Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Abstract

AbstractAttention deficit hyperactivity disorder (ADHD) is a prevalent childhood psychiatric disorder, with a major genetic component. Here we present a GWAS meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, which is more than twice the number previously reported. Fine-mapping risk loci highlighted 76 potential risk genes enriched in genes expressed in brain, particularly the frontal cortex, and in early brain development. Overall, ADHD was associated with several brain specific neuronal sub-types and especially midbrain dopaminergic neurons. In a subsample of 17,896 exome-sequenced individuals, we identified increased load of rare protein-truncating variants in cases for a set of risk genes enriched with likely causal common variants, suggesting implication of SORCS3 in ADHD by both common and rare variants. We found ADHD to be highly polygenic, with around seven thousand variants explaining 90% of the SNP heritability. Bivariate gaussian mixture modeling estimated that more than 90% of ADHD influencing variants are shared with other psychiatric disorders (autism, schizophrenia and depression) and phenotypes (e.g. educational attainment) when both concordant and discordant variants are considered. Additionally, we demonstrated that common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions including attention.