Large-scale multi-trait genome-wide analysis for inflammatory bowel disease reveals new insights into its molecular mechanisms and emphasizes the roles of systemic immune regulation.

Inflammatory bowel disease (IBD) is a hereditary and chronic inflammatory condition affecting the gastrointestinal tract, with two main subphenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Most IBD-related genetic associations are limited to independent subphenotypes and ancestral populations, and the heritability remains largely unexplained, prompting us to conduct the large-scale multi-trait genome-wide association study (GWAS) meta-analysis that incorporates both subphenotypes and diverse ancestral populations to reveal novel susceptibility loci through the substantially enhanced genetic discovery power. We initially identified IBD statistical association signals at 84 (12 novels) independent index loci by two-stage multi-trait analysis of GWAS and increased the number to 165 (29 novels) in cross-ancestry meta-analysis. Subtype-specific analysis revealed distinct genetic architectures for CD and UC. Leveraging multi-omics datasets, we performed a comprehensive functional post-GWAS annotation. Several therapeutic targets were identified by a multi-stage prioritization strategy, including JAK2, STAT3, IL18R1, IFNG, and CCL2, highlighting systemic immune regulation in IBD treatment. In the inflammatory injury model, we determined that increased GNA12 expression may disrupt the intestinal barrier. Cross-trait analyses and multi-omics Mendelian randomization showed potential causalities with immune-mediated diseases, cytokines, cell traits, and microorganisms. This study yields novel insights into the molecular etiology of IBD and reveals potential immunotherapy targets and pathways for medication.