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

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Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. / 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, Hanns-Ulrich; Vatn, Morten; Teufel, Andreas; Rust, Christian; Gieger, Christian; Wichmann, H-Erich; 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.

In: HEPATOLOGY, Vol. 58, No. 3, 3, 2013, p. 1074-1083.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, vol. 58, no. 3, 3, pp. 1074-1083. https://doi.org/10.1002/hep.25977

APA

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, 58(3), 1074-1083. [3]. https://doi.org/10.1002/hep.25977

Vancouver

Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T et al. Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. HEPATOLOGY. 2013;58(3):1074-1083. 3. https://doi.org/10.1002/hep.25977

Bibtex

@article{2dcfaba86b214a8a89416967f156a872,
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 × 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.",
keywords = "Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Belgium, Case-Control Studies, Cholangitis, Sclerosing, Colitis, Ulcerative, Comorbidity, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germany, Great Britain, Humans, Netherlands, Norway, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Risk Factors, Transcription Factors",
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}",
note = "Copyright {\textcopyright} 2012 American Association for the Study of Liver Diseases.",
year = "2013",
doi = "10.1002/hep.25977",
language = "English",
volume = "58",
pages = "1074--1083",
journal = "HEPATOLOGY",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

RIS

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

N1 - Copyright © 2012 American Association for the Study of Liver Diseases.

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 × 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.

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 × 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.

KW - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

KW - Belgium

KW - Case-Control Studies

KW - Cholangitis, Sclerosing

KW - Colitis, Ulcerative

KW - Comorbidity

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Germany

KW - Great Britain

KW - Humans

KW - Netherlands

KW - Norway

KW - Polymorphism, Single Nucleotide

KW - Receptors, G-Protein-Coupled

KW - Risk Factors

KW - Transcription Factors

U2 - 10.1002/hep.25977

DO - 10.1002/hep.25977

M3 - SCORING: Journal article

C2 - 22821403

VL - 58

SP - 1074

EP - 1083

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 3

M1 - 3

ER -