Joint analysis of genome‐wide cross‐trait and multi‐omics reveals molecular mechanisms of inflammatory bowel disease and nominates its novel therapeutic genes

Abstract Inflammatory bowel disease (IBD) with the two predominant endophenotypes—Crohn's disease (CD) and ulcerative colitis (UC)—represents a group of chronic gastrointestinal inflammatory conditions. Since most genetic associations with IBD are often limited to independent subtypes, we reported a genome‐wide association study (GWAS) cross‐trait analysis combined with CD and UC to enhance statistical power. Initially, we detected 256 association signals at 54 genomic susceptibility loci and further characterized the functionality of variants within these regions. Subsequently, we revealed tissue and cell‐specific heritability enrichment, particularly in whole blood, small intestine terminal ileum, spleen, lung, and colon transverse. Leveraging multi‐omics datasets, we adopted a two‐pronged approach comprising summary data‐based Mendelian randomization (SMR) and transcriptome‐wide association study (TWAS) to pinpoint likely causal genes and variants. Further, RNA‐seq analysis facilitated the evaluation of differential expression and co‐expression in intestinal tissues. Through a multi‐stage prioritization strategy, compelling evidence for putative targets was nominated; notably highlighting several potential susceptibility genes such as IL27 and SBNO2 . Finally, we utilized Mendelian randomization (MR) analysis with diverse datasets to verify the convergence of these two endophenotype‐driven genes. Our investigation yields valuable insights to inform genetic mechanisms in IBD and reveal potential causal gene targets.