Multi-ancestry genome-wide and transcriptome-wide association analyses identify new risk loci and genes for inflammatory bowel disease

To advance genetic understanding of inflammatory bowel disease (IBD), we conduct multi-ancestry genome-wide association studies (GWAS) meta-analyses of 63,415 cases of Europeans and East Asians, and identified 60 previously unreported susceptibility loci. Integrating multi-ancestry transcriptome-wide association studies (TWAS), cell type-specific TWAS, alternative splicing, and alternative polyadenylation analyses using RNA-sequencing data from normal colon tissues of 707 Europeans and 364 East Asians, we identify 441 candidate risk genes, including 324 not previously implicated by GWAS or TWAS, of which 291 were further supported by colocalization or summary-data-based Mendelian randomization analyses. These genes converge on pathways central to IBD pathogenesis (e.g., immune regulation), with over half showing transcriptional dysregulation supported by single-cell and spatial omics analyses. We further identify 44 druggable genes linked to 221 approved drugs or Phase II/III clinical-stage compounds. Our findings deepen the understanding of IBD genetics and provide insights for future research relevant to precision medicine for IBD.