Investigating shared genetic architecture between inflammatory bowel diseases and primary biliary cholangitis

Background&Aims: Inflammatory bowel disease (IBD) is commonly associated with extraintestinal complications, including autoimmune liver disease. The co-occurrence of IBD and primary biliary cholangitis (PBC) has been increasingly observed, but the underlying relationship between the two conditions remains unclear.MethodsUsing genome-wide association studies (GWAS) summary statistics, we investigated the causal effect between PBC and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). We also analyzed the shared genetic architecture between IBD and PBC using data from GWAS, bulk tissue RNA sequencing, single-cell RNA sequencing, and explored potential functional genes.ResultWe found a strong positive genetic correlation between PBC and IBD (LDSC: rg =0.2249, P = 3.38 × 10-5). Cross-trait analysis yielded 10 shared risk SNPs, as well as 9 novel SNPs, that were associated with both traits. Using Mendelian randomization, we established a stable causal effect of PBC on IBD. Genetically predicted PBC was found to have a risk effect on IBD (1.105[95% confidence interval (CI): 1.058-1.15], P = 1.16 x 10−10) but not vice versa. We identified shared tissue-specific heritability enrichment for PBC and IBD (including CD and UC) in lung, spleen, and whole blood samples. Furthermore, we observed shared enrichment of specific cell types (T cells, B cells, and NK cells) and their subtypes. 9 functional genes were identified base on SMR.ConclusionOur study detected shared genetic architecture between IBD and PBC and demonstrated a stable causal relationship of genetically predicted PBC on the risk of IBD. These findings shed light on the biological basis of comorbidity between IBD and PBC, and have important implications for intervention and treatment targets of these two diseases simultaneously.