Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD

Abstract

AbstractBackgroundAttention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component, characterized by persistent symptoms of inattention, hyperactivity, and/or impulsivity. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for rare variants.MethodsHere, we present an analysis of common and rare variant contributions to ADHD in a Hong Kong sample comprising 279 cases and 432 controls, who were genotyped using the Illumina Infinium Global Screening Array.ResultsWe identified 41 potential genomic risk loci with a suggestive association (p< 1e−4), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum.POC1B, a gene previously found in a genome-wide significant locus of ADHD in the European population, was replicated in the current study, potentially implicating a trans-ancestral effect in ADHD. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks, which is consistent with the neural pathophysiology for ADHD. In rare variant analyses, we discovered that ADHD cases carried an elevated load of rare damaging variants inTEP1,MTMR10,DBH,TBCC,andANO1. ADHD genetic risk was associated with immune processes, demonstrated in both common and rare variant analyses.ConclusionsThese findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective.