Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies

Abstract

Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression and functional studies, and applied network-based analytics in search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential- and hub-genes. In addition to disease-specific modules, we found a substantial overlap of disease neighborhoods, and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing STAT3, IL6, TNF and FOXP3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the AGE-RAGE pathway, and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC and PSC. This article is protected by copyright. All rights reserved.

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