carlos de Salud Carlos III (PI16/00998), Comissionat per a Universi- III, Centro de Investigación Biomédica en Red de Salud Men- tats i Recerca del DIUE (2017SGR1577). tal (CIBERSAM)

5 University of Göttingen Disclosure: Nothing to disclose.

6 University of Göttingen, Asklepios Hospital for Forensic Psychiatry & Psychotherapy Reference

7 Max Planck Institute of Experimental Medicine, Göttingen, DFG Research Center for Nanoscale Microscopy and Molec- Mitjans et al. Molecular Psychiatry 2018. ular Physiology of the Brain (CNMPB) doi: 10.1016/j.euroneuro.2018.08.471 Background: Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously SU108 that accumulated environmental risk markedly decreases INFLUENCE OF GENETIC VARIATIONS ASSOCIATED age at schizophrenia onset. Following matched extreme WITH SCHIZOPHRENIA ON VERBAL FLUENCY group individuals ( ≤1 vs. ≥3 risk factors), we unexpectedly observed that high-risk subjects had > 5 times greater prob- Tobias Wustmann, Tobias Ludwig, Bettina Konte, ability of forensic hospitalization than low-risk individuals. Annette Hartmann, Ina Giegling, Dan Rujescu This intriguing discovery led us hypothesize that accumulation of risks before adulthood predisposes to violent Martin-Luther-University Halle-Wittenberg aggression and criminal conduct, independent of mental illness. Moreover, we hypothesized that these environmental Background: Schizophrenia is one of the most devastating hits have lasting epigenetic alteration effects. psychiatric disorders and presents with an unclear etiology. Methods: We determined in 4 independent schizophre- Multiple environmental and genetic factors have been iden- nia samples from the Göttingen Research Association for tiﬁed as potentially contributing to the development of the Schizophrenia (GRAS; discovery: n = 134 males; replication disease. To shed more light on the genetic contributions, ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 57

the PGC carried out the currently largest GWAS in 2014. Pak Sham 8, Ulrich Reininghaus 6, Robin Murray 4,

Significant associations between schizophrenia and 128 Marta Di Forti 4 linkage-disequilibrium-independent single-nucleotide polymorphisms (SNP) were found in 108 conservatively defined 1 MRC Social, Genetic & Developmental Psychiatry Centre, loci (Ripke et al. 2014). Patients suffering from schizophre- Institute of Psychiatry, Psychology & Neuroscience, King’s nia usually experience additional neuropsychiatric deficits College London of which the disturbance of verbal fluency has been exten- 2 King’s College London sively described in the literature. The aim of this study was 3 Cardiff University to examine schizophrenia-associated SNPs for their associa- 4 Institute of Psychiatry, Psychology & Neuroscience, King’s tion with verbal fluency. College London

Methods: The PAGES sample includes 1000 schizophrenia 5 University of Palermo patients who were diagnosed according to DSM IV, and 3000 6 School for Mental Health and Neuroscience, Maastricht randomly selected psychiatrically healthy controls that per- University formed a multi-stage selection procedure. Verbal fluency 7 Maastricht University Medical Centre was assessed by the Regensburg word fluency test (RWT) in 8 The University of Hong Kong a subset of 361 cases and 559 controls. Genotype data was obtained using chip technology and imputation. After strin- Background: Historically, gene X environment examinations gent quality controls, 107 loci were analyzed applying linear in psychotic disorders have employed candidate gene meth- regression using an additive model. ods and environmental determinants impacting on similar Results: Of the 127 SNPs tested, rs11191419 showed a sig- biological mechanisms. However, genome wide association = nificant association (P 0.00025) with the word switch do- studies (GWAS) show that many variants associated with main after multiple testing. Further evaluation in cases schizophrenia have a modest effect size on risk. In this re- = = (P 0.002257) and controls (P 0.02287) separately also spect, it is unclear whether the effect of cannabis on psy- showed an association. The SNP is located 2 kb upstream chosis phenotypes is modified by a few genes, e.g. those of the BLOC-1 Related Complex Subunit 7 (BORCS7) gene. involved in dopamine signalling, or by the overall genetic In addition, rs3849046 localized in the Eukaryotic Transla- susceptibility to schizophrenia. Indeed, candidate gene ap- tion termination Factor 1 (ETF1) showed a suggestive asso- proaches might be complementary to GWAS to test gene X = ciation (P 0.00071) with the same cognitive domain in the cannabis interaction. We aimed to investigate the interac- combined group. tive effects of cannabis use on variants in DRD2 gene on: 1) Discussion: The BLOC-1 Related Complex (BORC) is thought the risk of developing first episode psychosis (FEP); and 2) to be involved in lysosome localization and movement in pe- the frequency of positive symptoms at FEP. ripheral regions of the cell. BORCS7, one of the 8 subunits of We undertook a replication study of previous Gene X BORC, in particular is expressed in adult human neurons and Cannabis interactions for DRD2 (rs1076560); further, we astrocytes and shows upregulation in stem cells while they tested interactions between cannabis use and any SNP as- differentiate toward neuronal cell types. In addition, BORC sociated with schizophrenia within DRD2 gene in the last and Biogenesis of Lysosome-related Organelles Complex 1 Psychiatric Genomics Consortium (PGC) GWAS. (BLOC-1) share three proteins and thus may be functionally Methods: We genotyped ∼830 FEP patients and ∼1200 con- related. BLOC-1 has been suggested to play a role in neu- trols recruited across six countries as part of the large EUGEI rite outgrowth and deficiencies in this complex may con- study. OPerational CRITeria system and Cannabis Experience tribute to the neurodevelopmental etiology of schizophre- Questionnaire were used for evaluating psychopathology nia. The results indicate an influence of the schizophrenia and patterns of cannabis use. Dimensions of psychopathol- risk variant rs11191419 on verbal fluency performance in ogy, which included a specific dimension of positive symp- healthy subjects, thereby implicating an underlying mecha- toms, were estimated using multidimensional item response nism which might be involved in such deficits in schizophre- modelling in Mplus. nia. Functional relevance of the associated SNP as well as We tested for an interaction between risk allele count replication in independent samples remains to be deter- and daily cannabis use on: 1) the risk of psychotic disorder mined. in the case-control study; 2) the positive symptom dimension in the case-only sample. Only one SNP in DRD2 was sig-

Disclosure: Nothing to disclose. nificantly associated with schizophrenia in the PGC study, doi: 10.1016/j.euroneuro.2018.08.472 so we tested for interaction with rs2514218, in addition to rs1076560. These regression models, conducted in STATA 14, were adjusted for age, gender, ethnicity, 10 principal components SU109 (PC) for population stratification and SNP-environment and IS THE ERA OF CANDIDATE GENES X CANNABIS USE SNP-PC interaction terms. Results were corrected for mul- REALLY DEAD? tiple testing of four SNPs (p < 0.0125 as significance threshold).

Diego Quattrone 1, Cathryn Lewis 2, Alexander Richards 3, Results: We found a signiﬁcant interaction between

Evangelos Vassos 2, Charlotte Gayer-Anderson 4, cannabis use and the rs2514218 in DRD2: daily cannabis

Laura Ferraro 5, Giada Tripoli 2, Bart Rutten 6, users with one risk allele showed a 2.5-fold increased

Michael O’Donovan 3, Craig Morgan 2, Jim Van Os 7, probability to suffer a psychotic disorder (OR = 2.43; 95% ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 58 Abstracts confidence interval [CI]: 1.52–3.89). We did not repli- nia patients (Fisher’s Exact Test P = 0.0000001418) as well cate previous findings of an interaction between cannabis as in schizophrenia patients with no history of substance use and rs1076560 in DRD2 for increasing psychosis risk use (Fisher’s Exact Test P = 0.0014). There were no asso- (p = 0.092). Higher levels of positive symptoms were seen ciations of the Asn40Asp polymorphism of OPRM with sub- in FEP who were daily cannabis users with either rs2514218 stance dependence among schizophrenia patients and nor- (B = 0.34; 95% CI: 0.04–0.64; p = 0.024) or rs1076560 risk al- mal control. This allelic association suggests that the func- leles (B = 0.54; 95% CI: 0.15–0.93; p = 0.006). tional Asn40 variant of OPRM may play a role in susceptibil- Discussion: Our results suggest that dopamine signaling ity to schizophrenia. is implicated in cannabis associated psychosis, and, more Discussion: Various investigations have evaluated the OPRM specifically, that variation within the DRD2 gene may mod- polymorphism with regard to drug abuse vulnerability. Com- ulate the effect of cannabis use on psychosis phenotypes. paring to other studies, our results did not reveal any associ- Such findings require a replication for rs2514218. ations of the Asn40Asp polymorphism of the OPRM with substance dependence among schizophrenia patients and nor- Disclosure: Nothing to disclose. mal control. However, contrary to other studies, we found high Asp40 allele among normal controls and high Asn40 al- doi: 10.1016/j.euroneuro.2018.08.473 lele among the schizophrenia patients. The frequency of the Asn40 allele was significantly increased in all schizophrenia patients (Fisher’s Exact Test P = 0.0000001418) as well as

SU110 in schizophrenia patients with no history of substance use ASSOCIATION STUDY OF SCHIZOPHRENIA WITH POLY- (Fisher’s Exact Test P = 0.0014) (tab.4). Although the sample MORPHISMS AT FOUR CANDIDATE GENES size is small, we observed highly signiﬁcant differences of the distribution of Asn40Asp polymorphism of OPRM among 1 2 2 2 Anna Li , Jiaxin Yuan , John Ni , Lili Zhang , schizophrenia patients and normal control. To our knowl- 1 1 Steven Dubovsky , Junzhe Xu edge this is the ﬁrst study to show that a functional polymorphism in schizophrenia patients. Our association results

1 SUNY at Buffalo provide evidence that the functional Asn40 variant of the

2 VHAWNY Healthcare System OPRM receptor confers susceptibility to schizophrenia, further replication studies are necessary to confirm the present Background: Clinical studies have shown that there is a ge- tentative allelic association. netic contribution to the pathogenesis of schizophrenia. The molecular mechanisms of effective antipsychotic drugs and Disclosure: Nothing to disclose. recent advances in neural development suggest that several doi: 10.1016/j.euroneuro.2018.08.474 dopamine receptors, serotonin receptor and opiate receptor genes might be involved in the disorder. In this study, we assessed the associations between schizophrenia and poly- SU111 morphisms in the dopamine receptor 2 (DRD2), the serotonin 2A receptor (5HTR2A), the δ opioid receptor (OPRD), GENOME-WIDE ANALYSIS OF COPY NUMBER VARI- and the μ opioid receptor (OPRM) in 100 schizophrenic pa- ATION IN A SOUTH AFRICAN XHOSA POPULATION tients and 100 control individuals in an attempt to deter- AFFECTED BY SCHIZOPHRENIA mine whether they have an association with the disease. Methods: Subjects: Lerato Majara, Celia Van Der Merwe, Mary-Anne Mufford, The study sample consisted of 100 schizophrenia or Emile Chimusa, Dan Stein, Raj Ramesar schizoaffective disorder and 100 healthy individuals. Extraction of genomic DNA: University of Cape Town Blood samples were collected in anonymously identified 10-ml Vacutainer tubes (Becton Dickinson). DNA was pre- Background: Schizophrenia (SCZ) is a mental disorder pared by a modified SDS/Proteinase K procedure. whose genetic etiology is largely unknown. It is well- PCR-RFLP established that both genome-wide common single nu- The genotypes of polymorphism of the DRD2, 5HTR2A, cleotide polymorphisms (SNPs) and rare copy number vari- OPRD, and OPRM1 polymorphisms were assessed by the PCR- ants (CNVs) increase risk of developing schizophrenia –with RFLP methods. CNVs having a larger effect size. The Psychiatric Genetics Statistical Analysis: Consortium (PGC) recently identified 17 CNVs significantly Comparisons between sets of two populations used the associating with SCZ in over 41 000 subjects, largely of Eu- fisher exact test (FET). Significance was accepted at P < ropean descent. With drug development as a goal in mind, it 0.05. is necessary to determine if risk variants found in one pop- Results: Our results suggest that the polymorphisms at ulation have the same association in other populations to the DRD2, 5HTR2A, OPRD gene loci are unlikely to make minimize disparities in global mental healthcare that may our sample more genetically susceptible to schizophrenia. arise. Thus, we aim to investigate genome-wide copy num- However, we found significant differences in Al18G allele ber variation in a cohort of 200 schizophrenia cases and 200 frequencies between schizophrenic and control groups for controls from South Africa. OPRM in the whole sample. The frequency of the Asn40 al- Methods: DNA was extracted from whole blood using the lele of OPRM was significantly increased in all schizophre- salting out method. All DNA samples were genotyped on ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 59 the Affymetrix CytoscanHDÒ chip with over 2million CNV teresting findings showed also an association with lower cog- probes. Cel files were analyzed using the Chromosome Anal- nitive functioning in psychotic patients, and some degree of ysis Suite (ChAS) where CNVs were defined as any genomic stability of JTC over the course of illness. Overall, findings aberration of a size larger than 20kb covered by at least 10 to date could suggest a shared genetic liability between the probes. Samples that did meet the QC requirements (MAPD occurrence of JTC and psychosis. score > 0.25, snpQ < 15 and waviness SD > 0.12) were ex- The present study aims to investigate in a sample of FEP cluded. CNVs that occurred within 100kb of the telomere on and healthy controls: 1) environment, cognitive, and clini- either end of the chromosome were also excluded. cal factors associated with JTC bias 2) whether the addition Results: In contrast to the PGC analysis, ours did not reveal of SZ Polygenic Risk Score (PRS) explains any further vari- the pattern of a higher frequency of risk CNVs in cases; and ance in the model. protective CNVs in controls. Of the 17 loci analyzed, no CNVs Methods: We analyzed data on JTC (Beads task 60:40) in were found in seven loci in the South African sample. This a sample of 503 FEP and 959 population controls for which could be that these CNVs are so rare, that a larger sample genetic information was available, recruited as part as the size is required to for better resolution or could mean that EU-GEI study across UK, Netherlands, France, Spain, Italy the CNVs in the South African population are smaller than and Brazil. In the first step, logistic regressions have been expected given the shorter blocks of linkage disequilibrium. performed to predict JTC respectively in cases and controls Discussion: Our results suggest that there might common considering as covariates: age, gender, level of education, risk CNVs between the PGC and the South Africa samples, in IQ, country, frequency of cannabis use, population density, agreement with the argument for common risk variants be- positive symptoms, and 20 principal components (PCs) for tween populations. However, they do also suggest that there population stratification. In the second step, we estimated might in fact be population-specific variation that cannot be a model adding SZ PRS to the aforementioned terms. ignored. Together with data from whole exome sequencing, Results: Individuals coming from Brazil were about 6 times the data obtained from this analysis will be used in the de- more likely to jump to conclusions in case group (OR = 6.69; sign of a Xhosa-specific copy number dense chip. This data CI 95% = 2.23-20.06; p = 0.001) and around 5 times among may contribute towards identifying genetic variation in an controls (OR = 4.76; CI 95% = 2.28-9.93; p < 0.001). Likewise, African population and provide insight into additional CNVs age and low IQ were found to be associated with JTC in that may be associated with SCZ. both cases (age: OR = 1.04; CI 95% = 1.02-1.06; p < 0.001. IQ: OR = 0.98; CI 95% = 0.94-0.98; p < 0.001) and controls (age: Disclosure: Nothing to disclose. OR = 1.04; CI 95% = 1.02-1.05; p < 0.001. IQ: OR = 0.96; CI 95% = 0.95-0.97; p < 0.001), although a small effect size was doi: 10.1016/j.euroneuro.2018.08.475 observed. A similar trend was detected regarding the association with increased positive symptoms in cases (OR = 1.27; CI 95% = 1.02-1.57; p = 0.02), whereas controls presenting

SU112 higher level of psychotic-like experiences showed about a

DOES POLYGENIC RISK SCORE FOR SCHIZOPHRENIA 3-fold risk to jump to conclusions (OR = 2.6; CI 95% = 1.12- IMPACT ON JUMPING TO CONCLUSIONS? PRELIMINARY 6.02; p = 0.02). In addition, being female resulted as signif- FINDINGS FROM THE EU-GEI CASE-CONTROL STUDY icant predictor in cases only (OR = 1.87; CI 95% = 1.16-3.01; p = 0.009). 1 2 Giada Tripoli , Diego Quattrone , Finally, PRS for schizophrenia seemed not to be associ- 2 2 Charlotte Gayer-Anderson , Victoria Rodríguez , ated with jumping to conclusions in both groups, therefore 2 3 Natasha Benzian-Olsson , Laura Ferraro , Caterina La it does not add any variance explained in the abovemen- 3 3 3 Cascia , Crocettarachele Sartorio , Lucia Sideli , tioned model (Cases: R2 = 0.27; Controls: R2 = 0.22). 3 3 2 Fabio Seminerio , Daniele La Barbera , Craig Morgan , Discussion: This study suggests that the occurrence of 4 2 2 Pak Sham , Marta Di Forti , Robin Murray jumping to conclusions cannot be explained by schizophrenia genetic underpinnings using polygenic risk score strat-

1 King’s College London egy. However, these preliminary results identiﬁed interest-

2 Institute of Psychiatry, Psychology & Neuroscience, King’s ing environment, cognitive, and clinical factors associated College London with JTC bias.

3 University of Palermo

4 The University of Hong Kong Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.476 Background: Jumping to conclusions (JTC) is a reasoning and data gathering bias that results in the tendency to require less evidence and make hasty decisions. Preliminary SU113 work on reasoning bias focused primarily on the association NRG1 GENETIC RISK SCORE PREDICTS ANTISAC- with delusions, although jumping to conclusions has also CADE AND MEMORY-GUIDED SACCADE LATENCY IN been found in non-deluded schizophrenia (SZ) patients. Lit- SCHIZOPHRENIA erature to date has shown JTC as a well-established bias in psychosis even at First Episode Psychosis (FEP), after remis- Elizabeth Thomas 1, Susan Rossell 2, Jessica Myles 1, sion, and in individuals with at risk mental state. Further- Eric Tan 3, Erica Neill 4, Sean Carruthers 3, Philip Sumner 3, more, JTC has been found to be associated with proneness Kiymet Bozaoglu 5, Caroline Gurvich 1 to psychotic-like experiences in the general population. In- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 60 Abstracts

1 Monash Alfred Psychiatry Research Centre (MAPrc), The guided saccade latency (p = 0.018, r = 0.435) and explained Alfred Hospital and Central Clinical School, Monash Univer- 18.9% of the total variance of the model. There was no sity, Melbourne relationship between NRG1 risk score with antisaccade or

2 Monash Alfred Psychiatry Research Centre (MAPrc), The memory-guided saccade error rate or gain in patients. There Alfred Hospital and Central Clinical School, Monash Uni- was no relationship between NRG1 risk score with antisac- versity, Brain and Psychological Sciences Research Centre cade or memory-guided saccade latency, error rate or gain (BPsyC), School of Health Sciences, Swinburne University, in controls. St Vincent’s Mental Health Discussion: This is the ﬁrst study to use risk scores to ob-

3 Monash Alfred Psychiatry Research Centre (MAPrc), The serve the relationship between NRG1 and eye movement Alfred Hospital and Central Clinical School, Monash Uni- performance. Preliminary ﬁndings indicate that a risk score versity, Brain and Psychological Sciences Research Centre derived from NRG1 SNPs signiﬁcantly predicts antisaccade (BPsyC), School of Health Sciences, Swinburne University and memory-guided saccade latency in schizophrenia. This

4 Brain and Psychological Sciences Research Centre (BPsyC), identiﬁes NRG1 as a potential candidate gene for cognitive School of Health Sciences, Swinburne University impairment in schizophrenia. This ﬁnding also supports the

5 Bruce Lefroy Centre for Genetic Health Research, Mur- use of aggregate genetic risk scores to investigate multi- doch Children’s Research Institute, University of Melbourne factorial disorders. Future research should investigate other genes associated with saccadic performance in schizophre- Background: Neuregulin-1 (NRG1), involved in neuronal de- nia. velopment, migration, myelination and synaptic plasticity, has been identified in numerous linkage association studies Disclosure: Nothing to disclose. as a promising candidate gene for schizophrenia risk. Sev- doi: 10.1016/j.euroneuro.2018.08.477 eral single nucleotide polymorphisms (SNPs) in the NRG1 gene have been associated with schizophrenia and cognitive deficits. In particular, saccadic (eye movement) deficits are one of the most replicated findings in schizophrenia. SU114 Previous research investigating NRG1 and saccadic perfor- ASSOCIATE STUDY OF SCHIZOPHRENIA WITH THE mance has looked at single SNPs. However, genetic liabil- POLYMORPHISMS OF GLUR6 KAINATE RECEPTOR GENE ity for schizophrenia is multifactorial, with contributions of multiple risk variants. Therefore, analysis of genetic risk GRIK2 scores may better capture the genetic contribution to cog- 1 2 3 3 3 nitive performance in schizophrenia compared to single SNP Junzhe Xu , Jianxin Yuan , Anna Li , Lili Zhang , John Ni , 1 analysis which have small effect sizes. This study aims to in- Stiven Dubovsky vestigate whether the genetic risk score for NRG1 predicts 1 saccadic performance in patients and controls. School of Medicine, SUNY at Buffalo 2 Methods: One-hundred and sixty-six Caucasian participants SUNY at Buffalo 3 (44 patients with schizophrenia/schizoaffective disorder VHAWNY Healthcare System and 122 healthy controls) completed the antisaccade and memory-guided saccade tasks, which engage spatial work- Background: The dysfunction of glutamatergic neurotrans- ing memory and inhibition processes. The variables ana- mission is one of the plausible hypotheses for the patho- lyzed for both saccade paradigms were error rate, latency genesis of schizophrenia. The GluR6 kainate receptor gene (i.e. reaction time) and gain (i.e. spatial accuracy). Partici- GRIK2 is located on chromosome 6q16.3-q21, a schizophre- pants were also genotyped for five NRG1 SNPs; rs10503929, nia susceptibility region, as suggested by multiple linkage rs3924999, rs2466058, rs35753505 and rs6994992. Genetic studies. The aim of this study is to clarify the contribution risk scores were then created by assigning one point to the of four polymorphisms of the glu -tamate receptor ionotropic score for each risk allele that a participant had at each of kainate 2 gene with schizophrenia the five polymorphic results, resulting in a genetic risk score Methods: After informed consent was obtained, 100 ranging from zero to ten. Independent T-tests were con- schizophrenia patients and 100 control subjects were en- ducted to demonstrate significant differences in saccadic rolled in this study. All subjects were administered the Di- performance between patients and controls. Correlations agnostic Interview for Genetic Studies by a research assis- were then conducted separately for patients and controls tant with extensive training in this interview. Blood samples to observe relationships between risk score and saccade were collected in anonymously identified 10-ml Vacutainer performance and significant variables were subsequently in- tubes (Becton Dickinson). DNA was prepared by a modi- cluded in standard multiple regressions. fied SDS/Proteinase K procedure (Gusells et al., 1979). We Results: Antisaccade and memory-guided saccade latency genotyped polymorphism rs1338165, rs728024, rs1408768, and error rate were significantly different between patients rs1335042 of the glu -tamate receptor ionotropic kainate 2 and controls (p < 0.001). Both antisaccade and memory- gene (GRIK2 or GLUR6) with the PCR-RFLP methods. The PCR guided saccade gain did not significantly differ between the products were digested by restricted enzyme. two groups. In patients, the NRG1 risk score significantly Results: We observed no significant associations with the correlated with antisaccade latency (p = 0.037, r = 0.389) schizophrenia and polymophism rs728024 (Chi-Square Test and explained 15.1% of the total variance of the model. The p-value 0.628135), rs1408768 (Chi-Square Test p-value NRG1 risk score also significantly correlated with memory- 0.465334) and rs1335042 (Chi-Square Test p-value 0.448). However, there is a significant association between the poly- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 61 morphism rs1338165 and the schizophrenia (Chi-Square Test sity, Melbourne Neuropsychiatry Centre, University of Mel- P = 0.0449). bourne

Discussion: Schizophrenia is characterized by thought dis- 5 Institute of Psychiatry, Psychology and Neuroscience, orders, hallucinations and delusions. Many hypotheses have King’s College London been made to explain the pathophysiology of schizophrenia 6 University of Calgary and several studies suggest that dysfunctions in metabolism of neurotransmitters, such as dopamine, serotonin and glu- Background: Childhood adversity increases the risk of cog- tamate, are directly implicated in the pathogenesis of this nitive deficits and schizophrenia. Gene and environment severe illness. A growing number of studies focused the at- factors synergistically contribute to possible aetiology, but tention on dysfunctions in glutamatergic pathway as a ma- evidence also points to variable effects of adversity on brain jor susceptibility factor for schizophrenia [12]. An increase development. Glutamate regulates synaptic plasticity dur- in the basic metabolic activity along the glutamatergic ax- ing brain development. However, the study of its link with ons has been demonstrated by PET scan studies in the cin- childhood adversity is limited. The present study aimed to gulate cortex and hippocampal region of schizophrenic pa- examine from a brain developmental perspective the extent tients. [13, 14]. Genetic studies have shown a high link- to which i) structural brain volume mediates the association age at chro -mosome 6q16-21. Among the genes located in between childhood adversity and cognition in schizophre- this region is the glu -tamate receptor ionotropic kainate 2 nia, and ii) glutamatergic genetic variation moderates the gene (GRIK2 or GLUR6), a functional candidate for suscep- association between childhood adversity and cognition via tibility to schizophrenia [2]. A significant decrease of GRIK2 brain structure as mediator. mRNA expression level has been reported in schizophrenic Methods: Participants were 176 cases and 118 healthy brains [2]. These lines of evidence suggest that GRIK2 is a controls from the Australian Schizophrenia Research Bank. strong candidate for the susceptibility locus for schizophre- Childhood adversity was measured using the Childhood Ad- nia. Furthermore, abnormal synaptogenesis involving glu- versity Questionnaire. Cognitive performance was assessed tamatergic synapses, was recently shown to be associated using the Repeatable Battery for Assessment of Neuropsy- with schizophrenia [15]. Several studies report decreased chological Status, Controlled Oral Word Association Test, kainate receptor expression (including GRIK2) in the brain of Letter-Number Sequencing test, and the Wechsler Test of schizophrenic patients [2, 16]. In this study we tested for an Adult Reading. We assessed intracranial volume, subcorti- association of schizophrenia with the glu -tamate receptor cal volume, and brain lobe volume as regions of interest, ionotropic kainate 2 gene (GRIK2 or GLUR6) using 4 common adjusting for total brain volume. PLINK was used to calcu- SNAPs rs1338165, rs728024, rs1408768 and rs1335042. We late a weighted polygenic risk score (PRS) as the sum of the found there is not association with rs728024, rs1408768 and schizophrenia risk alleles carried by an individual. Mediation rs1335042. However, the frequency of the polymorphism and moderated mediation analyses were tested using the of rs1338165 was significantly increased in schizophrenia PROCESS macro for SPSS with 5000 bootstrap iterations. The patients. This allelic association suggests that the func- goodness of fit test was determined using structural equa- tional polymorphism rs1338165 of the glu -tamate receptor tion modelling. ionotropic kainate 2 gene (GRIK2 or GLUR6) may play a role Results: Schizophrenia participants performed worse on in susceptibility to schizophrenia. Further study with larger cognitive measures in all domains and were 1.2 times more sample sizes is required. likely to experience childhood adversity. Mediation modelling revealed that reduced intracranial volume mediated Disclosure: Nothing to disclose. the effects of childhood adversity on the poor performance doi: 10.1016/j.euroneuro.2018.08.478 of delayed memory in schizophrenia, independent of the effect of IQ. Meanwhile, subcortical brain volume mediated poor performance of working memory in schizophrenia with childhood adversity. Schizophrenia participants with

SU115 high glutamatergic PRS and a history of childhood adversity

INTERACTION EFFECTS OF CHILDHOOD ADVERSITY showed increased frontal lobe volume. These effects were AND GLUTAMATERGIC POLYGENIC RISK SCORE ON not observed in schizophrenia with low PRS and healthy con- BRAIN STRUCTURE AND COGNITION IN SCHIZOPHRENIA trols. Discussion: We found mediating effects of global and sub- 1 2 2 Suriati Mohamed Saini , Sam Mancuso , Chenxing Liu , cortical brain volume on the memory of schizophrenia par- 2 3 Md Shaki Mostaid , Vanessa Cropley , Tamsyn Van ticipants who had experienced childhood adversity. The 4 5 6 Rheenen , Ian Paul Everall , Chad Bousman , present ﬁndings also suggest possible resilience effects of 3 Christos Pantellis glutamatergic variation on frontal lobe in schizophrenia with a history of childhood adversity.

1 University Kebangsaan Malaysia Medical Centre

2 University of Melbourne Disclosure: Nothing to disclose.

3 Melbourne Neuropsychiatry Centre, University of Mel- doi: 10.1016/j.euroneuro.2018.08.479 bourne

4 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash Uni- versity, Brain and Psychological Sciences Research Cen- tre (BPsyC), School of Health Sciences, Swinburne Univer- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 62 Abstracts

SU116 frequencies of sequence sharing between the influenza virus PEPTIDE SHARING BETWEEN SCHIZOPHRENIA-RELATED proteins and reference sets. PROTEINS AND THE INFLUENZA A VIRUS MAY OFFER A Discussion: This evidence suggests that peptide sharing oc- LINK BETWEEN IMMUNITY AND PSYCHOTIC DISORDERS curs between schizophrenia-related proteins and specific proteins integral to the influenza virus rather across the en- Adrianna Kepinska, Thomas Pollak, Robin Murray, tire virus proteome. Future research should establish the bi- Conrad Osamede Iyegbe ological relevance of this finding and assess whether an immune reaction against particular schizophrenia-related pro-

Institute of Psychiatry, Psychology & Neuroscience, King’s teins is a plausible mechanism contributing to psychotic dis-

College London orders. Also, exploring peptide sharing in different influenza strains could offer insights into links between influenza pan- demics, maternal infection, and psychosis. Elucidating pep- Background: Immunity and influenza infection are impli- tide sharing might have implications for schizophrenia risk cated in schizophrenia by historical epidemiological evi- management and safe influenza prevention. dence and recent genome-wide association study (GWAS) findings. One potential mechanism underlying the associa- Disclosure: Nothing to disclose. tion is molecular mimicry; a model whereby specific sub- regions of brain proteins become targets of a misdirected doi: 10.1016/j.euroneuro.2018.08.480 immune response due to sequence sharing with the influenza virus. This study evaluates the profile of sequence sharing between influenza and the translated protein products of schizophrenia GWAS hits. The 1918 influenza virus is SU117 used, given that it was associated with an increased number POLYGENIC RISK SCORE AND CNV BURDEN INFLUENCES of psychosis cases observed following the 1918 pandemic. ON BROADLY AND NARROWLY DEFINED PSYCHOSIS The study aims to provide insights into links between influenza and schizophrenia. Eirini Zartaloudi 1, Johan Hilge Thygesen 1, Aritz Irizar 1, Methods: All sequences used were downloaded from the Stella Calafato 1, Andrew McQuillin 1, UniProt database ( http://www.uniprot.org/ ) and included: Jasmine Harju-Seppanen 1, Isabelle Austin-Zimmerman 1, 110 coding proteins identified based on 110 out of 145 Anjali Bhat 1, Robin Murray 2, Elvira Bramon 1 reported GWAS significant associations for schizophrenia

(Schizophrenia Working Group of the Psychiatric Genomics 1 University College London Consortium, 2014; GWAS proteins) and the 1918 influenza 2 virus proteome. 14 themed reference sets were created King’s College London for comparison from the following genes: null GWAS genes (with GWAS p-value > .75); central nervous system (CNS)- Background: Over 100 genetic loci have been associated expressed genes, e.g. in the brain; non-CNS genes expressed with psychosis and their combination into a polygenic risk in various tissues, e.g. in lung; and foetal genes expressed score (PRS) is a strong disease predictor. Several copy num- in the first trimester, a key neurodevelopmental period ber genetic variants (CNVs) have also been associated with (BrainSpan Atlas; http://www.brainspan.org/ ). Risk protein psychosis. Aims: (i) To examine whether schizophrenia and alignments of 5 amino acids were evaluated systematically bipolar PRS and CNV burden can distinguish between peo- with a combination of Python scripts and the Batch Pep- ple with psychosis, their unaffected first-degree relatives tide Match software (downloadable from https://research. and unrelated healthy controls, (ii) to investigate whether bioinformatics.udel.edu/peptidematch/index.jsp ). In each there is a relationship between CNV burden and PRS. reference set, the 100 subgroups served as independent Methods: The effects of the burden of large and rare CNVs replicates against which the rates of sequence sharing in and the PRS are investigated in a multi-center family based the single GWAS group were compared statistically. genetic association study with 11521 individuals. Results: Differences between GWAS proteins and reference Results: Preliminary results show that CNV burden, as sets were non-significant when mean frequencies of se- measured by the number of genes affected, and PRS for quence sharing between the influenza virus proteome and both schizophrenia and bipolar disorder are associated with GWAS proteins were compared to mean frequencies of se- broadly defined psychosis. The schizophrenia PRS explained quence sharing between the influenza virus proteome and a higher proportion of the variance in the diagnosis status reference sets proteins (z range = 0.000666-0.384720755, compared to the bipolar PRS. p > .05). However, when frequencies of sequence shar- Discussion: A better understanding of PRS and CNVs influ- ing were compared per each influenza virus protein, the ences on the risk of developing psychosis could be useful frequency of sequence sharing between GWAS proteins towards early detection and treatment of psychosis, which and the influenza virus proteins were significantly higher leads to better outcomes and prognosis. than the frequency of peptide sharing between reference sets and the influenza virus proteins ( χ2 (1) = 131.984, Disclosure: Nothing to disclose. p < .001, two-tailed), in particular when frequencies of se- doi: 10.1016/j.euroneuro.2018.08.481 quence sharing between GWAS proteins and the influenza virus hemagglutinin and matrix protein 1 were compared to ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 63

SU118 SU119 NETRIN ISOFORM VARIATION AS A FACTOR IN GENETIC OVERLAP AND CAUSALITY AMONG SCHIZOPHRENIA SCHIZOPHRENIA AND SUBSTANCE USE: FINDINGS FROM THE GENOMIC PSYCHIATRY COHORT

James Wilcox 1, David Briones 2

Roseann Peterson 1, Tim Bigdeli 2, Jacquelyn Meyers 2,

1 University of Arizona Giulio Genovese 3, Michele Pato 2, Steven McCarroll 4,

2 Texas Tech University Carlos Pato 2, Genomic Psychiatry Cohort Consortium,

Ayman Fanous 2 Background: Introduction

Netrin variation in the neocortex has been postulated as 1 Virginia Commonwealth University an etiology for schizophrenia (1, 2, 3, 4, 5). Such isoform 2 SUNY Downstate Medical Center changes in NTNG have been associated with subtle neurolog- 3 Broad Institute ical changes including variation of NMDA receptor-mediated 4 Stanley Center for Psychiatric Research, Broad Institute postsynaptic responses, associated with psychosis (5, 6,7, of MIT and Harvard 8). Netrins have multiple isoforms and allelic subtypes (2, 3, 4). NTNG1 is located on chromosome 1p13.3, a linkage Background: Despite epidemiological and genetic reports zone associated with psychosis in studies of schizophrenia on the association between schizophrenia and substance (4, 5). This study examines isoforms of NTNG1 in an attempt use, there has been limited research on the nature of to examine allelic variation contributes to risk for psychosis. causality with respect to these psychiatric disorders, par- Permission for this study was obtained from the appropriate ticularly in cohorts of diverse ancestry. university ethics board. NTNG1 isoforms were selected as Methods: We used the latest results from the Genomic the analysis of interest based upon the positive findings of Psychiatry Cohort (GPC) to dissect genetic overlap and previous studies. causality between schizophrenia and tobacco and cannabis Methods: 400 subjects with schizophrenia and 400 controls use. The GPC has undertaken the largest collection effort were evaluated. Three SNPs (rs4132604-SNP1, rs2218404- among persons of African ancestry to date, with 6,152 cases SNP2 and rs1373336-SNP3 were genotyped in this study. with a diagnosis of schizophrenia and 3,918 screened con- All samples were run blind to diagnosis. (reverse). A case- trols among 12,548 admixed African individuals with geno- control design was used for statistical comparison with the type data and includes participants of Latino (1,234 cases SPSS. Deviation from the Hardy-Weinberg equilibrium was and 3,090 controls) and European ancestry (6,046 cases examined using the Chi Square test and pairwise linkage dis- and 4,534 controls). Using data from the GPC, we esti- equilibrium. mated genetic correlations between schizophrenia and sub- Results: Strong pairwise linkage disequilibrium was found stance use traits including cross-ancestry associations. We between the three SNPs; rs4132604, rs2218404 and also tested whether polygenic risk scores constructed from rs1373336 (all [D‘] > 0.60). Significant differences of haplo- the results of the Tobacco and Genetics Consortium (TAG) type containing rs4132604 alleles were found between cases meta-analyses of smoking behaviors and the International and controls with GG (p = .001) and TG (P = .0001) between Cannabis Consortium (ICC) were associated with schizophre- rs4132604 and rs2218404, GGT (P = .0001), TGT (P = .01) nia risk or substance use behaviors among schizophrenia among the three SNPs. The allele frequencies of rs4132604 cases. in psychotic cases was much different than among healthy Results: Results indicated significant genetic correlations of controls (p = .0001). schizophrenia with smoking initiation, cigarettes-smoked- Discussion: Our study demonstrated positive association be- per-day, and age-of-onset of smoking, as well as lifetime tween rs4132604 and schizophrenia on the basis of the cannabis use. Comparing substance use behaviors among alleles (chi square = 7.912, p = .005) and genotype (chi schizophrenia cases to the general population (TAG, ICC), square = 7.772, p = .021) frequency distribution differences we observe positive genetic correlations for smoking initi- between cases and controls. The occurrence of allele G was ation and cannabis use. Similarly, TAG and ICC based poly- much higher than T alleles in rs4132604. This suggested that genic risk scores were significantly associated with smok- the chromosome that contained allele G (odds ratio = 1.423, ing behaviors and cannabis use among schizophrenia cases. 95% CI = 1.102-1.731) had a possible contribution to the sus- Additionally, we report on the first cross-ancestry genome- ceptibility to schizophrenia. wide association studies of smoking and cannabis use be- Our findings replicate early work on Netrin variations in haviors among schizophrenia cases. We will also explore psychosis Our study was among the first to document this whether these traits show genetic correlation because of association in Caucasian population and suggests that previ- shared genetic effects independently on each trait (i.e., ous Asian work may be generalizable to other populations. pleiotropy) or because of causal processes as indexed by genetic instruments through Mendelian randomization. Disclosure: Nothing to disclose. Discussion: Results provide additional support for a partially doi: 10.1016/j.euroneuro.2018.08.482 shared genetic basis for schizophrenia and substance use and for substance use among schizophrenia patients and the ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 64 Abstracts general population and suggest possible population differ- identified the combination of C4A and the retroviral inser- ences in patterns of genome-wide pleiotropic effects. tion creating long version (C4AL) as a risk haplotype for SCZ. We found mixed preliminary evidence for a link between the Disclosure: Nothing to disclose. C4 haplotype component and SCZ risk. Further, we found no evidence to support the relationship between the C4 CNV doi: 10.1016/j.euroneuro.2018.08.483 variation and SCZ phenotypes. More detailed analyses involving the C4 haplotype (as opposed to CNV) and neural C4A expression are needed to further clarify the role of C4

SU120 in SCZ risk and phenotypes. COMPLEMENT COMPONENT (C4) STRUCTURAL VARI- ANTS IN THE RISK AND CLINICAL CHARACTERISTICS OF Disclosure: Nothing to disclose. SCHIZOPHRENIA doi: 10.1016/j.euroneuro.2018.08.484 Cheng Chen, Julia Woo, Jennie Pouget, Clement Zai, James L. Kennedy

Centre for Addiction and Mental Health SU121 GENETIC VARIATION RELATED TO IMMUNE FUNCTION

Background: Schizophrenia (SCZ) is a heritable psychiatric AND SCHIZOPHRENIA RISK: EVIDENCE FOR EFFECTS ON disorder which affects approximate 0.7% of the population. COGNITION The disease is characterized by both positive and negative 1 1 1 symptoms, as well as decline in cognitive functioning. SCZ Gary Donohoe , Jessica Holland , David Mothersill , 2 2 1 often becomes clinically apparent from late adolescence to Aiden Corvin , Michael Gill , Donna Cosgrove , 3 early adulthood and severely impacts the quality of life. Al- Derek Morris though treatments exist, the development of preventive or curative interventions is hindered by the lack of mechanistic 1 National University of Ireland Galway understanding of the pathophysiology of SCZ. The comple- 2 Trinity College Dublin ment component 4 (C4) gene has been identified as one of 3 Neuroimaging and Cognitive Genomics (NICOG) Centre, the largest effect size markers for SCZ risk (Sekar et al., School of Psychology, National University of Ireland Galway 2016). Sekar et al. have shown the longer version of C4A (C4AL) is linked with higher neural C4A expression which Background: Altered immune response is associated is associated with higher SCZ risk. The C4 gene discovery with many psychiatric disorders, but whether and how opened a new direction in SCZ research. In this study, we these changes confer increased risk remains unclear. In aim to replicate the findings from Sekar et al. and further schizophrenia, robust association between illness risk and explore the relationship between C4 genetics variants and the MHC region general, and complement component 4 (C4) SCZ, as well as treatment response in SCZ. specifically, has been demonstrated, along with evidence Methods: 537 subjects with SCZ or schizoaffective disorder from both gene enrichment and other genetic analysis high- were recruited from our CAMH hospital. Clinical and demo- lighting the broader role of genetic variation in additional graphic information was gathered through structured clini- immune related networks to schizophrenia risk. cal interviews (SCID) and chart review. The copy numbers of Methods: In a series of recent studies from our group, we the C4A, C4B, C4L, and C4S in each sample were determined examined the effects of immune-related genetic variation, using ABI TaqMan copy number variation (CNV) protocol. In implicated in neural function both behaviorally in samples addition, C4 CNV data on healthy controls were obtained on of ∼1200 cases and controls, and cortically in samples of a small preliminary sample (n = 93) from the Sekar et al. pa- ∼150 cases and controls for whom GWAS data was avail- per. All statistical analyses were conducted using IBM SPSS able. We further investigated immune gene-set enrichment software. analysis in three datasets (PGC, ENIGMA, and UK Biobank). Results: Following Bonferroni correction, our SCZ subjects Results: We found that (1) increased predicted C4A RNA had significantly lower copy numbers of C4A compared to expression predicted poorer performance on measures of control group (p = 0.03), whereas there was no difference memory recall (p = 0.016, corrected) and a pattern of re- in C4L CNV between groups. Among patients, there was no duced cortical activity in middle temporal cortex during a significant relationship between C4 CNV and any of the fol- measure of visual processing (p < 0.05, corrected); (2) varia- lowing: age of onset; symptom severity; Global Assessment tion in a geneset associated with both increased Schizophre- of Function; and presence of symptoms such as delusions, nia risk and immune function (CSMD1, DPP4, SRPK2, TRIM8, hallucinations, disorganized speech or behavior, catatonia, STAT6, FES, EP300, TNFRSF13c) were associated with both alogia, avolition, inappropriate affect, and affective flat- variation in both episodic memory and general cognitive tening. ability; and (3) in an enrichment analysis of immune gene- Discussion: In the brain, C4 plays a crucial role in synap- sets using MAGMA, a gene set related to complement func- tic pruning. The process of synaptic pruning reaches a peak tion emerged as showing significant enrichment for cogni- in late adolescence which is the same time when SCZ be- tion. comes clinically apparent. Synaptic pruning also explains Discussion: Based on these findings we conclude that the deficit of synaptic connections, as well as the cognitive schizophrenia risk associated with variation within immune decline that is commonly seen in SCZ. Sekar et al. previously related genes is likely to be conferred at least partly via ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 65 effects on cognition, and that genetic variation within the after Bonferroni correction (PCorr = 0.029). RARB rare vari- complement system may have a particularly important role. ant burden was also associated with reduced posterior cerebellar volume in the CD group (PCorr = 0.023), and with co- Disclosure: Nothing to disclose. variation in grey matter (R2 = 0.638, P = 0.049), particularly in the cerebellum and parietal regions. Further, we demon- doi: 10.1016/j.euroneuro.2018.08.485 strated preliminary evidence that rare variation impacting DR5-RARE, and potentially retinoid receptor binding, is enriched in schizophrenia (P = 0.0226).

SU122 Discussion: Our ﬁndings suggest that retinoid signaling is

SCHIZOPHRENIA AND ITS SEVERE COGNITIVE SYMP- disrupted by common variation in schizophrenia, while pa- TOMS ARE ASSOCIATED WITH POLYGENIC ALTERATION tients with poor cognitive performance are affected dis- OF RETINOID SIGNALING proportionately by high impact rare variants. RARB variant burden was associated with reduced cerebellar volume in a 1 1 2 2 William Reay , Joshua Atkins , Yann Quide , Vaughan Carr , region with both known implications for cognition and vul- 2 1 Melissa Green , Murray Cairns nerability to retinoid pathologies. Downstream dysregulation of retinoid signaling may also be conferred by rare vari-

1 University of Newcastle ation altering DR5-RARE binding motifs. Future work will ex-

2 University of New South Wales amine whether patients with high genomic risk of retinoid disruption would benefit from targeted pharmacological in- Background: The biologically active retinoid metabolites of tervention. vitamin A are intrinsically linked to neural development, connectivity and plasticity, and have been implicated in the Disclosure: Nothing to disclose. pathophysiology of schizophrenia. This is supported by pre- doi: 10.1016/j.euroneuro.2018.08.486 liminary trials of a retinoid receptor agonist, Bexarotene, as an adjuvant and the association of five common variants in proximity to members of this pathway at genome wide significance. We suspect that the polygenic burden of common SU123 variation, along with high impact rare variants, in retinoid PREDICTION OF MORTALITY USING DNA METHYLA- loci may be clinically significant, particularly for the cogni- TION AGE IN SCHIZOPHRENIA tive symptoms of the disorder. 1 2 3 Methods: Schizophrenia cases and controls from the Aus- Kaarina Kowalec , Eilis Hannon , Georgina Mansell , 3 3 4 tralian Schizophrenia Research Bank were genotyped via Joe Burrage , Jonathan Mill , Patrick Sullivan SNP microarray (N = 676). Cases were clustered by a battery of cognitive measures to derive a severe cognitive deficit 1 Karolinska Institutet

(CD) subtype, along with a cognitively spared (CS) subpop- 2 University of Exeter Medical School ulation. Summary statistics from the 2014 schizophrenia 3 University of Exeter

GWAS were obtained and the effect of common variants 4 University of North Carolina at Chapel Hill, Karolinska In- aggregated in a panel of 107 retinoid genes using MAGMA. stitutet Genes with nominal significance (PMAGMA < 0.05) were selected to construct a retinoid polygenic risk score (PRS), Background: DNA methylation levels vary over the course and its enrichment tested in schizophrenia along with CD of life. Surprisingly, pre-selected combinations of methy- cases only. Rare variant (Frequency < 0.01%) association lation array probes can be used to estimate “methylation from a subset who underwent whole genome sequencing age” (mAge), which usually correlates highly with chrono- (N = 469) was calculated in these prioritized genes with the logical age. Occasionally, mAge is greater than chronologi- sequence kernel association test (SKAT-O). The impact of cal age, and this difference is a replicated predictor of all- rare variant burden in significant genes after correction on cause mortality. Schizophrenia (SCZ) is associated with sig- neuroanatomy was investigated for patients with MRI imag- nificantly higher mortality and decreased life expectancy. ing available (N = 210). Voxel-based morphometry (VBM) and We tested the association between mAge and mortality in multivariate source-based morphometry (SBM) tested the individuals with SCZ and controls, hypothesizing that mAge effect of rare variant burden on grey matter concentration. predicts subsequent death in SCZ. Non-coding rare variation was also mapped to genome wide Methods: We selected 190 SCZ cases and 190 controls sam- predicted retinoic acid response elements (DR5-RARE), to pled between 2004-2010 from the Sweden Schizophrenia which retinoid receptors bind. Study. SCZ cases were identified from the Swedish Hospital Results: We revealed evidence of a polygenic variant sig- Discharge Register with ≥5 specialist treatment contacts, nal in retinoid genes from the schizophrenia GWAS with 22 and ≥5 antipsychotic prescriptions. Controls are those with retinoid genes nominally significant. Retinoid PRS in these no lifetime psychotic disorder or antipsychotic prescrip- genes was associated with schizophrenia in the ASRB co- tions. Subjects were selected if deceased ( ≥1 year after hort covaried for genome wide PRS (P = 1.78 × 10-4, χ^ 2 sampling) or alive ( ≥3 years after sampling) as determined test of residual deviance). However, it did not differentiate using the Swedish Cause of Death Register (4-10 years of CD and CS patients. In contrast, in cases with marked cogni- follow-up). We excluded those who died by suicide, acci- tive deficit (CD) rare variants were enriched in the retinoic dent, or violence. Cases and controls were matched 2:1 on acid receptor gene RARB compared to the CS subpopulation sex and 5-year age band. DNA from whole blood was as- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 66 Abstracts sayed on the Illumina MethylationEPIC array. mAge was cal- splice acceptor) in loss of function intolerant genes; KDM5C, culated using the Hannum, Horvath, and Levine clocks. We PIK3CD and PIAS4. These genes have previously been shown regressed mAge on chronological age to obtain a measure to harbour truncating and missense mutations in previous of age acceleration for each clock. Using Cox proportional sequencing studies of adult-onset schizophrenia, as well as hazards regression, the association between age accelera- autism and the deciphering developmental disorders (DDD) tion and mortality was tested: SCZ deceased vs. SCZ alive, cohort. KDM5C is a particularly interesting candidate as it SCZ deceased vs. controls alive, and SCZ deceased vs. con- is also a Mendelian disease gene responsible for a range of trols deceased. X-linked intellectual disability phenotypes. Results: Among individuals with SCZ, 126 died and 63 were In addition to the loss of function variants, we identified alive, whereas for the controls, 127 died and 62 were 7 damaging (CADD > 15) missense variants, majority (6/7) alive, following quality control of the methylation data. We of which have been shown to harbour truncating and mis- did not find a significant association between any of the sense mutations in previous sequencing studies of adult- three age acceleration clocks and mortality in SCZ (adjusted onset schizophrenia and other neurodevelopmental disor- P = 0.16-0.62). We had 88% power to detect the effect size ders. Four of these de novo variants were in genes intoler- for mAge and mortality. ant to missense variation (RVIS < 35) and very deleterious to Discussion: We did not confirm our hypothesis that age ac- protein function (CADD > 20 and polyphen > 0.9). These were celeration would predict subsequent mortality in people GPR107, RANBP1, LEMD3 and NEDD9. Interestingly the pre- with SCZ. Further analyses of these data will be presented vious de novo study of COP reported GPR153 as a novel COP at the conference. candidate, which is in the same gene family as GPR107. The majority of these genes are involved in neuronal and synap- Disclosures: Emerald Lake Safety - Consultant, Self. tic function and are therefore interesting candidates for fol- Fraser Health Multiple Sclerosis Clinic - Honoraria, Self. low up functional studies. Discussion: This work suggests that de novo variants could doi: 10.1016/j.euroneuro.2018.08.487 make up an important aspect of the genetic architecture that underlies the development of childhood onset psychosis. SU124 DE NOVO VARIANTS IN CHILDHOOD-ONSET-PSYCHOSIS Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.488 Mitra Sato 1, Marinos Kyriakopoulos 2, Anthony James 3,

Niran Okewole 4, Anna Need 1 SU125

1 Imperial College London MODELLING THE IMPACT OF SCHIZOPHRENIA GWAS

2 Bethlem Royal Hospital LOCI DURING HUMAN BRAIN DEVELOPMENT USING

3 Warneford Hospital SPATIO-TEMPORAL GENE EXPRESSION DATA

4 Neuropsychiatric Hospital, Ogun State

Sathish Periyasamy 1, Bryan Mowry 2 Background: Childhood-Onset Psychosis (COP) is a very rare

(prevalence 0.2 in 100,000 in the UK) and debilitating dis- 1 Queensland Brain Institute order characterised by the onset of psychotic symptoms 2 Queensland Brain Institute, The University of Queensland before age 14. COP has been shown to be neurobiologically continuous with the adult-onset form of the disease, Background: Epidemiological data and the recent brain- schizophrenia. Copy number variant (CNV) examination has specific molecular and genetic discoveries have revealed previously revealed a higher frequency of pathogenic CNVs that early neurodevelopmental activities have been im- in the childhood-onset form, in comparison to adult-onset plicated in pathogenesis. Mapping the genetic, epigenetic schizophrenia. and environmental factors affecting the human brain devel- Methods: In order to elucidate the de novo variant spectrum opment will be fundamental to identifying disease mech- in this rare group of patients we performed exome sequenc- anisms in schizophrenia. Remarkably many collaborative ing on 17 trios with COP. GWAS studies have recently identified discrete risk loci as- Results: We identified 13 de novo variants in 9/17 probands, sociated with schizophrenia. The vast majority of these are across 13 genes. We found a coding de novo mutation rate situated in non-coding regions such as enhancers and pro- of 0.76 per exome in this cohort, which is lower than the moters that affect gene regulation. Enhancers control the previously reported rate of 1.17 per exome in the de novo correct temporal and cell-type-specific activation of gene study of COP and adult-onset schizophrenia (1.03 per ex- expression in multicellular eukaryotes. Moreover, heritabil- ome). This decrease in de novo rate is most likely due to the ity tends to be enriched in transcriptionally- active regions enrichment of positive family history for psychiatric illness in relevant tissues. Numerous -omics data sources have in the studied cohort. In addition, we found that the ratio of emerged to aid the development of spatio-temporal gene non-synonymous (n = 10) to synonymous (n = 3) de novo vari- expression models. We adopted a molecular systems ap- ants in COP probands were consistent with the previous de proach to reconstruct the regulatory activities in the de- novo study of COP. veloping human brain using time-series gene expression and A total of 10 de novo damaging (CADD > 15) missense gene regulatory data. and protein truncating variants were identified. We found Methods: Brain eQTL datasets were used to identify the 3 de novo protein truncating variants (2 frameshifts and 1 regulatory regions in PGC2-SCZ significant loci. Various reg- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 67 ulatory databases such as RegNetwork were used to iden- known, partially because it remains unclear how the func- tify transcription factors (TF), transcription cofactors (TcoF) tional change of the genes within the regions of the CNVs and miRNAs present in all PGC2-SCZ loci. We reconstructed lead to the pathogenesis of neuropsychiatric disorders. On the dynamic TF/miRNA regulated interaction network us- the other hand, there is growing evidence that rare SNVs, ing dynamic regulatory event minor (DREM) that incorpo- discovered from deep sequencing of SCZ candidate genes, rates developmental transcriptome data obtained from post may have large effect sizes, as well as contribute to un- conception to adulthood (i.e. prenatal and postnatal) in derstanding of the pathogenesis of neuropsychiatric disease 16 brain regions. Integrated analysis of time-series gene through in vitro and in silico functional analysis. Thus, se- expression data and static regulatory interaction data re- quencing the candidate genes from CNV analyses of neu- constructed dynamic developmental activities regulated by ropsychiatric disorders may be a promising method for elu- TFs and miRNAs. Significant regulators in every brain re- cidating the pathophysiology of neuropsychiatric disorders gion were identified and mapped to the disease-associated such as SCZ and ASD. TFs/miRNAs obtained from the genome-wide significant Methods: To discover rare variants with large effect size loci. ReMap was used to identify statistical enrichment of and to evaluate their role in the pathophysiology of SCZ and TF bindings present within PGC2-SCZ associated regulatory ASD, we sequenced the genes involved in neurodevelopment regions compare to random expectations. This permitted in the several regions of CNV associated with Japanese SCZ to prioritise TFs based on over-represented bindings at the by Sanger or Next Generation sequencing method (Thermo disease-associated loci. Fisher Scientific Ion PGM) with 370 SCZ. Nonsense muta- Results: More than 600 genome-wide significant variants tions, missense mutations, small insertions/deletions and and 49 TFs associated with gene regulation were iden- canonical splicing site variations with an allele frequency tified from PGC2-SCZ GWAS loci. Of these, one TF was of < 1% were selected from the sequencing data. Then, we identified as a significant regulator impacting the prenatal performed genetic association analysis using a large num- developmental activities across all brain regions; another ber of unrelated individuals, and in silico structural analysis seven TFs were significant in some of the brain regions. and in vitro functional assays of the variants that could have Most regulatory activities were observed during prenatal large effects. stages of brain development. The target genes of these Results: Through the mutation screening, prioritizing the TFs are involved in cell differentiation, proliferation and discovered variants and genetic association analysis, we mitogenesis. ReMap analysis revealed that some TF bindings found that rare SNVs in genes (NDE1 in chr16p13.11, RTN4R were over-represented at the disease-associated loci. in chr22q11.2) related to neurodevelopment have statisti- Discussion: The purpose of this analysis was to associate cally significant association with SCZ. Based on in silico 3D crucial TFs identified in schizophrenia GWAS loci with TFs in- protein structure analysis of RTN4R-R292H and NDE1-S214F, volved in neurodevelopment. Some of the over-represented we predicted that the variants could be located at the site TFs could be the core genes having the most direct ef- of protein-protein interactions. We discovered a reduced in- fect on schizophrenia pathogenesis. To re-analyze future teraction by the GST-binding assay as our in silico structural GWAS studies with the latest versions of -omics databases, analysis predicted. Furthermore, in vitro functional assays we developed an adaptable bioinformatic pipeline integrat- showed that the rare mutations affected the neurodevelop- ing significant regulators identified from DREM analysis with ment. TFs/miRNAs obtained from GWAS loci. Discussion: This study strengthens the evidence for association between rare variants in the regions of CNV associ- Disclosure: Nothing to disclose. ated with SCZ and ASD and may shed light on the molecular mechanisms underlying the neurodevelopmental disorder. doi: 10.1016/j.euroneuro.2018.08.489

Disclosure: Nothing to disclose.

SU126 doi: 10.1016/j.euroneuro.2018.08.490 TARGET SEQUENCING OF GENES INVOLVED IN NEU- RODEVELOPMENT FROM WHOLE GENOME COPY NUM- BER VARIATION ANALYSIS OF JAPANESE SCHIZOPHRE- SU127 NIA INVESTIGATION OF MATERNAL EFFECTS, MATERNAL- FETAL INTERACTIONS AND PARENT-OF-ORIGIN EFFECTS

Hiroki Kimura 1, Branko Aleksic 1, Kanako Ishizuka 2, (IMPRINTING) FOR CANDIDATE GENES POSITIONALLY

Chenyao Wang 1, Itaru Kushima 1, Norio Ozaki 1 ON CHROMOSOME 18Q21, USING MOTHERS AND THEIR OFFSPRING WITH SCHIZOPHRENIA

1 Nagoya University

2 Nagoya University Hospital Byung Dae Lee, Kang Yoon Lee, Je Min Park, Young Min Lee, Eunsoo Moon, Hee Jeong Jeong, Soo Yeon Kim, Hwagyu Suh, Background: Recent large-scale whole genome sequencing Young In Chung, Dae Wook Kim, Chan Hum Park and copy-number variant (CNV) analysis with Schizophre- nia (SCZ) and Autism Spectrum disorder (ASD) samples have Pusan National University Hospital revealed that rare single-nucleotide variants (SNVs) and CNV exert significantly larger effects than common single- Background: A popular design for the investigation of such nucleotide polymorphisms (SNPs). Despite large effect size effects, including effects of parent-of-origin (imprinting), of the CNV, the pathological roles of CNV remains largely un- maternal genotype, and maternal-fetal genotype interac- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 68 Abstracts tions, is to collect DNA from affected offspring and their We, therefore, aimed to investigate whether (poly)genetic mothers (case/mother duos) and to compare with an appro- risk score for T2D and SCZ, and antipsychotic drugs are as- priate control sample. We investigate the effects of estima- sociated with T2D among patients with SCZ. tion of maternal, imprinting and interaction effects using Methods: Data of 820 patients with non-affective psy- multimodal modeling using parents and their offspring with chosis were extracted from the Genetic Risk and Outcome schizophrenia in Korean population. of Psychosis (GROUP) cohort in the Netherlands and Bel- Methods: We have recruited 27 probands (with schizophre- gium. A weighted (poly)genetic risk score was calculated nia) with their parents and siblings whenever possible. We by summing the phenotype associated risk alleles across analyzed 20 SNPs of 7 neuronal genes in chromosome 18 genetic loci, which were multiplied by the corresponding for DNA samples that was checked for the data quality and effect sizes, estimated from a meta-analysis of genome- genotype error. We used EMIM analysis program for the esti- wide association studies. Multiple linear regression analy- mation of maternal, imprinting and interaction effects using sis was applied to identify factors associated with glycated multimodal modeling. hemoglobin (HbA1C), which is a proxy measure for T2D. Results: Of analyzed 20 SNPs, significant SNP (rs 2276186) Results: The genome-wide significant genetic risk score was suggested in EMIM analysis for child genetics effects of T2D (p-value = 0.002) was significantly associated with (p = 0.0225438044) (and child genetic effects allowing for HbA1C and explained 3.4% of the variance in HbA1C. The maternal genetic effects: p = 0.0209453210) with very polygenic risk score of SCZ and high metabolic risk an- stringent multiple comparison Bonferroni correction. Addi- tipsychotics explained 0.7% and 0.1% of the variance of tionally, analysis results for maternal genetic effects (and HbA1C, although the association was not significant (p- maternal genetic effects allowing for child genetic effects) value = 0.31 and p-value = 0.89, respectively). In addition, was presented. gender, daily cigarette smoking and history of cardiovascu- Discussion: Alternative methodologies in genetic research lar diseases were significantly associated with HbA1C. To are required with many methodological limitations in ap- examine shared genetic susceptibility, we tested another proaches evaluating the correlations between genotyping model using GRS-T2D instead of HbA1C as an outcome vari- and phenotyping. Epigenetics and gene-environment inter- able and only PRS-SCZ as a predictor. Consequently, the ge- actions are represented underlying statistical genetics. Our netic overlap was 0.1% and there was no significant associa- results are the pilot study for epigenetic study in mental dis- tion ( β = 0.01, 95% CI = -0.02-0.04, p-value = 0.50). order and help to understanding and use of EMIM (Estimation Discussion: The public health burden of the comorbidity be- of Maternal, Imprinting and interaction effects using Multi- tween SCZ and T2D is high and leads to poor functioning and nomial modelling) statistical genetics analysis program with quality of life, poor prognosis of both diseases and prema- many limitations including small pedigree numbers. ture death due to complications. Thus, our study has important implications for clinical practice and evidence-based Disclosure: Nothing to disclose. medicine, as three-fourths of T2D cases in patients with SCZ were undiagnosed. In addition, our study helps to advance doi: 10.1016/j.euroneuro.2018.08.491 understanding the underlying pathogenetic mechanisms of this comorbidity. Since the genetic biomarker of T2D was used, which is believed to be sensitive to alteration due to SU128 genetic liability, GRST2D can also be used as a tool for the OPEN BOARD prediction of T2D among patients with SCZ. Altogether, this may ultimately contribute to improve quality of later life and healthy aging in patients with psychotic disorder. SU129 TYPE 2 DIABETES MELLITUS IN PATIENTS WITH Disclosure: Nothing to disclose. SCHIZOPHRENIA: THE EFFECT OF (POLY)GENETIC

RISK SCORE OF SCHIZOPHRENIA AND TYPE 2 DIABETES doi: 10.1016/j.euroneuro.2018.08.493 AND ANTIPSYCHOTIC MEDICATION USE

Tesfa Habtewold 1, Richard Bruggeman 2, SU130

Edith J. Liemburg 1, Md. Atiqul Islam 3, Behrooz Z. Alizadeh 1 ANALYSING SCHIZOPHRENIA RISK VARIANTS IN NRXN1 USING FUNCTIONAL AND MATURE NEURONAL CUL-

1 University of Groningen, University Medical Center TURES FROM PATIENT-DERIVED IPS CELLS Groningen

2 University of Groningen, University Medical Center Matthias Jung, Annika Majer, Jessica Reinsch, Groningen, University Center for Psychiatry, Rob Giel Re- Jovita Schiller, Annette Hartmann, Bettina Konte, search Center Ina Giegling, Dan Rujescu

3 Shahjalal University of Science and Technology Martin-Luther-University Halle-Wittenberg Background: Type 2 diabetes (T2D) is a common comorbidity in patients with schizophrenia (SCZ). The underly- Background: Schizophrenia is a complex psychiatric disor- ing pathophysiologic mechanisms are yet to be found, al- der that affects nearly 1% of the world’s population. We pre- though it can be argued that antipsychotic usage and ge- viously described deletions in neurexin 1 (NRXN1) to be as- netic susceptibility are involved in the emergence of T2D. sociated with schizophrenia. Neurexins are transcribed from ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 69 of three different genes in mammalians (NRXN1, NRXN2, and to migration, urbanicity of drug-taking. Given the avail- NRXN3) and are widely expressed in excitatory as well as in- ability of locations of birth and current residence, cross- hibitory neurons, in particular in presynaptic terminals re- referencing with population density data from the National quired for normal synapse function. Neurexins are neuronal Office of Statistics, we were able to investigate migration adhesion molecules functioning as a receptor for neuroli- patterns, and substance abuse from the corresponding ICD gins. Disruption of the neurexin 1 gene leads to changing code. We further investigate the complex relationship be- properties of synapses and to the disruption of neuronal tween migration, urbanicity and schizophrenia. networks. Deletions in α-neurexin 1 are involved in altered Results: Self-reported risk-taking is associated with neural connectivity. UK-based internal migration, in terms of distance- Methods: For further analysis of neurexin1-related disease moved (P = 3 × 10-123) and increasing population density mechanisms, we used an in vitro cell culture model based on (P = 7 × 10-37), and also with substance abuse (P = 8 × 10- human induced pluripotent stem cells (iPS cells). iPS cells 74), and schizophrenia PRS were also associated with each have been obtained by reprogramming of B-lymphoblastoid of these. We also report results from Mendelian Randomiza- cell lines (B-LCLs) that have been obtained from two tion conducted to test the hypothesized pathway from risk- schizophrenia patients carrying CNVs in NRXN1. In one case taking genetics, via migration/drug-taking, to schizophre- the deletion is located in promotor region and exon 1-6 nia. and in the other case in exon 4-6. Patient derived induced Discussion: Behaviour plays a potentially important role in pluripotent stem cells and healthy control cells were dif- schizophrenia aetiology, and given the high heritability of ferentiated into mature and functional cortical neurons by many high-risk behaviours, the large portion of the genetics using a four-step culture system. The analysis focused on of schizophrenia is the genetics of relevant patterns of be- altered gene expression and function of signaling molecules haviour, such as risk-taking, migration and substance abuse. of NRXN1 related cellular pathways using IF, WB, flow cy- tometry, and metabolic phenotyping. Disclosure: Nothing to disclose. Results: Transcript and immunofluorescence analysis con- doi: 10.1016/j.euroneuro.2018.08.495 firmed the successful generation of glial and neuronal cells (TUBB3, STX, GFAP, and CD68). The presence of different neuronal subtypes such as GABAergic and glutamatergic neurons was demonstrated (SLC17A7, GAD1, GABBR1,

GRIA2, and GRIN1). Immunofluorescence-microscopy veri- SU132 fied the presence of NRXN1 and its interaction partners such CANNABIS USE AND SCHIZOPHRENIA: CAN GENET- as neuroligins. ICS TELL IF IS IT “THE CHICKEN OR THE EGG”? Discussion: In summary, the characterization of iPS cells 1 1 1 bearing patient-specific genetic information and their dif- Marta Di Forti , Beatrice Wu , Diego Quattrone , 2 2 1 ferentiation into schizophrenia-specific neurons has poten- Alexander Richards , Michael O’Donovan , Craig Morgan , 3 4 5 tial to elucidate the impact of specific genetic variations Jim van Os , Bart Rutten , Paul O’Reilly , 5 1 6 in NRXN1. It also carries major opportunities to enable the Evangelos Vassos , Giada Tripoli , Pak Chung Sham , 1 1 identification of potential therapeutic targets in schizophre- Robin Murray , Cathryn Lewis nia.

1 Institute of Psychiatry, Psychology & Neuroscience, King’s Disclosure: Nothing to disclose. College London

2 Cardiff University doi: 10.1016/j.euroneuro.2018.08.494 3 University of Utrecht

4 School for Mental Health and Neuroscience, Maastricht University

SU131 5 King’s College London

THE ROLE OF BEHAVIOUR IN THE GENETIC AETIOLOGY 6 Centre for Genomic Sciences, University of Hong Kong OF SCHIZOPHRENIA Background: Cannabis use remains the most widely used Paul O’Reilly, Jessye Maxwell, Adam Socrates, recreational drug worldwide. In the USA several states have Evangelos Vassos legalized its used and in some for medicinal use. Never- theless, a significant amount of Epidemiological and exper- King’s College London imental studies have reported that cannabis use, especially frequent use of high potency varieties, increases the risk of Background: Exploiting schizophrenia PRS, we performed psychosis. a survey of shared aetiology between schizophrenia and a Therefore, it becomes a research priority to identify range of behavioural traits across the UK Biobank data. A those individuals at greatest risk to develop psychosis fol- key objective was to investigate the degree of mediation of lowing cannabis use. schizophrenia by behaviour. Methods: Using the genetic and cannabis use data from a Methods: Among the top findings was an association be- large first episode case-control study (N = 2300), we aim 1) tween schizophrenia PRS and risk-taking (P = 2 × 10-26), to use Polygenic Risk Scores for Psychosis (PRS) to test if and so we hypothesized that part of the genetics of genetic load for psychosis increases the individual vulner- schizophrenia may be the genetics of risk-taking, leading ability to the psychotogenic effects of cannabis; 2) to test ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 70 Abstracts if those with high PRS for psychosis are also more likely to timated using the Block Design and Information subtests of smoke cannabis and with high frequency. the WAIS-III. Tw o SNPs at AKT1 were genotyped (rs2494732 Results: Subjects with a PRS for schizophrenia in the high- and rs1130233), individual haplotypes were estimated, and est quartile had a 7-fold increase in the odds to suffer each subject was defined as a carrier of zero, one or two from a psychotic disorder (Adj OR = 7.0; 95% CI 3.46-14.25). copies of the haplotype CA (rs2494732(C)-rs1130233(A)). Regular, users of high potency cannabis did not differ on Multiple linear regressions were used to test the effect of PRS profiles from occasional users or never users (Pearson genetic and environmental factors and their interaction on chi2(3) = 5.6001 Pr = 0.133). We did not find a significant in- cognitive scores (adjusted for sex, age, IQ and the use of teraction between PRS X cannabis use in influencing risk to other drugs). Psychosis. Results: Cannabis use was not associated with any cognitive Discussion: Summary scores, such as PRS for Schizophrenia, measure. A main effect of AKT1 was found on CPT d’ shapes do not explain individual susceptibility to the psychotogenic (rs2494732: β= 0.14 p = 0.003; rs1130233: β= 0.16 p < 0.001; effects of cannabis. More research is needed to investigate haplotype: β= 0.17 p < 0.001) but not on d’ digits. Individuals the role of genes mapping at biological plausible pathways. with the genotype CC for rs2494732, the AA for rs1130233 and with two copies of the CA haplotype presented better Disclosure: Nothing to disclose. d’ shapes performance. Evidence for AKT1 x cannabis interaction was not found. doi: 10.1016/j.euroneuro.2018.08.496 Discussion: Our findings indicate the AKT1 effect on a measure of sustained attention independently of cannabis use in healthy subjects. This result is in line with: i) several stud-

SU133 ies that have reported the AKT1 involvement on different

AKT1 GENE AND CANNABIS USE: ANALYSIS OF MOD- cognitive domains (e.g. Tan et al. 2008, Pietiläinen et al. ERATION EFFECTS ON COGNITIVE PERFORMANCE IN 2009); ii) evidence on the role of AKT1 in normal dopamin- NON-CLINICAL SUBJECTS ergic transmission and expression of dopamine-associated behaviours (Beaulieu et al. 2005, 2007). Therefore, it is 1 2 3 Mar Fatjó-Vilas , Jordi Soler , Manuel Ignacio Ibáñez , plausible that variability in AKT1 may result in changes in 4 3 5 Jorge Moya , Generós Ortet , Maria Guardiola , responses to dopamine receptors stimulation and dopamin- 2 2 Lourdes Fañanás , Bárbara Arias ergic deregulations (Arguello and Gogos 2008). Despite the AKT1 moderation of cannabis-induced cogni-

1 FIDMAG Hermanas Hospitalarias Research Foundation tive alterations has been previously reported in psychotic

2 University of Barcelona, CIBERSAM disorders (van Winkel et al, 2011); we have not observed

3 Universitat Jaume I, CIBERSAM such effect in non-clinical subjects.

4 University of Lleida, CIBERSAM Acknowledgements: i) Plan Nacional Sobre Drogas, Min-

5 FIDMAG Research Foundation, CIBERSAM, University of isterio de Salud (2008/090), ii) ISCIII through de project Barcelona PI15/01420 (co-funded by European Regional Development Fund/European Social Fund) "Investing in your future"), iii) Background: Genetic factors may explain the differences 2014SGR1636, iv) APIF-UB JS and CD16/00264 to MF-V. in individual sensitivity to the psychosis-inducing effects of cannabis (Di Fort et al. 2012). Investigation of the interac- Disclosure: Nothing to disclose. tion between cannabis use and genetic variability on rele- doi: 10.1016/j.euroneuro.2018.08.497 vant intermediate phenotypes for psychosis, such as cognition, may help to clarify the underlying mechanism of such sensitivity.

AKT1 gene has been identified as a candidate for SU134 gene × cannabis interaction (van Winkel et al. 2011). It A CASE REPORT OF A CAT-EYE SYNDROME PRESENTING codes for a protein kinase that is a key-signalling molecule WITH AN AUTISM SPECTRUM DISORDER downstream of the dopamine receptor and hence has a plau- 1 1 1 sible biological mechanism for interacting with cannabis to Sofia Barbosa , Marta Lages , Nuno Borja-Santos , 1 2 1 confer an increased risk of psychosis. Patrícia Gonçalves , Ana Barreta , Teresa Maia Our aim was to analyze the effect of lifetime cannabis use, AKT1 variability and their interaction on cognitive per- 1 Hospital Prof. Doutor Fernando Fonseca, E.P.E. formance in non-clinical individuals. 2 Joaquim Chaves Saúde Methods: The sample consisted of 389 Spanish non-clinical subjects (43% males, mean age = 21.1(2.19)). Subjects were Background: Cat-Eye syndrome (CES) is a genomic disorder interviewed on their cannabis frequency of cannabis con- associated with a highly variable phenotype. Concerning its sumption and then dichotomized as users (29%) or non- psychiatric manifestations, the most described is mental re- users (71%). Attention (d’ shapes/digits of CPT-IP), Verbal tardation. Memory (percentile scores of WMS-R) and Working Memory CES results from trisomy or tetrasomy of proximal 22q (perseverative errors of WCST) were selected as the cogni- usually originated by a small supernumerary marker chro- tive outcome measures based on previously described effect mosome (sSMC). of cannabis use on these tasks (Henquet et al. 2006; van Methods: We report the case of a male presenting with an Winkel et al. 2011). The intellectual quotient (IQ) was es- autism spectrum disorder (according to DSM-5 criteria) and ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 71 dysmorphic features; with a karyotype identifying a small to the trajectory of psychiatric diagnoses, and for all se- supernumerary marker chromosome. To ascertain the chro- quence pairs we computed a dissimilarity corresponding to mosomal origin and segmental composition of the sSMC mi- the number of alterations required to turn one sequence croarray was performed. into the other. Results: The patient presented with an autism spectrum Our data consist of date of first hospital contact for all disorder, with mild mental retardation and behavioural psychiatric ICD codes. We also obtained birth related out- changes; also, mild non-specific facial dysmorphism was comes, as well as date of first hospital contact for any noted. ICD code corresponding to infection diagnosis at discharge. A constitutional karyotype identified a small supernu- Genotype data were obtained on a subset of 24249 subjects merary marker chromosome; and the microarray revealed of European ancestry (2350 with schizophrenia). For geno- a copy number gain for 22q11.1q11.21 region, compati- typed subjects, we computed polygenic risk scores (PRS) ble with a derivative of chromosome 22 [del(22)(q11.21)]. for psychiatric disorders, personality traits, cognition, and Therefore, patient presents partial trisomy of proximal 22q anthropomorphic phenotypes, using as weights summary including the critical regions for CES (CESCRs). statistics from consortia not overlapping with the current Discussion: Our case illustrates the clinical heterogeneity of study sample. We also ascertained copy number variation the Cat-Eye Syndrome as well as the importance to carry out (CNV) for 12 large CNVs well characterized in the literature genetic evaluation of patients with autism spectrum disor- as well as genetic load for rare and damaging mutations ders, especially if they present atypical or dysmorphic char- Results: Individuals with schizophrenia had increased rela- acteristics. This clinical case also reinforces the wide ge- tive risk (RR) estimates ranging from 6 to more than 60 for netic complexity of autism spectrum disorders. developing comorbid psychiatric conditions, compared to population controls. Multidimensional scaling (MDS) based Disclosure: Nothing to disclose. on pairwise dissimilarity of sequences followed by multivariate analysis of covariance revealed significant associa- doi: 10.1016/j.euroneuro.2018.08.498 tion between 4 stable MDS dimensions and several genetic and phenotypic characteristics, such as PRS for schizophrenia and education years; several types of psychiatric con-

SU135 tacts; birth and pregnancy features; birth complications; GENETIC SUBTYPES OF SCHIZOPHRENIA ELUCIDATED and rare mutations. For example, Dimension 1 corresponds BY MULTISTATE DIAGNOSIS TRAJECTORIES to higher number of comorbidities and earlier age of ﬁrst diagnosis. Dimension 3 distinguishes trajectories with comor- 1 2 Gonçalo Espregueira Themudo , Morten Krebs , bid autism and ones with substance abuse. Dimension 3 is 3 Michael Benros , iPSYCH-BROAD Working Group, also associated with more rare and damaging mutations and 2 2 Thomas Werge , Wesley Thompson older maternal age but negatively associated with the PRS for schizophrenia.

1 Research Institute of Biological Psychiatry Discussion: Our results suggest that diagnosis sequence

2 Institute of Biological Psychiatry, Mental Health Centre analysis can be a useful method to subcategorize complex Sct. Hans, Mental Health Services of the Capital Region of disorders with high comorbidities and rare and common ge- Denmark netic variants may contribute separately to risk of develop-

3 Mental Health Centre Copenhagen, Copenhagen University ing schizophrenia.

Background: Schizophrenia is a disorder with a high degree Disclosure: Nothing to disclose. of heterogeneity. Identifying distinct subgroups that poten- doi: 10.1016/j.euroneuro.2018.08.499 tially reflect shared common etiology and clinical presentation is much needed. However, no studies have used genetic risk and disease trajectories in the context of an entire population to identify relations between clinical pro- SU136 files such as temporal patterns of disease and genetic risk. INTERACTION BETWEEN ZNF804A GENE AND CANNABIS These could advance our insight into etiological mechanisms USE ON THE RISK FOR PSYCHOSIS IN A NON-CLINICAL and more personalized treatments. To investigate if specific SAMPLE subtypes of schizophrenia can be identified in a population- based sample we combined longitudinal register data sum- Jordi Soler Garcia 1, Barbara Arias 2, Jorge Moya 3, marized into diagnosis trajectories with genetic data from Manuel Ignacio Ibañez 4, Generós Ortet 5, Lourdes Fañanás 6, the Danish population Mar Fatjó-Vilas 7 Methods: Using information from the nationwide Danish registers we conducted a cohort study on a population- 1 Universitat de Barcelona, Institut de Biomedicina de la based sample born in Denmark between 1981 and 2005, and Universitat de Barcelona (IBUB) during follow-up until 2016, we identified 5442 individuals 2 University of Barcelona, CIBERSAM (Biomedical Research with schizophrenia. We also obtained data on a true popula- Network in Mental Health; Instituto de Salud Carlos III) tion random sample of 30000 people born in Denmark within 3 University of Lleida, CIBERSAM the same time period, of which 29828 did not have a diagno- 4 Centro de Investigaciones Biomédicas en Red de Salud sis of schizophrenia. Total sample size was thus n = 35270. Mental (CIBERSAM), Universitat Jaume I

For all patients we constructed a sequence corresponding 5 Universitat Jaume I ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 72 Abstracts

6 University of Barcelona SU137

7 FIDMAG Research Foundation / University of Barcelona DIFFERENCES DETWEEN AUDIT-C AND AUD PHENO- TYPES REVEALED BY GENOME-WIDE ANALYSIS Background: The ZNF804A gene and cannabis use are risk factors for psychosis and both have also been associated Rachel Kember 1, Hang Zhou 2, Amy Justice 3, Rachel Smith 4, with schizotypal traits. This study aimed to investigate: Janet Tate 5, William Becker 3, John Concato 6, i) the association of life-time cannabis use (and its dose- David Fiellin 2, Ke Xu 3, Hongyu Zhao 7, Joel Gelernter 2, effect) with schizotypal personality traits, ii) whether the Henry Kranzler 8 genetic variability at ZNF804A gene modulates such association. 1 University of Pennsylvania

Methods: The sample consisted of 389 Spanish non-clinical 2 Yale University School of Medicine subjects (43% males, mean age = 21.1(2.19)). Schizotypy 3 Yale University School of Medicine, Veterans Affairs Con- was evaluated with the three factors of the Schizotypal necticut Healthcare System; Yale School of Public Health

Personality Questionnaire-Brief: Cognitive-Perceptual (SPQ- 4 School of Nursing, University of Louisville

CP), Interpersonal (SPQ-I) and Disorganized (SPQ-D). Sub- 5 Veterans Affairs Connecticut Healthcare System jects were classiﬁed regarding their cannabis frequency of 6 Connecticut Epidemiology Research Center consumption and then dichotomized as users or non-users. 7 Yale University

The effect of a genetic variant at ZNF804A (rs1344706) and 8 University of Pennsylvania, Crescenz VAMC cannabis use and their interaction on each of the three SPQ- B factors was tested by means of linear models. Sex, SCL Background: Excessive drinking is associated with a variety anxiety scores and the use of other drugs were included as of adverse medical, psychiatric, and social consequences, covariates. P-values were adjusted for false discovery rate including the development of alcohol use disorder (AUD), a < (FDR cutoff at p 0.05). chronic, relapsing condition characterized by impaired con- Results: The analyses showed a significant relationship trol over drinking. Patients with AUD often have psychiatric between ZNF804A and SPQ-I: homozygotes AA presented and medical comorbidities that can complicate their clinical β= = higher scores ( 0.884 p 0.018). An interaction between presentation and treatment. In contrast, in some studies, the genotype AA and the life-time cannabis use was found moderate alcohol consumption has been associated with po- β= = on SPQ-CP ( 1.29 p 0.029). This interaction showed a tential health benefits, including a decreased risk for heart dose-effect pattern among AA subjects: schizotypy scores disease and diabetes. Both AUD and levels of alcohol con- increased with the increment of the cannabis use frequency sumption have a genetic component, and genetic variants β= = β= (sporadically users: 0.74 p 0.20; monthly users: 1.68 have been identified that contribute to one or both pheno- = β= = p 0.091; intense users: 1.62 p 0.037). types. Discussion: On the one hand, the detected association be- Methods: To investigate the genetic similarities and dif- tween the rs1344706 genotype and schizotypy scores is in ferences between AUD and alcohol consumption, we uti- line with previous studies reporting the association of the A lized data from the Million Veteran Program, a genomic allele with schizophrenia risk (Purcell et al., 2009; Williams mega-biobank supported by the U.S. Department of Veter- et al., 2011) and with schizotypy (Stefanis et al., 2013; Ya- ans Affairs. Alcohol consumption was measured using lon- suda et al., 2011). On the other hand, our interaction anal- gitudinal self-report recorded in the VA electronic health yses report that life-time cannabis seems to act as a modi- record (EHR) via the Alcohol Use Disorders Identification fier of the association between the rs1344706 genotype and Test-Consumption questionnaire (AUDIT-C) and AUD was de- Cognitive Perceptual schizotypy. Among cannabis users, in- termined by ICD-9/10 diagnostic codes also from the EHR; a dividuals AA showed higher scores in SPQ-CP factor. In ad- blood sample for genetic testing was also obtained. We per- dition, we have also observed that the interaction effect formed a genome-wide association analysis (GWAS) for both followed a relation of dose-effect within AA subjects: the phenotypes in > 350,000 individuals. SPQ-CP scores increase as cannabis use frequency does. Results: Despite a high degree of overlap between the most These results add evidence on that ZNF804A gene is asso- significant SNPs for these traits, further analysis revealed ciated with schizotypy and suggest that the interaction be- distinguishable genetic architectures. The genetic correla- tween cannabis use and the ZNF804A genotype could modu- tion between AUD and AUDIT-C GWAS was significant, but late psychosis proneness. moderate (rg = 0.52, p = 2.4 × 10-43). Cross-trait linkage dis- Acknowledgements: i) Plan Nacional Sobre Drogas, Min- equilibrium (LD) score regression identified significant pos- isterio de Salud (2008/090), ii) ISCIII through de project itive genetic correlations between AUD (but not AUDIT-C) PI15/01420 (co-funded by European Regional Development and several psychiatric phenotypes (e.g., major depressive Fund/European Social Fund) "Investing in your future"), iii) disorder, rg = 0.41; p = 2.2 × 10-20), and significant negative 2014SGR1636, iv) APIF-UB JS and CD16/00264 to MF-V. genetic correlations between AUDIT-C (but not AUD) and both anthropometric and cardiometabolic measures (e.g.,

Disclosure: Nothing to disclose. body mass index, rg = -0.35, p = 3.6 × 10-19; coronary artery doi: 10.1016/j.euroneuro.2018.08.500 disease, rg = -0.21, p = 8.3 × 10-8). Using additional phenotype data from the EHR, we confirmed this dual relationship within the MVP sample. AUD was associated with higher rates of psychiatric, digestive and cardiometabolic phenotypes; AUDIT-C was associated with decreased car- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 73 diometabolic phenotypes, among others. Phenome-wide as- psychiatric, and psychological/personality traits. Increased sociation analysis (PheWAS) further identified significant alcohol consumption frequency was associated with higher pleiotropic effects for many genome-wide significant (GWS) SES and often lower risk of substance use and psychiatric variants. For example, rs13107325 in SLC39A8 increases risk disorders. for AUD and higher AUDIT-C scores (OR = 1.13, Beta = 0.10; Discussion: Although frequency and quantity of alcohol respectively), yet decreases risk for obesity, diabetes, and consumption show substantial overlap in genetic etiology, osteoarthrosis in MVP (OR = 0.91, 0.87, 0.91; respectively). they consistently show opposite pattern of rg in the re- Discussion: Collectively, this work demonstrates that AUD lation with SES-related phenotypes. Future studies should and AUDIT-C phenotypes, despite considerable genetic over- carefully consider the potential influence of SES on the lap, are not wholly congruent. In addition, many of the shared genetic etiology between alcohol and adverse (men- variants associated with one or both traits are highly tal) health outcomes. pleiotropic, which could partly explain the comorbidity of AUD with other psychiatric and medical disorders. Our re- Disclosure: Nothing to disclose. sults are consistent with a model of AUD in which heavy doi: 10.1016/j.euroneuro.2018.08.502 drinking is a necessary, but not sufficient, cause of AUD, and the findings underscore the need to identify variants that contribute uniquely to AUD to fully capture its genetic SU139 basis. GENOME-WIDE ASSOCIATION ANALYSIS OF LIFETIME = Disclosure: Nothing to disclose. CANNABIS USE (N 184,765) IDENTIFIES NEW RISK LOCI, GENETIC OVERLAP WITH MENTAL HEALTH, doi: 10.1016/j.euroneuro.2018.08.501 AND A CAUSAL INFLUENCE OF SCHIZOPHRENIA ON CANNABIS USE

SU138 Joelle Pasman 1, Karin Verweij 2, Eske Derks 3,

SHARING OF GENETIC RISK FACTORS BETWEEN DIFFER- Jacqueline Vink 1 ENT PROXY MEASURES OF ALCOHOL USE DISORDERS

AND RISK OF MENTAL HEALTH DISORDERS 1 Behavioural Science Institute, Radboud University Ni- jmegen

Andries Marees 1, Dirk Smit 2, Jue_Sheng Ong 3, 2 Amsterdam Medical Center

Stuart MacGregor 3, Jiyuan An 3, Damiaan Denys 2, Florence 3 QIMR Berghofer

Vorspan 4, Wim van den Brink 2, Eske Derks 3 Background: Cannabis use is a heritable trait that has been

1 Academic Medical Center, University of Amsterdam associated with adverse mental health outcomes, includ-

2 Academic Medical Center ing schizophrenia. We conducted the largest (N = 184,765)

3 QIMR Berghofer genome-wide association study (GWAS) for lifetime cannabis

4 AP-HP, Hôpital Fernand Widal use to date to provide insight into the genetic architecture of cannabis use. In addition, we explored the genetic asso- Background: Frequency and quantity of alcohol consump- ciation with other mental health phenotypes and the causal tion are metrics commonly used to measure alcohol con- relationship with schizophrenia. sumption behaviors. Epidemiological studies indicate that Methods: We meta-analyzed GWAS data from 3 gen- these alcohol consumption measures are differentially as- eral population cohorts (International Cannabis consortium, sociated with (mental) health outcomes and with levels of N = 35,297; UK-Biobank, N = 126,785; 23andMe, N = 22,683), socio-economic status (SES). The aim of the current study is followed up by gene-based tests. S-PrediXcan analysis was to elucidate to what extent genetic risk factors are shared used to test whether genes had different expression levels between the phenotypes alcohol consumption frequency in cannabis users versus non-users. LD score regression anal- and alcohol consumption quantity, and how these measures ysis was conducted to establish SNP-based heritability and relate to four broad phenotypic categories: (i) SES; (ii) sub- genetic correlations with other phenotypes. Mendelian ran- stance use disorders; (iii) other psychiatric disorders; and domization analysis was applied to test the causal direction (iv) psychological/personality traits. of the association with schizophrenia. Methods: GWA analyses were conducted to test genetic as- Results: We identified 8 genome-wide significant indepen- sociations with alcohol consumption frequency (N = 438,308) dent single nucleotide polymorphisms in 6 regions. All mea- and alcohol consumption quantity (N = 307,098 alcohol sured genetic variants combined explained 11% of the vari- drinkers) within UK Biobank. For the other phenotypes, we ance. Results revealed 35 significant genes in 16 regions, used GWAS summary statistics. Genetic correlations (rg) be- and analyses showed that 21 genes (including in 1 additional tween the alcohol measures and the other phenotypes were region) had different expression levels for cannabis users investigated using LD score regression. versus non-users. The strongest finding across the different Results: We found a substantial genetic correlation between analyses was CADM2. Significant genetic correlations were alcohol consumption frequency and alcohol consumption found with 14 of 25 tested substance use and mental health quantity (rg = 0.54). Frequency and quantity of alcohol traits, including smoking, alcohol use, schizophrenia, and consumption were consistently correlated in opposite risk-taking. Mendelian randomization analysis showed evi- directions with SES traits, and to many substance use, dence for a causal positive influence of schizophrenia risk ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] 74 Abstracts on cannabis use, but no significant evidence for a causal re- 18-45 years, prevalence of ecstasy use almost 10%). With lationship in the other direction. regard to aim 2, longitudinal data were available for around Discussion: In summary, our GWAS of lifetime cannabis use 5,000 participants with information on both licit and illicit revealed significant SNP and genes associations in 16 re- substance use. We calculated polygenic risk scores for gions, 15 of which have not been previously implicated in alcohol, tobacco and cannabis use, based on the summary cannabis use. Our strongest gene finding was CADM2, which statistics from the largest available genome-wide associa- has been associated with substance use, personality and tion meta-analyses to date. Note that for other substance risk-taking in previous studies. Genetic correlations also use phenotypes no large GWA data are available. Therefore, place the cannabis use phenotype within the personality and we explored the association between these polygenic risk mental health domain. The association between cannabis scores and multiple indices of illicit drug use (e.g. ecstasy use and schizophrenia is well investigated, but evidence for use, overall hard drug use). causal relations is still inconclusive. This study provides sup- Results: Preliminary results indicated ecstasy users were port for a causal relationship between schizophrenia and more likely to have used every other substance we investi- cannabis use, which is in line with the self-medication hy- gated, but ecstasy users especially differed from non-users pothesis. Overall, our study gives novel insights about the on illicit substance use. Smoking and alcohol use often pre- etiology of cannabis use and its relation to mental health. ceded first use of ecstasy, while first ecstasy use often preceded first use of other illicit substances. Preliminary results Disclosure: Nothing to disclose. indicate that only the polygenic risk score for cannabis (and not for smoking and alcohol) predicted ecstasy use/illicit doi: 10.1016/j.euroneuro.2018.08.503 drug use. Discussion: In conclusion, the phenotypic association between illicit substances (cannabis, ecstasy) is stronger than

SU140 the association between illicit substances and alcohol and

ILLICIT DRUG USE AND THE GENETIC OVERLAP WITH smoking. The genetic analyses showed there is genetic over- SMOKING, ALCOHOL CONSUMPTION AND CANNABIS lap between cannabis (not alcohol or smoking) and other il- USE licit drug use (ecstasy, others), suggesting a general genetic vulnerability for illicit drug use.

Jacqueline Vink 1, Laura Veul 2, Abdel Abdellaoui 2,

Jouke-Jan Hottenga 3, Dorret Boomsma 3, Karin Verweij 2 Disclosure: Nothing to disclose.

doi: 10.1016/j.euroneuro.2018.08.504 1 Radboud University Behavioural Science Institute

2 Amsterdam Medical Center

3 VU Amsterdam SU141 DECREASED CEREBROPLACENTAL RATIO IS ASSOCIATED Background: Commonly used illegal drugs include cannabis, heroin, cocaine, amphetamine, methamphetamines and WITH BIOLOGICAL AGE DECELERATION: AN EPIGE- club drugs such as ecstasy (MDMA). In the Netherlands, NETIC APPROACH BASED ON A CLINICAL POPULATION cannabis is the most frequently used illicit drugs, with ec- EXPOSED TO OBSTETRIC COMPLICATIONS stasy on the second place. Several attempts have been 1 2 2 made to investigate determinants of ecstasy use, with Helena Palma-Gudiel , Elisenda Eixarch , Fátima Crispi , 3 4 5 mixed results. We know from twin and family studies that Sebastián Morán , Anthony Zannas , Lourdes Fañanás licit and illicit substance use, such as cigarette smoking, alcohol use, lifetime cannabis, and ecstasy use are heritable 1 University of Barcelona, Centre for Biomedical Research traits. Tw i n studies have also indicated that there is genetic Network on Mental Health (CIBERSAM), Instituto de Salud overlap between the use of different substance. Genome- Carlos III, Barcelona wide association studies have successfully identiﬁed (some 2 Fetal i + D Fetal Medicine Research Center, BCNatal of the) genetic variants associated with smoking, alcohol - Barcelona Center for Maternal-Fetal and Neonatal use and cannabis use. Medicine (Hospital Clínic and Hospital Sant Joan de Déu) With methodological advances in molecular genetics and - CIBERER increased sample sizes in GWA studies it has become viable 3 Cancer Epigenetics & Biology Program (PEBC), IDIBELL, to use measured genetic variation among individuals to ex- L’Hospitalet amine the genetic relationship between substances. 4 Max Planck Institute of Psychiatry

Methods: In the present study we will: (1) Compare pro- 5 University of Barcelona, CIBERSAM files of ecstasy users with non-users with regard to (ab)use of other licit and illicit substances to explore phenotypic Background: Exposure to prenatal stress and/or obstet- overlap. (2) Explore the association between polygenic risk ric complications has been reliably associated with a wide scores and multiple indices of illicit drug use (e.g. ecstasy range of complex disorders, including those of a psychiatric use, overall hard drug use). nature. Placental insufficiency and hypoxia alter the blood Data of the Netherlands Tw i n Register will be used. With flow of the umbilical artery (UA) and middle cerebral artery regard to aim 1, a cross-sectional sample is available with (MCA), which can be prenatally measured via Doppler ul- data on ecstasy use and other licit and illicit substance trasound. Both stressors involve a decreased supply of oxy- use consisting of almost 10,000 participants (66,8% female, gen and nutrients to the fetus thus impairing neurodevel- ARTICLE IN PRESS JID: NEUPSY [m6+; October 2, 2018;12:59 ] Abstracts 75 opment. The ratio between both measures, cerebroplacen- SU142 tal ratio (CPR), has been widely used as a risk marker for NORDIC –NORDIC OCD AND RELATED DISORDERS adverse perinatal outcomes such as prematurity, caesarean CONSORTIUM birth and reduced birthweight and Apgar scores, among others. Exposure to adverse prenatal insults has been suggested Julia Boberg 1, James Crowley 2, David Mataix-Cols 1, to mediate long-term deleterious effects on adulthood via Christian Rück 1 epigenetic programming. In this regard, exposure to environmental threats has been hypothesized to accelerate bio- 1 Karolinska Institutet logical aging, which can be measured by means of the epi- 2 University of North Carolina genetic clock.

Methods: Genomic DNA was extracted from cord blood Background: Obsessive compulsive disorder (OCD) is a se- = samples from 30 monochorionic twin pregnancies (n 60). vere psychiatric condition with a prevalence of about 2%.

Genome-wide DNA methylation was analyzed by means OCD is often disabling, increases risk for suicide attempt of the Inﬁnium MethylationEPIC Kit, which measures DNA and has a chronic course if not treated. Genetic and en- methylation at over 850,000 CpG sites across the whole hu- vironmental factors each explain about 50% of variance of man genome. MCA and UA pulsatility index (PI) were mea- OCD in the general population, nevertheless we know very sured by means of Doppler ultrasound before birth (at a little about which speciﬁc genes or environmental factors. mean gestational age of 34 weeks, range: 28 to 36 weeks). 1: Collect the world’s largest richly phenotyped sample

CPR was measured as the ratio between MCA PI and UA PI. of OCD cases

The gestational age epigenetic clock was calculated follow- 2: Discover genomic loci for OCD, OC symptom dimensions ing the script published by Knight and colleagues (2016). and response to psychological and pharmacological treat-

Chronological gestational age at birth was calculated from ment last menstrual period before pregnancy as retrospectively 3: Identify gene ∗environment interactions using genetic, retrieved from clinical databases. Age acceleration was cal- clinical and epidemiological data culated as the epigenetic gestational age minus the chrono- Methods: Participants are adults and children that has been logical gestational age. diagnosed with a DSM-IV or DSM-5 diagnosis of OCD. Partici-

Results: Chronological and epigenetic gestational ages were pants are recruited from twelve specialist clinics in Sweden = < signiﬁcantly correlated (r 0.76; p 0.001). There was and 28 specialist clinics in Norway. no maternal contamination in genomic DNA collected from All participants provide DNA through blood or saliva. Sam- cord blood according to Morin et al. (2017). Increased CPR ples are being stored at the KI biobank. In tailored software was signiﬁcantly associated with gestational age accelera- solutions; Scarab LIMS and ViZu, samples are matched with = = tion (t 3.19; p 0.003) after adjusting for sex, chronolog- data for every individual. + ical gestational age, birthweight, cell types count (CD4 , In addition to DNA, all participants provide routine clinic + CD8 , B cells, NK cells, monocytes, granulocytes and nu- data; OCD symptoms are measured pre and post treatment cleated red blood cells) and the presence of obstetric com- with Y-BOCS/CY-BOCS and OCI-R/OCI-CV. Depression is mea- plications. sured pre and post treatment with MADRS, improvement

Discussion: The association of an obstetric predictor of is measured post treatment with CGI-I, disorder severity perinatal risk reﬂecting both placental insufﬁciency and is measured pre and post with CGI-S, global functioning is prenatal hypoxia with the epigenetic clock-based gesta- measured pre and post with GAF. Data on psychotropic drugs tional age deceleration suggests the critical role of epi- pre and post treatment, heredity for psychiatric disorder, genetic mechanisms in adjusting homeostasis to deal with comorbidity is also available from the clinic. stress. Further longitudinal prospective research focusing Data from the Swedish national registers will provide in- on epigenetic long-term programming of psychiatric pheno- formation about environmental factors such as perinatal types is required to disentangle which genes and pathways complications, smoking during pregnancy, maternal infec- are critically involved in the origin of these disorders and tions, etc. when are they most vulnerable to environmental program- Results: (NA, study description only). ming. Discussion: (NA, study description only).

Disclosure: Nothing to disclose. Disclosure: Nothing to disclose. doi: 10.1016/j.euroneuro.2018.08.505 doi: 10.1016/j.euroneuro.2018.08.506