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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by a General Research Fund (GRF) of the Hong Kong Research Grants Council (RGC) (RGC 449511). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Joint Chinese University of Hong Kong-New Territories East Cluster, the Hospital Authority Kowloon Central and Kowloon West Cluster Clinical Research Ethics Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors