Identification of Genetic Risk Factors For Conduct Disorder/Oppositional Defiant Disorder In The Context of ADHD

Abstract

Abstract Conduct Disorder (CD) is a childhood psychiatric disorder characterised by a persistent pattern of antisocial rule-breaking behaviours. The disorder is a common childhood psychiatric disorder with a prevalence of 3.2% across cultures around the world, with a higher occurrence in males compared with females (4:1). Both environmental and genetic factors influence the risk of CD. The genetic risk component is high with heritability estimates ranging from 40-70%. Additionally, CD is highly comorbid with ADHD and in Denmark 26% of the CD cases born after 1981 are also diagnosed with ADHD. Despite the strong evidence for genetic risk factors underlying CD, only a limited number of hypothesis free studies have aimed to identify genetic variants involved in the disorder, and one genome-wide significant locus have been reported, however this finding was based on a rather small sample comprising only 872 cases and 3091 controls. Additionally, the polygenic risk score (PRS) based on ADHD risk SNPs was found to be particularly elevated in individuals diagnosed with both ADHD and CD compared to those who only had ADHD. Here we will present results from the largest genome-wide association study (GWAS) of CD/Oppositional Defiant Disorder (ODD) (ICD10 F91.x diagnosis), in the context of ADHD based on 1,967 cases genotyped as a part of the large Danish iPSYCH sample consisting of more than 78,000 genotyped individuals. Furthermore, ADHD cohorts collected by the Psychiatric Genomics Consortium with available information about CD/ODD will be included in a GWAS meta-analysis. Additionally, we will present results from secondary analyses of CD/ODD in the context of ADHD including heritability estimates, gene-based and gene-set/pathway association analyses and association analysis of the genetically imputed gene-expression using PrediXcan and/or MetaXcan. Moreover, we will evaluate previous findings that suggest increased polygenic burden in ADHD individuals comorbid with CD/ODD compared to cases with ADHD alone. This will be done based on analyses of polygenic risk scores (PRS) for ADHD in our sample.