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.

Keywords: GWAS; ODD; irritability; neurite outgrowth; β-catenin.

Figure 1

Mean scores of dichotomized items of the Conners parent scale (CPRS‐R:L) oppositional scale assessing irritable (IRR1‐IRR4), and defiant/vindictive (DV1–DV6) behaviors as a function of latent classes for children and adolescents with ADHD combined type (N = 750). OPP, oppositionality.

Figure 2

Top: Manhattan plot of multivariate GWAS including ODD subtypes P1 (defiant vindictive), P2 (irritable), P3 (0 representing “low OPP/moderate OPP” and 1 representing “irritability/severe OPP”), and P4 (0 representing “low OPP/moderate OPP/irritability” and 1 representing “severe OPP”). Bottom: Top four regions (indicated by arrows in the manhattan plot) containing SNPs showing association at P < 1.00E‐5 in the multivariate GWAS. Top SNPs for each region are depicted in purple; rs7204436 on chromosome 16 (P = 1.98E‐07), rs1278352 on chromosome 10 (P = 1.24E‐06), rs12370275 on chromosome 12 (P = 2.41E‐06), and rs6060960 on chromosome 20 (P = 3.00E‐06). OPP, oppositionality.

Figure 3

Neurite outgrowth‐regulating molecular landscape implicated in ODD. The evidence linking the molecules in the landscape to neurite outgrowth can be found in the Supplementary Information.