Identification of Risk Genes for Attention-Deficit/Hyperactivity Disorder During Early Human Brain Development

Abstract

ObjectiveAttention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with high heritability. Demontis et al. (2023) identified 27 genome-wide significant loci for ADHD through genome-wide association studies (GWASs), but the identification of risk genes that confer susceptibility to ADHD has remained largely unexplored. MethodAs ADHD is a neurodevelopmental disorder, we integrated human brain prenatal gene and transcript expression weight data (n=120) and ADHD GWAS summary statistics (n=225,534; 38,691 cases and 186,843 controls) to perform a transcriptome-wide association study (TWAS) by FUSION (an analytic suite). ResultsOur analysis identified 10 genes, including LSM6, HYAL3, METTL15, RPS26, LRRC37A15P, RP11-142I20.1, ABCB9, AP006621.5, AC000068.5, and PDXDC1, that are significantly associated with ADHD, along with 8 transcripts of 7 genes. We also conducted TWAS analysis using CommonMind Consortium (CMC) adult brain gene and splicing expression weights (n=452), which highlighted several risk genes that showed associations with ADHD in both prenatal and postnatal stages, such as LSM6 and HYAL3. ConclusionOverall, our TWAS of ADHD, by integrating human prenatal brain transcriptome and ADHD GWAS results, uncovered the cis-effects of gene/transcript regulation that are predicted to be associated with ADHD. By combining colocalization and FOCUS fine-mapping analysis, we further unraveled potential causal candidate risk genes. The risk genes/transcripts we identified in this study can serve as a valuable resource for further investigation of the disease mechanisms underlying ADHD.