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.
Highlights
Oppositional defiant disorder (ODD) shows strong comorbidity with attention-deficit-hyperactivity disorder (ADHD), conduct disorder (CD), and mood disorders [Angold et al, 1999], in both epidemiological and clinical samples
All dimensions/subtypes were slightly correlated to teacher ratings of oppositionality (CTRS), and moderately correlated to SDQ conduct problems and DSM-IV diagnosis of ODD / CD
We tested specific polymorphisms and genes/genesets that have been previously implicated in aggression/disruptive behavior for their effect on the two dimensions and the two categorical subtypes
Summary
Oppositional defiant disorder (ODD) shows strong comorbidity with attention-deficit-hyperactivity disorder (ADHD), conduct disorder (CD), and mood disorders [Angold et al, 1999], in both epidemiological and clinical samples. Research into ODD has gained momentum due to its relation to later psychopathology such as affective disorders [Copeland et al, 2009] and antisocial personality disorder [Langbehn et al, 1998]. Youths with ADHD frequently show severe impulse control problems and are at high risk for developing ODD. A better understanding of the developmental pathways from ADHD to ODD is crucial to prevent further antisociality and psychopathology. There has been little research on the genetics of ODD, perhaps, because this disorder has been viewed primarily as the result of ineffective parenting [Frick et al, 1992]. The heritability of ODD has been estimated to be around 0.60 [Nadder et al, 1998; Coolidge et al, 2000] and ODD is familial among families of ADHD youth [Petty et al, 2009]
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