Integrative multi-omics analysis reveals GLP-1R agonists-driven proteins via Notch signaling as mediators of ulcerative colitis risk

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used to treat type 2 diabetes mellitus, yet their potential association with autoimmune diseases remains unclear. To systematically evaluate the effect of GLP-1RAs on autoimmune disease susceptibility, we implemented a multi-omics Mendelian randomization framework integrating genomics, transcriptomics, epigenomics, and proteomics data. Utilizing the cross-cohort molecular quantitative trait loci (molQTLs) of the GLP-1R gene as a genetic proxy for GLP-1RA exposure, we identified a significant increase in the risk of inflammatory bowel disease, particularly for the ulcerative colitis subtype, but not for Crohn's disease or other autoimmune diseases. The lead cis-eQTL rs9283907 was identified as a regulatory variant likely influencing GLP-1R expression and was also established as a shared causal variant for both GLP-1R expression and inflammatory bowel disease/ulcerative colitis risk. Furthermore, the expression level of GLP-1R was significantly altered in colon tissue from ulcerative colitis patients, with single-cell resolution revealing its specific enrichment in intestinal stem cells. Mediation analysis indicated that the effect of GLP-1RAs on ulcerative colitis risk was largely mediated by proteins such as DLL4 via the Notch signaling pathways. This study provides the first genetic evidence that GLP-1RAs may elevate ulcerative colitis risk through specific molecular mechanisms, offering valuable insights for clinical drug safety assessment.