Genetic architecture of primary sclerosing cholangitis: shared pathways with inflammatory bowel disease and gut–liver axis mediation

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease strongly linked to inflammatory bowel disease (IBD), yet its causal genetic drivers and the mechanisms underlying this comorbidity remain poorly understood. This study aimed to identify causal genes for PSC and elucidate the role of the gut-liver axis in its pathogenesis. Methods: We performed a multi-omics study integrating transcriptome-wide association studies (TWAS), summary Mendelian randomization (SMR), and colocalization using PSC GWAS data (2871 cases; 12 019 controls) and tissue-specific eQTL data. Bidirectional Mendelian randomization (MR) was employed to dissect causal relationships between identified genes, PSC, IBD, gut microbiota, and metabolites. Results: Seven genes were prioritized as potential causal targets for PSC: MMEL1, FUT2, PRKD2, C4A, HLA-DMA, VARS2, and RPL23AP1, with evidence supported by colocalization and expression in relevant immune and intestinal tissues. Bidirectional MR confirmed a causal link from IBD to PSC and identified shared genetic pathways. Crucially, MR analysis provided causal evidence for the role of specific gut microbiota in PSC risk, including increased risk with higher abundance of Clostridium and Veillonella . Mediation analyses further implicated FUT2 and HLA-DMA in modulating PSC risk via the gut microbiota, particularly through taxa such as Clostridium, Butyrivibrio crossotus , and Rhodospirillaceae . Conclusion: This study delineates PSC’s genetic architecture by identifying novel causal genes and confirms the gut-liver axis’s central role in its pathogenesis. We propose an integrated “dual-hit” model where host genetic susceptibility constitutes the “first hit” and subsequent gut dysbiosis acts as a “second hit.” These findings offer novel therapeutic targets and a mechanistic framework with potential implications for patient management in liver transplantation.