title: Gene-set and multivariate genome-wide association analysis of oppositional defiant behavior subtypes in attention-deficit/hyperactivity disorder.
abstract: Oppositional defiant disorder (ODD) is a frequent psychiatric disorder seen in children and adolescents with attention-deficit-hyperactivity disorder (ADHD). ODD is also a common antecedent to both affective disorders and aggressive behaviors. Although the heritability of ODD has been estimated to be around 0.60, there has been little research into the molecular genetics of ODD. The present study examined the association of irritable and defiant/vindictive dimensions and categorical subtypes of ODD (based on latent class analyses) with previously described specific polymorphisms (DRD4 exon3 VNTR, 5-HTTLPR, and seven OXTR SNPs) as well as with dopamine, serotonin, and oxytocin genes and pathways in a clinical sample of children and adolescents with ADHD. In addition, we performed a multivariate genome-wide association study (GWAS) of the aforementioned ODD dimensions and subtypes. Apart from adjusting the analyses for age and sex, we controlled for "parental ability to cope with disruptive behavior." None of the hypothesis-driven analyses revealed a significant association with ODD dimensions and subtypes. Inadequate parenting behavior was significantly associated with all ODD dimensions and subtypes, most strongly with defiant/vindictive behaviors. In addition, the GWAS did not result in genome-wide significant findings but bioinformatics and literature analyses revealed that the proteins encoded by 28 of the 53 top-ranked genes functionally interact in a molecular landscape centered around Beta-catenin signaling and involved in the regulation of neurite outgrowth. Our findings provide new insights into the molecular basis of ODD and inform future genetic studies of oppositional behavior. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Forensic Psychiatry, Child and Youth Forensic Service, University Hospital of Psychiatry, Zurich, Switzerland.|Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Aebi
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Marjolein M J
authors.initials: MM
authors.lastname: van Donkelaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Poelmans
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Developmental Brain-Behaviour Laboratory, Department of Psychology, University of Southampton, Southampton, UK.|Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.
authors.forename: Edmund J S
authors.initials: EJ
authors.lastname: Sonuga-Barke
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Argyris
authors.initials: A
authors.lastname: Stringaris
authors.affiliation: Department of Forensic Psychiatry, Child and Youth Forensic Service, University Hospital of Psychiatry, Zurich, Switzerland.
authors.forename: Image
authors.initials: I
authors.lastname: Consortium
authors.affiliation: Department of Psychiatry, SUNY Upstate Medical University, Syracuse, New York.|Departmentof Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.|Department of Biomedicine, K.G. Jebsen Centre for Psychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.|Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.|Department of Psychology, Clinical Psychology and Epidemiology, University of Basel, Basel, Switzerland.|Research Unit for Child and Adolescent Psychiatry, Psychiatric Hospital, Aalborg University Hospital, Aalborg, Denmark.
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Steinhausen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
authors.forename: Kimm J E
authors.initials: KJ
authors.lastname: van Hulzen
mesh_terms: D000293:Adolescent; D000374:Aggression / Q000523:psychology; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000523:psychology; D019958:Attention Deficit and Disruptive Behavior Disorders / Q000235:genetics* / Q000523:psychology*; D002648:Child; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D016487:Parenting / Q000523:psychology; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: GWAS; ODD; irritability; neurite outgrowth; β-catenin