Genome-wide association analysis in sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.
Approximately 60-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the purpose of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases and 2,977 controls and followed up top association signals in additional 1,012 PSC cases, 4,444 UC cases and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 rs3749171 at GPR35; P=3.010(-9) in the overall study population, combined odds ratio (OR; 95% confidence interval (CI)) of 1.39 (1.24-1.55), and at 18q21 rs1452787 at TCF4; P=2.6110(-8) , OR (95% CI) = 0.75 (0.68-0.83). In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, while TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2012.).