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

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with high heritability. A total of 27 genome-wide significant loci for ADHD were previously identified through genome-wide association studies (GWASs), but the identification of risk genes that confer susceptibility to ADHD has remained largely unexplored.

Method: As 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).

Results: Our 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 gene-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.

Conclusion: Overall, 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 that we identified in this study can serve as a valuable resource for further investigation of the disease mechanisms underlying ADHD.