Rare Comorbidity between Inflammatory Bowel Disease and Primary Biliary Cholangitis: Evidence from Causality, Shared Genetic Architecture and Transcriptomics

BackgroundClinical studies have found comorbidity between Inflammatory Bowel Disease (IBD) and primary sclerosing cholangitis (PSC). Primary biliary cholangitis (PBC) is another autoimmune liver disease but the coexistence of IBD and PBC is rare. Whether there exists comorbidity between IBD and PBC and potential mechanism remains unclear. MethodsWe assessed the casual effect between PBC and IBD, i.e., Crohn Disease (CD) and Ulcerative Colitis (UC) independently based on genome-wide association studies (GWAS) summary statistics. By leveraging data from GWAS data, Bulk tissue RNA sequencing (bulk RNA-seq) data, and Single-cell RNA sequencing (scRNA-seq) dataset, we investigated the shared genetic architecture between IBDs and PBC. The transcriptomic expressions of shared genes were explored in patients with IBD (intestinal biopsies) and PBC (peripheral CD4+ T cells). ResultWe found a bidirectional causal relationship for PBC and IBDs using Mendelian randomization. The IBDs had been considered as the protective factors on PBC (0.87[95% confidence interval (CI): 0.81-0.93], P = 8.72e-5, vice versa (0.91[95% CI: 0.81-0.93], P = 2.65e-09). We find a consistent negative genetic correlation between PBC and IBD (LDSC: rg = -0.2245, P = 2.89e-5). Cross-trait analysis yielded 9 shared risk SNPs and 7 nearest genes. In transcriptome analysis, we observed significant (P < 0.05) differences expression in intestinal biopsies (PGAP3 and DENND1B) and in peripheral CD4+ T cells (PTPN11 and PNMT). We identified shared tissue-specific heritability enrichment for PBC and IBD (including CD not UC) in lung, spleen and cells EBV-transformed lymphocytes and identified shared cell type-level enrichment for IBD, CD and PBC in type 1 dendritic cells, natural killer cells, CD8+ cytotoxic T lymphocytes in lung and activated CD8+ T cell in spleen. ConclusionOur study indicates that IBD and PBC are protective factors for each other and shared genetic architecture may contribute to the negative genetic correlation. These findings may explain the rare comorbidity between IBD and PBC.