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

Background Attention-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. Methods Here, 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. Results We 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 in TEP1 , MTMR10 , DBH , TBCC, and ANO1 . ADHD genetic risk was associated with immune processes, demonstrated in both common and rare variant analyses. Conclusions These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective.