Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4

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

doi:https://doi.org/10.1002/hep.25977

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4

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 WichmannHeiko 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

Research output: Contribution to journal › Article › Academic › peer-review

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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 x 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 x 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. (HEPATOLOGY 2013;58:1074-1083)

Original language	English
Pages (from-to)	1074-1083
Journal	Hepatology (Baltimore, Md.)
Volume	58
Issue number	3
DOIs	https://doi.org/10.1002/hep.25977
Publication status	Published - 2013

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Ellinghaus, D., Folseraas, T., Holm, K., Ellinghaus, E., Melum, E., Balschun, T., Laerdahl, J. K., Shiryaev, A., Gotthardt, D. N., Weismüller, T. J., Schramm, C., Wittig, M., Bergquist, A., Björnsson, E., Marschall, H.-U., Vatn, M., Teufel, A., Rust, C., Gieger, C., ... Karlsen, T. H. (2013). Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4. Hepatology (Baltimore, Md.), 58(3), 1074-1083. https://doi.org/10.1002/hep.25977

@article{7f741c29c72740bc8cc0b5d099b2d79b,

title = "Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4",

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 x 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 x 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. (HEPATOLOGY 2013;58:1074-1083)",

author = "David Ellinghaus and Trine Folseraas and Kristian Holm and Eva Ellinghaus and Espen Melum and Tobias Balschun and Laerdahl, {Jon K.} and Alexey Shiryaev and Gotthardt, {Daniel N.} and Weism{\"u}ller, {Tobias J.} and Christoph Schramm and Michael Wittig and Annika Bergquist and Einar Bj{\"o}rnsson and Hanns-Ulrich Marschall and Morten Vatn and Andreas Teufel and Christian Rust and Christian Gieger and H.-Erich Wichmann and Heiko Runz and Martina Sterneck and Christian Rupp and Felix Braun and Weersma, {Rinse K.} and Cisca Wijmenga and Ponsioen, {Cyriel Y.} and Mathew, {Christopher G.} and Paul Rutgeerts and S{\'e}verine Vermeire and Erik Schrumpf and Hov, {Johannes R.} and Manns, {Michael P.} and Boberg, {Kirsten M.} and Stefan Schreiber and Andre Franke and Karlsen, {Tom H.}",

year = "2013",

doi = "https://doi.org/10.1002/hep.25977",

language = "English",

volume = "58",

pages = "1074--1083",

journal = "Hepatology (Baltimore, Md.)",

issn = "0270-9139",

publisher = "John Wiley and Sons Ltd",

number = "3",

}

Ellinghaus, D, Folseraas, T, Holm, K, Ellinghaus, E, Melum, E, Balschun, T, Laerdahl, JK, Shiryaev, A, Gotthardt, DN, Weismüller, TJ, Schramm, C, Wittig, M, Bergquist, A, Björnsson, E, Marschall, H-U, Vatn, M, Teufel, A, Rust, C, Gieger, C, Wichmann, H-E, Runz, H, Sterneck, M, Rupp, C, Braun, F, Weersma, RK, Wijmenga, C, Ponsioen, CY, Mathew, CG, Rutgeerts, P, Vermeire, S, Schrumpf, E, Hov, JR, Manns, MP, Boberg, KM, Schreiber, S, Franke, A & Karlsen, TH 2013, 'Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4', Hepatology (Baltimore, Md.), vol. 58, no. 3, pp. 1074-1083. https://doi.org/10.1002/hep.25977

TY - JOUR

T1 - Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4

AU - Ellinghaus, David

AU - Folseraas, Trine

AU - Holm, Kristian

AU - Ellinghaus, Eva

AU - Melum, Espen

AU - Balschun, Tobias

AU - Laerdahl, Jon K.

AU - Shiryaev, Alexey

AU - Gotthardt, Daniel N.

AU - Weismüller, Tobias J.

AU - Schramm, Christoph

AU - Wittig, Michael

AU - Bergquist, Annika

AU - Björnsson, Einar

AU - Marschall, Hanns-Ulrich

AU - Vatn, Morten

AU - Teufel, Andreas

AU - Rust, Christian

AU - Gieger, Christian

AU - Wichmann, H.-Erich

AU - Runz, Heiko

AU - Sterneck, Martina

AU - Rupp, Christian

AU - Braun, Felix

AU - Weersma, Rinse K.

AU - Wijmenga, Cisca

AU - Ponsioen, Cyriel Y.

AU - Mathew, Christopher G.

AU - Rutgeerts, Paul

AU - Vermeire, Séverine

AU - Schrumpf, Erik

AU - Hov, Johannes R.

AU - Manns, Michael P.

AU - Boberg, Kirsten M.

AU - Schreiber, Stefan

AU - Franke, Andre

AU - Karlsen, Tom H.

PY - 2013

Y1 - 2013

N2 - 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 x 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 x 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. (HEPATOLOGY 2013;58:1074-1083)

AB - 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 x 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 x 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. (HEPATOLOGY 2013;58:1074-1083)

U2 - https://doi.org/10.1002/hep.25977

DO - https://doi.org/10.1002/hep.25977

M3 - Article

C2 - 22821403

SN - 0270-9139

VL - 58

SP - 1074

EP - 1083

JO - Hepatology (Baltimore, Md.)

JF - Hepatology (Baltimore, Md.)

IS - 3

ER -