Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10^-10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h²_SNP = 0.34) when compared to ADHD without DBDs (h²_SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (r_g = 0.81) and anti-social behaviors (r_g = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

Fig. 1. Manhattan plot and quantile–quantile plot of results from the GWAS meta-analysis of ADHD + DBDs.

A Results from GWAS meta-analysis of iPSYCH and PGC cohorts in total including 3802 cases and 31,305 controls. The x-axis represents autosomal chromosomes colored in light and dark blue. The y-axis represents two-sided P-values from meta-analysis using an inverse-variance weighted fixed effects model. The red horizontal line represents the threshold for genome-wide significant association (P = 5 × 10⁻⁸). B Quantile–quantile (q–q) plot with expected −log10 P-values on the x-axis and −log10 P-values from the GWAS meta-analysis on the y-axis. The dotted line indicates the distribution under the null hypothesis.

Fig. 2. Forest plot for the index variant in the genome-wide significant locus for ADHD + DBDs on chromosome 11.

Forest plot for the index variant (rs7118422) in the genome-wide significant locus on chromosome 11. Visualization of the effect size estimates (natural logarithm of the odds ratio (ln(OR)) in each included cohort, estimated from logistic regression, and in the trans-ancestry GWAS meta-analysis of European and Chinese cohorts (4208 cases and 32,222 controls) using an inverse-variance weighted fixed effects model. In addition, standard errors of the ln(OR) estimates. For information on sample sizes, allele frequencies and P-values for rs7118422 in the single cohorts see Supplementary Data 1.