Investigating the shared genetic architecture between inflammatory bowel disease and pancreatitis: a genome-wide cross-trait analysis.

Epidemiological studies suggested comorbidity between inflammatory bowel disease (IBD) and pancreatitis. However, little is known about their shared genetic architecture. Based on genome-wide association studies (GWAS), we utilized Mendelian randomization (MR) method to investigate the causal relationships between IBD (including ulcerative colitis (UC) and Crohn's disease (CD)) and pancreatitis (including acute pancreatitis (AP) and chronic pancreatitis (CP)). Cross-trait meta-analysis was performed to detect pleiotropic loci between them. The heritability enrichment analysis was conducted to detect their shared disease-associated cell types. TWAS (transcriptome-wide association studies) was used to localize pancreatitis-associated genes in the intestine. MR suggested that UC has a positive causal effect on AP in European populations but CP in East Asian populations. Cross-trait meta-analysis identified 71 SNPs between IBD and pancreatitis. Among those, SNPs within the human Major Histocompatibility Complex (MHC) region are strongly enriched in dendritic cell differentiation pathway. Two SNPs outside of the MHC region were rs1260326 and rs117770045. The proxy SNP of rs117770045 was located on a pancreas exocrine-specific enhancer regulating TRPV6 and also associated with the T cell receptor beta genes. Colocalization analysis revealed that rs1265098 (MHC region) was colocalized among IBD, pancreatitis, and gut microbiota Ruminiclostridium 9. Heritability enrichment demonstrated that IBD and pancreatitis are both associated with dendritic cells. TWAS indicated that SPINK5 in the intestine was associated with pancreatitis. Our findings identify genetic risk-sharing loci and convergent immune pathways linking IBD and pancreatitis.