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Genome‐wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4
Author(s) -
Ellinghaus David,
Folseraas Trine,
Holm Kristian,
Ellinghaus Eva,
Melum Espen,
Balschun Tobias,
Laerdahl Jon K.,
Shiryaev Alexey,
Gotthardt Daniel N.,
Weismüller Tobias J.,
Schramm Christoph,
Wittig Michael,
Bergquist Annika,
Björnsson Einar,
Marschall HannsUlrich,
Vatn Morten,
Teufel Andreas,
Rust Christian,
Gieger Christian,
Wichmann HErich,
Runz Heiko,
Sterneck Martina,
Rupp Christian,
Braun Felix,
Weersma Rinse K.,
Wijmenga Cisca,
Ponsioen Cyriel Y.,
Mathew Christopher G.,
Rutgeerts Paul,
Vermeire Séverine,
Schrumpf Erik,
Hov Johannes R.,
Manns Michael P.,
Boberg Kirsten M.,
Schreiber Stefan,
Franke Andre,
Karlsen Tom H.
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25977
Subject(s) - genome wide association study , primary sclerosing cholangitis , odds ratio , ulcerative colitis , single nucleotide polymorphism , genetic association , inflammatory bowel disease , biology , genetics , medicine , genotype , disease , gene
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. (H EPATOLOGY 2013;58:1074–1083)