Genome-Wide Significant LOCI Identified In Attention Deficit Hyperactivity Disorder And Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are both highly heritable childhood onset neurodevelopmental disorders affecting, respectively, around 1% and 5% of the population. A number of moderately sized genome-wide association studies (GWASs) have been performed but until now no genome-wide significant (GWS) loci have been robustly identified in either of the disorders. However, the estimated SNP heritability is relatively high in both disorders, indicating that common SNPs contribute substantially to the susceptibility and that increasing GWAS sample sizes is likely to yield significant results.Here we present large GWAS meta-analyses that identify the first robustly associated GWS loci in both ADHD and ASD. These studies are based on collaboration between the Danish iPSYCH initiative (The Lundbeck Foundation Initiative for Integrative Psychiatric Research), the Broad Institute, and the Psychiatric Genomics Consortium (PGC). The ADHD study included nine PGC samples (totaling ∼4,400 cases and ∼10,300 controls) and the iPSYCH sample (∼14,500 cases and ∼22,400 controls), resulting in a grand total of ∼18,900 cases and ∼32,700 controls. In ASD a total of ∼20,400 cases and ∼31,200 controls were included (iPSYCH: ∼13,000 cases and ∼22,600 controls; PGC: ∼7,400 cases and ∼8,600 controls).Ten loci surpassed the genome-wide significance level in ADHD and three in ASD. Gene-based analysis identified several significantly associated genes, some of which are located outside the GWS loci. Using LD score regression, significant enrichment in the heritability of central nervous system specific annotations was found. Additional information on potential functional effects was obtained by PrediXcan and MetaXcan analyses identifying differences in gene expression between cases and controls in various brain tissues. Finally, genetic correlation estimates using summary statistics from GWASs of childhood intelligence and educational attainment found correlations of opposite direction for ADHD (negative) and ASD (positive). The presented results represent a substantial progress in our understanding of the genetic architecture of ADHD and ASD, revealing new information on the underlying biology.