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(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 (WCPG): Poster Abstracts: Sunday Sunday, October 14, 2018 with a 2kb upstream and 1kb downstream region was consid- ered 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 re- mained 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
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