Article Text

Original Article
Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis
  1. Rudi Alberts1,
  2. Elisabeth M G de Vries2,
  3. Elizabeth C Goode3,4,
  4. Xiaojun Jiang5,6,
  5. Fotis Sampaziotis7,8,
  6. Krista Rombouts9,
  7. Katrin Böttcher9,
  8. Trine Folseraas5,6,
  9. Tobias J Weismüller10,11,
  10. Andrew L Mason12,
  11. Weiwei Wang12,
  12. Graeme Alexander13,
  13. Domenico Alvaro14,
  14. Annika Bergquist15,
  15. Niklas K Björkström16,
  16. Ulrich Beuers2,
  17. Einar Björnsson17,
  18. Kirsten Muri Boberg5,18,
  19. Christopher L Bowlus19,
  20. Maria C Bragazzi20,
  21. Marco Carbone21,
  22. Olivier Chazouillères22,
  23. Angela Cheung23,
  24. Georgios Dalekos24,
  25. John Eaton25,
  26. Bertus Eksteen26,
  27. David Ellinghaus27,
  28. Martti Färkkilä28,
  29. Eleonora A M Festen1,
  30. Annarosa Floreani29,
  31. Irene Franceschet30,
  32. Daniel Nils Gotthardt31,
  33. Gideon M Hirschfield32,
  34. Bart van Hoek33,
  35. Kristian Holm5,6,
  36. Simon Hohenester34,
  37. Johannes Roksund Hov5,6,
  38. Floris Imhann1,
  39. Pietro Invernizzi21,
  40. Brian D Juran25,
  41. Henrike Lenzen35,
  42. Wolfgang Lieb36,37,
  43. Jimmy Z Liu38,
  44. Hanns-Ulrich Marschall39,
  45. Marco Marzioni40,
  46. Espen Melum5,6,
  47. Piotr Milkiewicz41,
  48. Tobias Müller42,
  49. Albert Pares43,
  50. Christian Rupp44,
  51. Christian Rust45,
  52. Richard N Sandford4,
  53. Christoph Schramm46,
  54. Stefan Schreiber27,47,
  55. Erik Schrumpf6,48,
  56. Mark S Silverberg49,
  57. Brijesh Srivastava4,
  58. Martina Sterneck50,
  59. Andreas Teufel51,
  60. Ludovic Vallier7,38,
  61. Joanne Verheij52,
  62. Arnau Vich Vila1,
  63. Boudewijn de Vries1,
  64. Kalliopi Zachou53,
  65. The International PSC Study Group, The UK PSC Consortium,
  66. Roger W Chapman54,
  67. Michael P Manns10,11,
  68. Massimo Pinzani9,
  69. Simon M Rushbrook3,
  70. Konstantinos N Lazaridis25,
  71. Andre Franke27,
  72. Carl A Anderson38,
  73. Tom H Karlsen5,6,
  74. Cyriel Y Ponsioen2,
  75. Rinse K Weersma1
  1. 1Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
  2. 2Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
  4. 4Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
  5. 5Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  6. 6Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  7. 7Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK
  8. 8Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
  9. 9Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
  10. 10Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  11. 11Integrated Research and Treatment Center-Transplantation (IFB-tx) Hannover Medical School, Hannover, Germany
  12. 12Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
  13. 13Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK
  14. 14Department of Clinical Medicine, Division of Gastroenterology, Sapienza University of Rome, Rome, Italy
  15. 15Center for Digestive Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
  16. 16Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  17. 17Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
  18. 18K G Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  19. 19Division of Gastroenterology and Hepatology, University of California Davis, Davis, California, USA
  20. 20Sapienza University of Rome, Medico-Surgical Sciences and Biotechnologies, Rome, Italy
  21. 21Department of Medicine and Surgery, Program for Autoimmune Liver Diseases, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
  22. 22Department of Hepatology, AP-HP, Hôpital Saint Antoine, Paris, France
  23. 23General Internal Medicine, University Health Network, Toronto General Hospital, Toronto, Canada
  24. 24Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
  25. 25Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA
  26. 26Department of Medicine, Snyder Institute of Chronic Diseases, University of Calgary, Calgary, Canada
  27. 27Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
  28. 28Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland
  29. 29Department of Surgical Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
  30. 30Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy
  31. 31Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany
  32. 32Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK
  33. 33Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
  34. 34Department of Medicine II, Liver Center Munich, University of Munich, Munich, Germany
  35. 35Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  36. 36Popgen Biobank, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
  37. 37Institute for Epidemiology, Christian-Albrechts University, Kiel, Germany
  38. 38Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, UK
  39. 39Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden
  40. 40Department of Gastroenterology, Università Politecnica delle Marche, Ospedali Riuniti University Hospital, Ancona, Italy
  41. 41Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland
  42. 42Department of Internal Medicine Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
  43. 43Liver Unit Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
  44. 44Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany
  45. 45Department of Medicine I, Krankenhaus Barmherzige Brüder, Munich, Germany
  46. 461st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  47. 47Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
  48. 48Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  49. 49Inflammatory Bowel Disease (IBD) Group Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Ontario, Canada
  50. 50Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  51. 511st Department of Medicine, University of Mainz, Mainz, Germany
  52. 52Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
  53. 53Department of Internal Medicine, University of Thessaly, Larissa, Greece
  54. 54Department of Hepatology, John Radcliffe University Hospitals NHS Trust, Cambridge, UK
  1. Correspondence to Dr Rinse K Weersma, Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, PO Box 30.001, 9700RB, Groningen, the Netherlands; r.k.weersma{at}


Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.

Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.

Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.

Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

  • Primary sclerosing cholangitis
  • genetics
  • liver transplantation

Statistics from


  • Contributors RA, EMGdV, XJ, FS, KR, KS, ALM and WW: statistical analysis and interpretation of data. CYP and RKW: study supervision. KR, KS, XJ, FS and MP: performed experiments. RA, EMGdV, THK, SH, CS, TF, JRH, EM, FS, CYP and RKW wrote the manuscript. JZL, AFranke, DE and CAA performed genotyping, calling and QC. RA, EMGdV, ECG, XJ, FS, KR, KS, TF, TJW, ALM, WW, GA, DA, AB, NKB, UB,EB, KMB, CLB, MCB, MC, OC, AC, GD, JE, BE, DE, MF, EAMF, AFloreani, IF, DNG,GMH, BvH, KH, SH, JRH, FI, PI,BDJ, HL,WL, JZL, H-UM, MM, EM, PM, TM, AP, CRupp,CRust, RNS, CS, SS, ES, MSilverberg, BS, MSterneck, AT, LV, JV, AVV, BdV, KZ,RWC, MPM, MP, SMR, KNL, AFranke, CAA, THK, CYP, RKW, The UK–PSC Consortium and The International PSC Study Group contributed to sample and clinical data collection. All authors revised the manuscript for critical content and approved the finalversion.

  • Funding RA is supported by a PSC Partners Seeking a Cure grant ‘Unraveling genetics driving PSC subphenotypes: anIPSCSG study’. LV and FS are supported by the ERC grant Relieve IMDs and the Cambridge Hospitals National Institute for Health Research Biomedical Research Center. SH is supported by a grant from the German Research Community (DFG), grant HO 4460/2–1. TM is supported by the German Research Community (DFG), grants MU 2864/1–1 and MU 2864/1–3. KNL is supported by the NIH RO1 DK 084960 and Sigismunda Palumbo Charitable Trust. EAMF is supported by a Career Development Grant from Dutch Digestive Foundation (Maag Lever Darm Stichting, MLDS). RKW is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and a PSC Partners Seeking a Cure grant ‘The Exome in PSC’.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Subject recruitment was approved by the ethics committees or institutional review boards of all participating centres.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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