Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.

Authors:
David Ellinghaus, Trine Folseraas, Kristian Holm, Eva Ellinghaus, Espen Melum, Tobias Balschun, Jon K Laerdahl, Alexey Shiryaev, Daniel N Gotthardt, Tobias J Weismüller, Christoph Schramm, Michael Wittig, Annika Bergquist, Einar Björnsson, Hanns-Ulrich Marschall, Morten Vatn, Andreas Teufel, Christian Rust, Christian Gieger, H-Erich Wichmann, Heiko Runz, Martina Sterneck, Christian Rupp, Felix Braun, Rinse K Weersma, Cisca Wijmenga, Cyriel Y Ponsioen, Christopher G Mathew, Paul Rutgeerts, Séverine Vermeire, Erik Schrumpf, Johannes R Hov, Michael P Manns, Kirsten M Boberg, Stefan Schreiber, Andre Franke, Tom H Karlsen
Year of publication:
2013
Volume:
58
Issue:
3
Issn:
0270-9139
Journal title abbreviated:
HEPATOLOGY
Journal title long:
Hepatology : official journal of the American Association for the Study of Liver Diseases
Impact factor:
11.711
Abstract:
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 aim 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 an 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 G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-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, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.