The Role of Ultra-Rare Coding Variants In ADHD

Abstract

Attention-Deficit Hyperactivity Disorder (ADHD) is a highly heritable childhood behavioural disorder affecting 3-6% of school-age children, and has a heritability of around 0.80. The SNP heritability, estimating the amount of risk attributed to common genetic variation, has been estimated to 0.22. The difference between SNP heritability and total heritability indicates that the genetic component of ADHD most likely also includes effects of rare variants. The role of ultra-rare deleterious variants has been established for schizophrenia and autism, but the role of these variants in ADHD remains unknown.Here we present results from whole exome sequencing of two cohorts of ADHD cases and controls. A Danish cohort consisting of samples identified in the Danish Newborn Screening Biobank (DNSB) consisting of ~3,170 ADHD cases and ~6,100 controls, and a sample consisting of ~1,200 clinical ascertained ADHD cases from Germany and the Netherlands, and a control group of ~3,000 individuals with German, Dutch and Danish ancestries, giving a grand total of 7,542 cases and 9,100 controls.Preliminary results from the analysis of the DNSB ADHD cohort demonstrate a significant overrepresentation of ultra-rare deleterious variants in evolutionary constrained genes in cases compared to controls (P = 8.21x10-10). We will present results from analyses of the impact of ultra-rare deleterious variation on ADHD risk based on the full sample of ADHD cases and controls. We will especially focus on the burden of these variants in ADHD cases compared to controls in highly evolutionary constrained genes as well as specific gene-sets relevant to ADHD, e.g. “synaptic genes”, “neurite outgrowth genes”, “genes bound by the fragile X mental retardation gene FMRP” and “genes with high brain expression”. Furthermore, we will evaluate, whether ADHD risk genes identified based on common variant analyses also carry an increased burden of ultra-rare deleterious variants, and conduct gene-based association analyses to identify top-ranking genes most frequently hit by rare deleterious variants in ADHD cases compared to controls.