Rare Variant Analyses in Ancestrally Diverse Cohorts Reveal Novel ADHD Risk Genes

2025/01/17 by Seulgi Jung, Madison Caballero, Emily Olfson +3 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · Environmental Science · #Attention Deficit Hyperactivity Disorder #Genetics and Neurodevelopmental Disorders #Health, Environment, Cognitive Aging

paper · pdf · doi:10.1101/2025.01.14.25320294

openalex publication_date 2025/01/17 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, but its genetic architecture remains incompletely characterized. Rare coding variants, which can profoundly impact gene function, represent an underexplored dimension of ADHD risk. In this study, we analyzed large-scale DNA sequencing datasets from ancestrally diverse cohorts and observed significant enrichment of rare protein-truncating and deleterious missense variants in highly evolutionarily constrained genes. This analysis identified 15 high-confidence ADHD risk genes, including the previously implicated KDM5B . Integrating these findings with genome-wide association study (GWAS) data revealed nine enriched pathways, with strong involvement in synapse organization, neuronal development, and chromatin regulation. Protein–protein interaction analyses identified chromatin regulators as central network hubs, and single-cell transcriptomic profiling confirmed their expression in neurons and glial cells, with distinct patterns in oligodendrocyte subtypes. These findings advance our understanding of the genetic architecture of ADHD, uncover core molecular mechanisms, and provide promising directions for future therapeutic development.

Citations

• Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3
• Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
• The mutational constraint spectrum quantified from variation in 141,456 humans
• Rare coding variants in ten genes confer substantial risk for schizophrenia
• Mapping genomic loci implicates genes and synaptic biology in schizophrenia
• Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
• The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest
• Accurate proteome-wide missense variant effect prediction with AlphaMissense
• Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes

Discussions

• A second study analysed over 8K cases and 1049 trios from a more diverse cohort (NFE, AFR, AMR) and found EP400 to have a higher burden of damaging variants in AFR vs NFE - after adjusting for ancestr [bsky, 0 points, 1 comments]