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 & 64 others 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

Research output: Contribution to journalArticle

189 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 languageEnglish
Pages (from-to)670-675
Number of pages6
JournalNature Genetics
Volume45
Issue number6
DOIs
Publication statusPublished - Jun 2013

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Sclerosing Cholangitis
Immune System Diseases
Inflammatory Bowel Diseases
Population Control
HLA Antigens
Bile Ducts
Liver Transplantation
Single Nucleotide Polymorphism
Comorbidity
Liver Diseases
Genome

ASJC Scopus subject areas

  • Genetics

Cite this

Liu, J. Z., Hov, J. R., Folseraas, T., Ellinghaus, E., Rushbrook, S. M., Doncheva, N. T., ... 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

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

In: Nature Genetics, Vol. 45, No. 6, 06.2013, p. 670-675.

Research output: Contribution to journalArticle

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
Liu, Jimmy Z. ; Hov, Johannes Roksund ; Folseraas, Trine ; Ellinghaus, Eva ; Rushbrook, Simon M. ; Doncheva, Nadezhda T. ; Andreassen, Ole A. ; Weersma, Rinse K. ; Weismüller, Tobias J. ; Eksteen, Bertus ; Invernizzi, Pietro ; Hirschfield, Gideon M. ; Gotthardt, Daniel Nils ; Pares, Albert ; Ellinghaus, David ; Shah, Tejas ; Juran, Brian D. ; Milkiewicz, Piotr ; Rust, Christian ; Schramm, Christoph ; Muler, Tobias ; Srivastava, Brijesh ; Dalekos, Georgios ; Nöthen, Markus M. ; Herms, Stefan ; Winkelmann, Juliane ; Mitrovic, Mitja ; Braun, Felix ; Ponsioen, Cyriel Y. ; Croucher, Peter J P ; Sterneck, Martina ; Teufel, Andreas ; Andrew L Mason, L Mason ; Saarela, Janna ; Leppa, Virpi ; Dorfman, Ruslan ; Alvaro, Domenico ; Floreani, Annarosa ; Onengut-Gumuscu, Suna ; Rich, Stephen S. ; Thompson, Wesley K. ; Schork, Andrew J. ; Næss, Sigrid ; Thomsen, Ingo ; Mayr, Gabriele ; König, Inke R. ; Hveem, Kristian ; Cleynen, Isabelle ; Gutierrez-Achury, Javier ; Ricaño-Ponce, Isis ; Van Heel, David ; Björnsson, Einar ; Sandford, Richard N. ; Durie, Peter R. ; Melum, Espen ; Vatn, Morten H. ; Silverberg, Mark S. ; Duerr, Richard H. ; Padyukov, Leonid ; Brand, Stephan ; Sans, Miquel ; Annese, Vito ; Achkar, Jean Paul ; Boberg, Kirsten Muri ; Marschall, Hanns Ulrich ; Chazouillères, Olivier ; Bowlus, Christopher L. ; Wijmenga, Cisca ; Schrumpf, Erik ; Vermeire, Severine ; Albrecht, Mario ; Rioux, John D. ; Alexander, Graeme ; Bergquist, Annika ; Cho, Judy ; Schreiber, Stefan ; Manns, Michael P. ; Färkkilä, Martti ; Dale, Anders M. ; Chapman, Roger W. ; Konstantinos N Lazaridis, N Lazaridis ; Franke, Andre ; Anderson, Carl A. ; Karlsen, Tom H. / Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. In: Nature Genetics. 2013 ; Vol. 45, No. 6. pp. 670-675.
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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.",
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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.

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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.

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