Letter | Published:

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

Nature Genetics volume 45, pages 670675 (2013) | Download Citation

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 transplantation1,2,3. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip4. 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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Acknowledgements

We thank all individuals with PSC and healthy controls for their participation, and we are indebted to all physicians and nursing staff who recruited subjects. We thank T. Wesse, T. Henke, S. Sedghpour Sabet, R. Vogler, G. Jacobs, I. Urbach, W. Albrecht, V. Pelkonen, V. Barbu, K. Holm, H. Dahlen Sollid, B. Woldseth, J.A. Anmarkrud and L.W. Torbjørnsen for expert help. U. Beuers, F. Braun, W. Kreisel, T. Berg and R. Günther are acknowledged for contributing German individuals with PSC. B.A. Lie and The Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet (Oslo, Norway) and the Nord-Trøndelag Health Study (HUNT) are acknowledged for sharing healthy Norwegian controls. Banco Nacional de ADN (Salamanca, Spain) is acknowledged for providing Spanish control samples. This study makes use of genotyping data generated by the Dietary, Life style and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) consortium (see URLs), the Cooperative Research in the Region of Augsburg (KORA) study and the Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcification, and Lifestyle) study. We acknowledge the members of the International PSC Study Group, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Inflammatory Bowel Disease Genetics Consortium (IBDGC), the UK-PSC Consortium and the Alberta IBD Consortium for their participation. J. Barrett is acknowledged for contributions to the design of the Immunochip experiment. Individuals who have shared summary statistics and statistical software are acknowledged in the Supplementary Note.

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.

Author information

Author notes

    • Tobias J Weismüller

    Present address: Department of Internal Medicine 1, University Hospital of Bonn, Bonn, Germany.

    • Jimmy Z Liu
    • , Johannes Roksund Hov
    • , Trine Folseraas
    •  & Eva Ellinghaus

    These authors contributed equally to this work.

    • Andre Franke
    • , Carl A Anderson
    •  & Tom H Karlsen

    These authors jointly directed this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Jimmy Z Liu
    • , Tejas Shah
    • , Isabelle Cleynen
    •  & Carl A Anderson
  2. Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Johannes Roksund Hov
    • , Trine Folseraas
    • , Sigrid Næss
    • , Espen Melum
    • , Kirsten Muri Boberg
    • , Erik Schrumpf
    •  & Tom H Karlsen
  3. K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Johannes Roksund Hov
    • , Trine Folseraas
    • , Sigrid Næss
    • , Espen Melum
    •  & Tom H Karlsen
  4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Johannes Roksund Hov
    • , Trine Folseraas
    • , Ole A Andreassen
    • , Sigrid Næss
    • , Espen Melum
    • , Morten H Vatn
    • , Kirsten Muri Boberg
    •  & Erik Schrumpf
  5. Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Johannes Roksund Hov
    • , Morten H Vatn
    • , Kirsten Muri Boberg
    • , Erik Schrumpf
    •  & Tom H Karlsen
  6. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.

    • Eva Ellinghaus
    • , David Ellinghaus
    • , Ingo Thomsen
    • , Stefan Schreiber
    •  & Andre Franke
  7. Department of Gastroenterology and Hepatology, Norfolk and Norwich, University Hospitals National Health Service (NHS) Trust, Norwich, UK.

    • Simon M Rushbrook
  8. Max Planck Institute for Informatics, Saarbrücken, Germany.

    • Nadezhda T Doncheva
    • , Gabriele Mayr
    •  & Mario Albrecht
  9. K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Ulleval, Oslo, Norway.

    • Ole A Andreassen
  10. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.

    • Rinse K Weersma
  11. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

    • Tobias J Weismüller
    •  & Michael P Manns
  12. Integrated Research and Treatment Center–Transplantation (IFB-tx), Hannover Medical School, Hannover, Germany.

    • Tobias J Weismüller
    •  & Michael P Manns
  13. Snyder Institute of Chronic Diseases, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

    • Bertus Eksteen
  14. Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy.

    • Pietro Invernizzi
  15. Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Gideon M Hirschfield
  16. Centre for Liver Research, National Institute for Health Research (NIHR) Biomedical Research Unit, Birmingham, UK.

    • Gideon M Hirschfield
  17. Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.

    • Daniel Nils Gotthardt
  18. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Barcelona, Spain.

    • Albert Pares
  19. Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA.

    • Brian D Juran
    •  & Konstantinos N Lazaridis
  20. Liver Unit and Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland.

    • Piotr Milkiewicz
  21. Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany.

    • Christian Rust
  22. 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Christoph Schramm
  23. Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Tobias Müller
  24. Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.

    • Brijesh Srivastava
    •  & Richard N Sandford
  25. Department of Medicine, Medical School, University of Thessaly, Larissa, Greece.

    • Georgios Dalekos
  26. Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece.

    • Georgios Dalekos
  27. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Markus M Nöthen
    •  & Stefan Herms
  28. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

    • Markus M Nöthen
    •  & Stefan Herms
  29. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
  30. Department of Neurology, Technische Universität München, Munich, Germany.

    • Juliane Winkelmann
  31. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Juliane Winkelmann
  32. Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.

    • Mitja Mitrovic
    • , Javier Gutierrez-Achury
    • , Isis Ricaño-Ponce
    •  & Cisca Wijmenga
  33. Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Felix Braun
  34. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.

    • Cyriel Y Ponsioen
  35. Department of Environmental Science, Policy, and Management, University of California, Berkeley, Berkeley, California, USA.

    • Peter J P Croucher
  36. Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Martina Sterneck
  37. 1st Department of Medicine, University of Mainz, Mainz, Germany.

    • Andreas Teufel
  38. Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada.

    • Andrew L Mason
  39. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Janna Saarela
  40. Public Health Genomics Unit, FIMM, University of Helsinki and National Institute for Health and Welfare, Helsinki, Finland.

    • Virpi Leppa
  41. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Ruslan Dorfman
  42. Division of Gastroenterology, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy.

    • Domenico Alvaro
  43. Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.

    • Annarosa Floreani
  44. Center for Public Health Genomics, Division of Endocrinology & Metabolism, University of Virginia, Charlottesville, Virginia, USA.

    • Suna Onengut-Gumuscu
  45. Department of Internal Medicine, Division of Endocrinology & Metabolism, University of Virginia, Charlottesville, Virginia, USA.

    • Suna Onengut-Gumuscu
  46. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

    • Stephen S Rich
  47. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.

    • Stephen S Rich
  48. Department of Psychiatry, University of California, San Diego, La Jolla, California, USA.

    • Wesley K Thompson
  49. Graduate Program in Cognitive Science, University of California, San Diego, La Jolla, California, USA.

    • Andrew J Schork
  50. Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany.

    • Inke R König
  51. Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

    • Kristian Hveem
  52. Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.

    • Isabelle Cleynen
    •  & Severine Vermeire
  53. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • David van Heel
  54. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.

    • Einar Björnsson
  55. Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Peter R Durie
  56. EpiGen, Campus Akershus University Hospital (AHUS), Akershus University Hospital, Nordbyhagen, Norway.

    • Morten H Vatn
  57. Inflammatory Bowel Disease (IBD) Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Mark S Silverberg
  58. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  59. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Richard H Duerr
  60. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.

    • Leonid Padyukov
  61. Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University Munich, Germany.

    • Stephan Brand
  62. Department of Digestive Diseases, Centro Médico Teknon, Barcelona, Spain.

    • Miquel Sans
  63. Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievodella Sofferenza Hospital, San Giovanni Rotondo, Italy.

    • Vito Annese
  64. Unit of Gastroenterology SOD2, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.

    • Vito Annese
  65. Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jean-Paul Achkar
  66. Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jean-Paul Achkar
  67. Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy and University Hospital, Gothenburg, Sweden.

    • Hanns-Ulrich Marschall
  68. Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Saint Antoine, Department of Hepatology, University Pierre et Marie Curie (UPMC) Université de Paris 6, Paris, France.

    • Olivier Chazouillères
  69. Division of Gastroenterology and Hepatology, University of California, Davis, Davis, California, USA.

    • Christopher L Bowlus
  70. Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium.

    • Severine Vermeire
  71. Department of Bioinformatics, Institute of Biometrics and Medical Informatics, University Medicine Greifswald, Greifswald, Germany.

    • Mario Albrecht
  72. Université de Montréal, Research Center, Montreal, Quebec, Canada.

    • John D Rioux
  73. Montreal Heart Institute, Research Center, Montreal, Quebec, Canada.

    • John D Rioux
  74. Division of Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK.

    • Graeme Alexander
  75. Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.

    • Annika Bergquist
  76. Section of Digestive Diseases, Department of Medicine, Yale University, New Haven, Connecticut, USA.

    • Judy Cho
  77. Department for General Internal Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany.

    • Stefan Schreiber
  78. PopGen Biobank, University Hospital Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Germany.

    • Stefan Schreiber
  79. Division of Gastroenterology, Department of Medicine, Helsinki University Hospital, Helsinki, Finland.

    • Martti Färkkilä
  80. Department of Radiology, University of California, San Diego, La Jolla, California, USA.

    • Anders M Dale
  81. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Anders M Dale
  82. Department of Hepatology, John Radcliffe University Hospitals NHS Trust, Oxford, UK.

    • Roger W Chapman
  83. Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

    • Tom H Karlsen

Consortia

  1. The UK-PSCSC Consortium

    Further details appear in the Supplementary Note.

  2. The International IBD Genetics Consortium

    Further details appear in the Supplementary Note.

  3. The International PSC Study Group

    Further details appear in the Supplementary Note.

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  66. Search for Olivier Chazouillères in:

  67. Search for Christopher L Bowlus in:

  68. Search for Cisca Wijmenga in:

  69. Search for Erik Schrumpf in:

  70. Search for Severine Vermeire in:

  71. Search for Mario Albrecht in:

  72. Search for John D Rioux in:

  73. Search for Graeme Alexander in:

  74. Search for Annika Bergquist in:

  75. Search for Judy Cho in:

  76. Search for Stefan Schreiber in:

  77. Search for Michael P Manns in:

  78. Search for Martti Färkkilä in:

  79. Search for Anders M Dale in:

  80. Search for Roger W Chapman in:

  81. Search for Konstantinos N Lazaridis in:

  82. Search for Andre Franke in:

  83. Search for Carl A Anderson in:

  84. Search for Tom H Karlsen in:

Contributions

J.Z.L., J.R.H., T.F., E.E., N.T.D., I.T., G.M., I.R.K., O.A.A., W.K.T., A.M.D., T.S. and C.A.A. performed data and statistical analyses. A. Franke, C.A.A. and T.H.K. coordinated the project and supervised the data analysis. J.Z.L., J.R.H., T.F., E.E., A. Franke, C.A.A. and T.H.K. drafted the manuscript. S.M.R., R.K.W., T.J.W., B.E., P.I., G.M.H., D.N.G., A.P., D.E., B.D.J., P.M., C.R., C.S., T.M., B.S., G.D., M.M.N., S.H., J.W., M.M., F.B., C.Y.P., P.J.P.C., M. Sterneck, A.T., A.L.M., J.S., V.L., R.D., D.A., A. Floreani, S.O.-G., S.S.R., A.J.S., S.N., K.H., I.C., J.G.-A., I.R.-P., D.v.H., E.B., R.N.S., P.R.D., E.M., M.H.V., M.S.S., R.H.D., L.P., S.B., M. Sans, V.A., J.-P.A., K.M.B., H.-U.M., O.C., C.L.B., C.W., E.S., S.V., M.A., J.D.R., G.A., A.B., J.C., S.S., M.P.M., M.F., R.W.C., K.N.L., The UK-PSC Consortium, The International IBD Consortium and The International PSC Study Group contributed to the ascertainment of affected individuals and/or sample and clinical data collection. All authors revised the manuscript for critical content and approved the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carl A Anderson or Tom H Karlsen.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–16, Supplementary Tables 1–7, 10, 11, 16 and 17, Supplementary Note

Excel files

  1. 1.

    Supplementary Table 8

    Association analysis for the classical HLA class I genes (Separate Excel file).

  2. 2.

    Supplementary Table 9

    Association analysis for the classical HLA class II genes. (Separate Excel file).

  3. 3.

    Supplementary Table 12

    Genes closest to the PSC and IBD lead SNPs considered for inclusion in the PSC&IBD functional similarity network shown in Supplemetary Figure 9 (Separate Excel file).

  4. 4.

    Supplementary Table 13

    Lead SNPs in 33 pleiotropic loci with false discovery rate(FDR)<0.001 given associations in at least one of seven diseases associated with PSC (Separate Excel file).

  5. 5.

    Supplementary Table 14

    Lead SNPs in 89 pleiotropic loci with 0.01<false discovery rate(FDR)<0.001 given associations in at least one of seven diseases associated with PSC (Separate Excel file).

  6. 6.

    Supplementary Table 15

    Genes within 0.1 cM of all PSC SNPs considered for inclusion in the PSC functional similarity network shown in Supplementary Figure 13(Separate Excel file).

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2616

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