Meta-analysis of Genome wide Association Studies on Childhood ADHD Symptoms and Diagnosis Reveals 17 Novel Loci and 22 Potential Effector Genes

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder for which genetic factors explain up to 75% of the variance. In this study, we performed a genome-wide association meta-analysis (GWAMA) of ADHD symptom measures, with an effective sample size of 120,092 (71,733 unique individuals from 28 population-based cohorts, with 288,887 quantitative ADHD symptom measures). Next, we meta-analyzed the results with a genome-wide association study (GWAS) of ADHD diagnosis. The GWAMA of ADHD symptoms returned no genome-wide significant variants. However, we estimated strong genetic correlations between our study of quantitative ADHD symptoms and the earlier study of ADHD diagnosis (r!= 1.00, SE= 0.06). Moderate negative genetic correlations (r! < -0.40) were observed with several cognitive traits. Genetic correlations between ADHD and aggressive behavior and antisocial behavior were around 1. This provides further evidence of the wide pleiotropic effects of genetic variants and the role that genetic variants play in the co-occurrence with (mental) health traits. The GWAMAs of ADHD symptoms and diagnosis identified 2,039 genome-wide significant variants, representing 39 independent loci, of which 17 were new. Using a novel fine-mapping and functional annotation method, we identified 22 potential effector genes which implicate several new potential biological processes and pathways that may play a role in ADHD. Our findings support the notion that clinical ADHD is at the extreme end of a continuous liability that is indexed by ADHD symptoms. We show that including ADHD symptom counts in large-scale GWAS can be useful to identify novel genes implicated in ADHD and related symptoms.