Statistical colocalization identifies twenty-four novel risk loci associated with disease risk of primary biliary cholangitis

Genome-wide association (GWA) studies of primary biliary cholangitis (PBC) have identified more than 60 risk loci for the disease. Causal variants and candidate genes at those loci remain obscure, however, limiting biological insight. We sought to address this limitation using statistical colocalisation. Accordingly, we applied coloc and HyPrColoc to summary statistics from the genome wide meta-analysis (GWMA) of PBC by Cordell et al. (2021); GWA studies of 15 other immune mediated inflammatory diseases; and GWA studies of DNA methylation, gene expression, and plasma proteins, respectively, focusing on loci with at least suggestive evidence of association with PBC (P <1×10–5). For each locus and each trait, we determined the likelihood that PBC and the other trait share a common association signal; defined a credible set of variants which could account for that shared association; and, for each variant in the credible set, determined its probability of being the single causal variant at that locus. We used colocalisation with methylation, expression, or protein quantitative trait loci to prioritize candidate genes for in silico drug efficacy screening. We found robust evidence of colocalization (PP3+PP4 ≥0.7) at 74 loci, including 24 loci with only suggestive evidence of association (5×10–8

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