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

Area of Science:

• Neurogenetics
• Psychiatric Disorders
• Genomics

Background:

• Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic basis.
• Previous genome-wide association studies (GWAS) have identified ADHD risk loci primarily in European populations.
• Genetic risk factors, particularly low-frequency/rare variants, are less understood in Asian populations.

Purpose of the Study:

• To investigate the contribution of common and low-frequency/rare variants to ADHD in a Hong Kong Chinese sample.
• To comprehensively analyze the genetic basis of ADHD using multi-omics data and large-scale summary statistics.
• To identify novel genetic risk factors and pathways associated with ADHD in an Asian cohort.

Main Methods:

• Genotyping of 279 ADHD cases and 432 controls using the Illumina Infinium Global Screening Array.
• Application of diverse analytical methods, including polygenic risk score analysis and rare variant association tests.
• Integration of multi-omics data and large-scale summary statistics for comprehensive genetic analysis.

Main Results:

• Identified 41 potential genomic risk loci and 111 candidate risk genes, enriched for those involved in late infancy brain development.
• Implicated the cerebellum and its functional connectivity in attention/central executive networks.
• Found significant associations with common variant risks from European ancestry and identified correlations between ADHD and rare damaging variants in specific genes (TEP1, MTMR10, DBH, TBCC, ANO1).
• Both common and rare variant analyses indicated an association between ADHD genetic risk and immune processes.

Conclusions:

• Re-validated abnormal neural system development in ADHD, extending the neuro-dysfunction hypothesis to a multi-system perspective.
• Identified convergent risk factors from common and low-frequency/rare variants, highlighting vulnerability in late-infancy brain development, particularly involving the cerebellum.
• Highlighted the involvement of immune processes in the genetic etiology of ADHD.