Contribution of Intellectual Disability-Related Genes to ADHD Risk and to Locomotor Activity in <i>Drosophila</i>.

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using <i>Drosophila melanogaster</i>. Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in <i>Drosophila</i> by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were <i>MEF2C</i>, <i>ST3GAL3</i>, and <i>TRAPPC9</i>. Performing functional characterization of the two evolutionarily conserved genes in <i>Drosophila melanogaster</i>, the authors found that their knockdown in dopaminergic (<i>dMEF2</i>) and circadian neurons (<i>dTRAPPC9</i>) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified <i>TRAPPC9</i>, <i>MEF2C</i>, and <i>ST3GAL3</i> as novel ADHD candidate genes. Characterization in <i>Drosophila</i> suggests that <i>TRAPPC9</i> and <i>MEF2C</i> contribute to ADHD-related behavior through distinct neural substrates.