Multi-tissue transcriptome-wide association study identifies 29 risk genes associated with attention-deficit/hyperactivity disorder

Abstract

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a common heritable neurodevelopmental disorder, affecting [~]7 million children (11.4%) in the U.S. However, ADHDs underlying genetic architecture remains largely unknown. Transcriptome-wide association studies (TWAS), which integrate expression quantitative trait loci (eQTL) and GWAS summary data, can identify differentially expressed risk genes underlying complex phenotypes. Here we conduct a TWAS of ADHD using expression data from multiple brain tissues to improve understanding of the complex genetic architecture underlying this psychopathology. MethodsWe applied the TWAS framework OTTERS to train multiple gene expression imputation models using cis-eQTL summary statistics from MetaBrain for three brain regions: cortex (n=2,683), basal ganglia (n=208), and cerebellum (n=492), and GWAS summary statistics from the most recent meta-analysis of ADHD (n=225,534; case fraction =0.17). We further conducted fine-mapping, colocalization analysis, and functional enrichment analysis. ResultsWe identified 29 significant TWAS risk genes for ADHD (11 in cortex, 4 in basal ganglia, and 14 in cerebellum). Six genes appear novel for ADHD (MPL, C1orf210, MDFIC, NKX2-2, FAM183A, HIGD1A) while four genes were previously implicated in autism spectrum disorder (XRN2, KIZ, NKX2-4, NKX2-2). Pathway analysis indicated cortex and basal ganglia were enriched for neurodevelopmental pathways and regulation of cell development, and the protein-protein interaction network was statistically significant (p=1.12E-04). ConclusionThis multi-tissue TWAS refines the genetic architecture of ADHD by identifying genes whose genetically regulated expression is associated with risk, including six candidates not previously linked to ADHD. Together, these findings provide novel insights for potential targets in translational research and drug discovery.