Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Jimmy Z. Liu; Johannes Roksund Hov; Trine Folseraas; Eva Ellinghaus; Simon M. Rushbrook; Nadezhda T. Doncheva; Ole A. Andreassen; Rinse K. Weersma; Tobias J. Weismüller; Bertus Eksteen; Pietro Invernizzi; Gideon M. Hirschfield; Daniel Nils Gotthardt; Albert Pares; David Ellinghaus; Tejas Shah; Brian D. Juran; Piotr Milkiewicz; Christian Rust; Christoph Schramm; Tobias Muler; Brijesh Srivastava; Georgios Dalekos; Markus M. Nöthen; Stefan Herms; Juliane Winkelmann; Mitja Mitrovic; Felix Braun; Cyriel Y. Ponsioen; Peter J.P. Croucher; Martina Sterneck; Andreas Teufel; L Mason Andrew L Mason; Janna Saarela; Virpi Leppa; Ruslan Dorfman; Domenico Alvaro; Annarosa Floreani; Suna Onengut-Gumuscu; Stephen S. Rich; Wesley K. Thompson; Andrew J. Schork; Sigrid Næss; Ingo Thomsen; Gabriele Mayr; Inke R. König; Kristian Hveem; Isabelle Cleynen; Javier Gutierrez-Achury; Isis Ricaño-Ponce; David Van Heel; Einar Björnsson; Richard N. Sandford; Peter R. Durie; Espen Melum; Morten H. Vatn; Mark S. Silverberg; Richard H. Duerr; Leonid Padyukov; Stephan Brand; Miquel Sans; Vito Annese; Jean Paul Achkar; Kirsten Muri Boberg; Hanns Ulrich Marschall; Olivier Chazouillères; Christopher L. Bowlus; Cisca Wijmenga; Erik Schrumpf; Severine Vermeire; Mario Albrecht; John D. Rioux; Graeme Alexander; Annika Bergquist; Judy Cho; Stefan Schreiber; Michael P. Manns; Martti Färkkilä; Anders M. Dale; Roger W. Chapman; N Lazaridis Konstantinos N Lazaridis; Andre Franke; Carl A. Anderson; Tom H. Karlsen

doi:10.1038/ng.2616

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

Jimmy Z. Liu, Johannes Roksund Hov, Trine Folseraas, Eva Ellinghaus, Simon M. Rushbrook, Nadezhda T. Doncheva, Ole A. Andreassen, Rinse K. Weersma, Tobias J. Weismüller, Bertus Eksteen, Pietro Invernizzi, Gideon M. Hirschfield, Daniel Nils Gotthardt, Albert Pares, David Ellinghaus, Tejas Shah, Brian D. Juran, Piotr Milkiewicz, Christian Rust, Christoph SchrammTobias Muler, Brijesh Srivastava, Georgios Dalekos, Markus M. Nöthen, Stefan Herms, Juliane Winkelmann, Mitja Mitrovic, Felix Braun, Cyriel Y. Ponsioen, Peter J.P. Croucher, Martina Sterneck, Andreas Teufel, L Mason Andrew L Mason, Janna Saarela, Virpi Leppa, Ruslan Dorfman, Domenico Alvaro, Annarosa Floreani, Suna Onengut-Gumuscu, Stephen S. Rich, Wesley K. Thompson, Andrew J. Schork, Sigrid Næss, Ingo Thomsen, Gabriele Mayr, Inke R. König, Kristian Hveem, Isabelle Cleynen, Javier Gutierrez-Achury, Isis Ricaño-Ponce, David Van Heel, Einar Björnsson, Richard N. Sandford, Peter R. Durie, Espen Melum, Morten H. Vatn, Mark S. Silverberg, Richard H. Duerr, Leonid Padyukov, Stephan Brand, Miquel Sans, Vito Annese, Jean Paul Achkar, Kirsten Muri Boberg, Hanns Ulrich Marschall, Olivier Chazouillères, Christopher L. Bowlus, Cisca Wijmenga, Erik Schrumpf, Severine Vermeire, Mario Albrecht, John D. Rioux, Graeme Alexander, Annika Bergquist, Judy Cho, Stefan Schreiber, Michael P. Manns, Martti Färkkilä, Anders M. Dale, Roger W. Chapman, N Lazaridis Konstantinos N Lazaridis, Andre Franke, Carl A. Anderson^*, Tom H. Karlsen

^*Corresponding author for this work

Institute of Medical Biometry and Statistic

357 Citations (Scopus)

Abstract

Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

Original language	English
Journal	Nature Genetics
Volume	45
Issue number	6
Pages (from-to)	670-675
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2616
Publication status	Published - 06.2013

Funding

The study was supported by The Norwegian PSC Research Center (see URLs), by the German Ministry of Education and Research through the National Genome Research Network (01GS0809-GP7), by the Deutsche Forschungsgemeinschaft (FR 2821/2-1), by the EU Seventh Framework Programme FP7/2007-2013 (262055) ESGI, by the Integrated Research and Treatment Center–Transplantation (01EO0802) and by the PopGen Biobank (see URLs). J.Z.L., T.S. and C.A.A. are supported by a grant from the Wellcome Trust (098051). Additional financial support of the study and the coauthors is listed in the Supplementary Note.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/ng.2616

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Liu, J. Z., Hov, J. R., Folseraas, T., Ellinghaus, E., Rushbrook, S. M., Doncheva, N. T., Andreassen, O. A., Weersma, R. K., Weismüller, T. J., Eksteen, B., Invernizzi, P., Hirschfield, G. M., Gotthardt, D. N., Pares, A., Ellinghaus, D., Shah, T., Juran, B. D., Milkiewicz, P., Rust, C., ... Karlsen, T. H. (2013). Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics, 45(6), 670-675. https://doi.org/10.1038/ng.2616

@article{b90bd6396b96494c82e3762c2fe3eb56,

title = "Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis",

abstract = "Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72\% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.",

author = "Liu, \{Jimmy Z.\} and Hov, \{Johannes Roksund\} and Trine Folseraas and Eva Ellinghaus and Rushbrook, \{Simon M.\} and Doncheva, \{Nadezhda T.\} and Andreassen, \{Ole A.\} and Weersma, \{Rinse K.\} and Weism{\"u}ller, \{Tobias J.\} and Bertus Eksteen and Pietro Invernizzi and Hirschfield, \{Gideon M.\} and Gotthardt, \{Daniel Nils\} and Albert Pares and David Ellinghaus and Tejas Shah and Juran, \{Brian D.\} and Piotr Milkiewicz and Christian Rust and Christoph Schramm and Tobias Muler and Brijesh Srivastava and Georgios Dalekos and N{\"o}then, \{Markus M.\} and Stefan Herms and Juliane Winkelmann and Mitja Mitrovic and Felix Braun and Ponsioen, \{Cyriel Y.\} and Croucher, \{Peter J.P.\} and Martina Sterneck and Andreas Teufel and \{Andrew L Mason\}, \{L Mason\} and Janna Saarela and Virpi Leppa and Ruslan Dorfman and Domenico Alvaro and Annarosa Floreani and Suna Onengut-Gumuscu and Rich, \{Stephen S.\} and Thompson, \{Wesley K.\} and Schork, \{Andrew J.\} and Sigrid N{\ae}ss and Ingo Thomsen and Gabriele Mayr and K{\"o}nig, \{Inke R.\} and Kristian Hveem and Isabelle Cleynen and Javier Gutierrez-Achury and Isis Rica{\~n}o-Ponce and \{Van Heel\}, David and Einar Bj{\"o}rnsson and Sandford, \{Richard N.\} and Durie, \{Peter R.\} and Espen Melum and Vatn, \{Morten H.\} and Silverberg, \{Mark S.\} and Duerr, \{Richard H.\} and Leonid Padyukov and Stephan Brand and Miquel Sans and Vito Annese and Achkar, \{Jean Paul\} and Boberg, \{Kirsten Muri\} and Marschall, \{Hanns Ulrich\} and Olivier Chazouill{\`e}res and Bowlus, \{Christopher L.\} and Cisca Wijmenga and Erik Schrumpf and Severine Vermeire and Mario Albrecht and Rioux, \{John D.\} and Graeme Alexander and Annika Bergquist and Judy Cho and Stefan Schreiber and Manns, \{Michael P.\} and Martti F{\"a}rkkil{\"a} and Dale, \{Anders M.\} and Chapman, \{Roger W.\} and \{Konstantinos N Lazaridis\}, \{N Lazaridis\} and Andre Franke and Anderson, \{Carl A.\} and Karlsen, \{Tom H.\}",

note = "Funding Information: The study was supported by The Norwegian PSC Research Center (see URLs), by the German Ministry of Education and Research through the National Genome Research Network (01GS0809-GP7), by the Deutsche Forschungsgemeinschaft (FR 2821/2-1), by the EU Seventh Framework Programme FP7/2007-2013 (262055) ESGI, by the Integrated Research and Treatment Center–Transplantation (01EO0802) and by the PopGen Biobank (see URLs). J.Z.L., T.S. and C.A.A. are supported by a grant from the Wellcome Trust (098051). Additional financial support of the study and the coauthors is listed in the Supplementary Note.",

year = "2013",

month = jun,

doi = "10.1038/ng.2616",

language = "English",

volume = "45",

pages = "670--675",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

}

Liu, JZ, Hov, JR, Folseraas, T, Ellinghaus, E, Rushbrook, SM, Doncheva, NT, Andreassen, OA, Weersma, RK, Weismüller, TJ, Eksteen, B, Invernizzi, P, Hirschfield, GM, Gotthardt, DN, Pares, A, Ellinghaus, D, Shah, T, Juran, BD, Milkiewicz, P, Rust, C, Schramm, C, Muler, T, Srivastava, B, Dalekos, G, Nöthen, MM, Herms, S, Winkelmann, J, Mitrovic, M, Braun, F, Ponsioen, CY, Croucher, PJP, Sterneck, M, Teufel, A, Andrew L Mason, LM, Saarela, J, Leppa, V, Dorfman, R, Alvaro, D, Floreani, A, Onengut-Gumuscu, S, Rich, SS, Thompson, WK, Schork, AJ, Næss, S, Thomsen, I, Mayr, G, König, IR, Hveem, K, Cleynen, I, Gutierrez-Achury, J, Ricaño-Ponce, I, Van Heel, D, Björnsson, E, Sandford, RN, Durie, PR, Melum, E, Vatn, MH, Silverberg, MS, Duerr, RH, Padyukov, L, Brand, S, Sans, M, Annese, V, Achkar, JP, Boberg, KM, Marschall, HU, Chazouillères, O, Bowlus, CL, Wijmenga, C, Schrumpf, E, Vermeire, S, Albrecht, M, Rioux, JD, Alexander, G, Bergquist, A, Cho, J, Schreiber, S, Manns, MP, Färkkilä, M, Dale, AM, Chapman, RW, Konstantinos N Lazaridis, NL, Franke, A, Anderson, CA & Karlsen, TH 2013, 'Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis', Nature Genetics, vol. 45, no. 6, pp. 670-675. https://doi.org/10.1038/ng.2616

TY - JOUR

T1 - Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

AU - Liu, Jimmy Z.

AU - Hov, Johannes Roksund

AU - Folseraas, Trine

AU - Ellinghaus, Eva

AU - Rushbrook, Simon M.

AU - Doncheva, Nadezhda T.

AU - Andreassen, Ole A.

AU - Weersma, Rinse K.

AU - Weismüller, Tobias J.

AU - Eksteen, Bertus

AU - Invernizzi, Pietro

AU - Hirschfield, Gideon M.

AU - Gotthardt, Daniel Nils

AU - Pares, Albert

AU - Ellinghaus, David

AU - Shah, Tejas

AU - Juran, Brian D.

AU - Milkiewicz, Piotr

AU - Rust, Christian

AU - Schramm, Christoph

AU - Muler, Tobias

AU - Srivastava, Brijesh

AU - Dalekos, Georgios

AU - Nöthen, Markus M.

AU - Herms, Stefan

AU - Winkelmann, Juliane

AU - Mitrovic, Mitja

AU - Braun, Felix

AU - Ponsioen, Cyriel Y.

AU - Croucher, Peter J.P.

AU - Sterneck, Martina

AU - Teufel, Andreas

AU - Andrew L Mason, L Mason

AU - Saarela, Janna

AU - Leppa, Virpi

AU - Dorfman, Ruslan

AU - Alvaro, Domenico

AU - Floreani, Annarosa

AU - Onengut-Gumuscu, Suna

AU - Rich, Stephen S.

AU - Thompson, Wesley K.

AU - Schork, Andrew J.

AU - Næss, Sigrid

AU - Thomsen, Ingo

AU - Mayr, Gabriele

AU - König, Inke R.

AU - Hveem, Kristian

AU - Cleynen, Isabelle

AU - Gutierrez-Achury, Javier

AU - Ricaño-Ponce, Isis

AU - Van Heel, David

AU - Björnsson, Einar

AU - Sandford, Richard N.

AU - Durie, Peter R.

AU - Melum, Espen

AU - Vatn, Morten H.

AU - Silverberg, Mark S.

AU - Duerr, Richard H.

AU - Padyukov, Leonid

AU - Brand, Stephan

AU - Sans, Miquel

AU - Annese, Vito

AU - Achkar, Jean Paul

AU - Boberg, Kirsten Muri

AU - Marschall, Hanns Ulrich

AU - Chazouillères, Olivier

AU - Bowlus, Christopher L.

AU - Wijmenga, Cisca

AU - Schrumpf, Erik

AU - Vermeire, Severine

AU - Albrecht, Mario

AU - Rioux, John D.

AU - Alexander, Graeme

AU - Bergquist, Annika

AU - Cho, Judy

AU - Schreiber, Stefan

AU - Manns, Michael P.

AU - Färkkilä, Martti

AU - Dale, Anders M.

AU - Chapman, Roger W.

AU - Konstantinos N Lazaridis, N Lazaridis

AU - Franke, Andre

AU - Anderson, Carl A.

AU - Karlsen, Tom H.

N1 - Funding Information: The study was supported by The Norwegian PSC Research Center (see URLs), by the German Ministry of Education and Research through the National Genome Research Network (01GS0809-GP7), by the Deutsche Forschungsgemeinschaft (FR 2821/2-1), by the EU Seventh Framework Programme FP7/2007-2013 (262055) ESGI, by the Integrated Research and Treatment Center–Transplantation (01EO0802) and by the PopGen Biobank (see URLs). J.Z.L., T.S. and C.A.A. are supported by a grant from the Wellcome Trust (098051). Additional financial support of the study and the coauthors is listed in the Supplementary Note.

PY - 2013/6

Y1 - 2013/6

N2 - Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

AB - Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.

UR - https://www.scopus.com/pages/publications/84878725018

U2 - 10.1038/ng.2616

DO - 10.1038/ng.2616

M3 - Journal articles

C2 - 23603763

AN - SCOPUS:84878725018

SN - 1061-4036

VL - 45

SP - 670

EP - 675

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis

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UN SDGs

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