Letter | Published:

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Nature Genetics volume 49, pages 269273 (2017) | Download Citation

Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.

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Acknowledgements

We thank the patients and healthy controls for their participation, and are grateful to the physicians, scientists and nursing staff who recruited individuals whose data is used in our study. We acknowledge the use of DNA or genotype data from a number of sources, including: the Health and Retirement Study (HSR) conducted by the University of Michigan, funded by the National Institute on Aging (grant numbers U01AG009740, RC2AG036495 and RC4AG039029) and accessed via dbGaP; Popgen 2.0, supported by a grant from the German Ministry for Education and Research (01EY1103); The Mayo Clinic Biobank, supported by the Mayo Clinic Center for Individualized Medicine; the INTERVAL study, undertaken by the University of Cambridge with funding from the National Health Service Blood and Transplant (NHSBT) (the views expressed in this publication are those of the authors and not necessarily those of the NHSBT); the FOCUS biobank. We thank the investigators of the 1000 Genomes and UK10K projects for generating and sharing the population haplotypes and Jie Huang for advice regarding imputation. We thank all members of the International IBD Genetics Consortium for sharing genetic data vital to the success of our study. This study was supported by NoPSC, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK RO1DK084960, KNL), the Wellcome Trust (098759/Z/12/Z: L.J.; 098051: S.-G.J., J.Z.L., T.S., J.G.-A., N.K., D.J.G. and C.A.A.), the Kwanjeong Educational Foundation (S.-G.J.), the German Federal Ministry of Education and Research (B.M.B.F.) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A) and the Chris M. Carlos and Catharine Nicole Jockisch Carlos Endowment in PSC. This project received infrastructure support from the DFG Excellence Cluster 306 “Inflammation at Interfaces” and the PopGen Biobank (Kiel, Germany), an endowment professorship (A.F.) by the Foundation for Experimental Medicine (Zurich, Switzerland). The recruitment of patients in Hamburg was supported by the YAEL-Foundation and the DFG (SFB841). B.A. Lie and the Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet in Oslo are acknowledged for sharing the healthy Norwegian controls. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (http://www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (http://www.cambridge-brc.org.uk). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Research Cambridge Biomedical Research Centre. We thank K. Cloppenborg-Schmidt, I. Urbach, I. Pauselis, T. Wesse, T. Henke, R. Vogler, V. Pelkonen, K. Holm, H. Dahlen Sollid, B. Woldseth, J. Andreas and L. Wenche Torbjørnsen for expert help. R.K.W. is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research. B.E. receives support from Medical Research Council, United Kingdom. T.M. and D.G. are supported by Deutsche Forschungsgemeinschaft, Grant. A.P. is supported by Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), grant PI071318 Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, and grant PI12/01448, from Ministerio de Economía y Competitvidad, Spain. P.R.D. is supported by Canadian Institutes of Health research (CIHR) and Genome Canada. C.W. is supported by grants from the Celiac Disease Consortium (BSIK03009) and Netherlands Organization for Scientific Research (NWO, VICI grant918.66.620). We acknowledge members of the International PSC Study Group, the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC), and the UK-PSC Consortium for their participation. We thank J. Rud for secretarial support.

Author information

Author notes

    • Sun-Gou Ji
    •  & Brian D Juran

    These authors contributed equally to this work.

    • Konstantinos N Lazaridis
    •  & Carl A Anderson

    These authors jointly directed this work.

Affiliations

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

    • Sun-Gou Ji
    • , Natsuhiko Kumasaka
    • , Jimmy Z Liu
    • , Tejas Shah
    • , Javier Gutierrez-Achury
    • , Willem H Ouwehand
    • , John Danesh
    • , Daniel J Gaffney
    •  & Carl A Anderson
  2. Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Brian D Juran
    • , Erik M Schlicht
    • , Aliya F Gulamhusein
    • , John E Eaton
    •  & Konstantinos N Lazaridis
  3. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Sören Mucha
    • , David Ellinghaus
    • , Stefan Schreiber
    •  & Andre Franke
  4. Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Trine Folseraas
    • , Espen Melum
    • , Kirsten M Boberg
    •  & Tom H Karlsen
  5. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Trine Folseraas
    • , Espen Melum
    •  & Tom H Karlsen
  6. Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Trine Folseraas
    • , Kirsten M Boberg
    •  & Tom H Karlsen
  7. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Luke Jostins
  8. Christ Church, University of Oxford, St Aldates, Oxford, UK.

    • Luke Jostins
  9. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.

    • Elizabeth J Atkinson
    •  & Mariza de Andrade
  10. Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Kirsten M Boberg
    •  & Tom H Karlsen
  11. Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.

    • Annika Bergquist
  12. Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

    • Severine Vermeire
  13. Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium.

    • Severine Vermeire
  14. Snyder Institute for Chronic Diseases, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.

    • Bertus Eksteen
  15. Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Peter R Durie
  16. Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland.

    • Martti Farkkila
  17. Department of Internal Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Tobias Müller
  18. 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Christoph Schramm
  19. Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Martina Sterneck
  20. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

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

    • Tobias J Weismüller
    •  & Michael P Manns
  22. Department of Internal Medicine 1, University Hospital of Bonn, Bonn, Germany.

    • Tobias J Weismüller
  23. Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.

    • Daniel N Gotthardt
  24. Department of General, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Felix Braun
  25. Department of Medicine I, University Medical Center, Regensburg, Germany.

    • Andreas Teufel
  26. Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.

    • Mattias Laudes
  27. Institute of Epidemiology and Biobank PopGen, University Hospital Schleswig-Holstein, Kiel, Germany.

    • Wolfgang Lieb
    •  & Gunnar Jacobs
  28. Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Ulrich Beuers
  29. Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

    • Rinse K Weersma
  30. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

    • Cisca Wijmenga
  31. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Hanns-Ulrich Marschall
  32. Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.

    • Piotr Milkiewicz
  33. Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.

    • Albert Pares
  34. Department of Medicine, University of Helsinki, Helsinki, Finland.

    • Kimmo Kontula
  35. AP-HP Hôpital Saint Antoine, Department of Hepatology, UPMC University Paris 6, Paris, France.

    • Olivier Chazouillères
  36. Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.

    • Pietro Invernizzi
  37. Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.

    • Elizabeth Goode
    • , Kelly Spiess
    • , Brijesh Srivastava
    • , George Mells
    • , Richard N Sandford
    •  & Simon M Rushbrook
  38. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Carmel Moore
    • , Willem H Ouwehand
    • , David J Roberts
    •  & John Danesh
  39. INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Carmel Moore
    • , Jennifer Sambrook
    •  & John Danesh
  40. Department of Hematology, University of Cambridge, Cambridge, UK.

    • Jennifer Sambrook
    •  & Willem H Ouwehand
  41. NHS Blood and Transplant, Cambridge, UK.

    • Willem H Ouwehand
  42. NHS Blood and Transplant–Oxford Centre, John Radcliffe Hospital, Oxford, UK.

    • David J Roberts
  43. Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • David J Roberts
  44. Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.

    • Annarosa Floreani
  45. Department for General Internal Medicine, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.

    • Stefan Schreiber
  46. Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada.

    • Catalina Coltescu
  47. Division of Gastroenterology and Hepatology, University of California at Davis, Davis, California, USA.

    • Christopher L Bowlus
  48. Gastroenterology and Hepatology Section, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Velimir A Luketic
  49. Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.

    • Joseph A Odin
  50. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Kapil B Chopra
  51. Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA.

    • Kris V Kowdley
  52. Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Naga Chalasani
  53. Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK.

    • George Mells
  54. Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK.

    • Graeme Alexander
  55. Department of Translational Gastroenterology, Oxford University Hospitals NHS Trust, Oxford, UK.

    • Roger W Chapman
  56. Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.

    • Gideon M Hirschfield
  57. University of Toronto and Liver Center, Toronto Western Hospital, Toronto, Ontario, Canada.

    • Gideon M Hirschfield

Consortia

  1. The UK-PSC Consortium

    A list of members and affiliations appears in the Supplementary Note.

  2. The International IBD Genetics Consortium

    A list of members and affiliations appears in the Supplementary Note.

  3. The International PSC Study Group

    A list of members and affiliations appears in the Supplementary Note.

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Contributions

S.-G.J., B.D.J., N.K., T.S., J.G.-A. and C.A.A. performed statistical data analysis. S.-G.J., B.D.J., S.M., T.F., E.M., E.J.A. and C.A.A. performed initial quality control and sample identification. L.J., J.Z.L., D.J.G., M.d.A. and C.A.A. provided statistical and analytical advice. T.H.K., K.N.L. and C.A.A. coordinated the project and supervised the analyses. S.-G.J., B.D.J., T.H.K., K.N.L. and C.A.A. drafted of the manuscript. E.M.S., K.M.B., A.B., S.V., B.E., P.R.D., M.F., T.M., C.S., M.S., T.J.W., D.N.G., D.E., F.B., A.T., M.L., W.L., G.J., U.B., R.K.W., C.W., H.-U.M., P.M., A.P., K.K., O.C., P.I., E.G., K.S., C.M., J.S., W.H.O., D.J.R., J.D., A.F., A.F.G., J.E.E., S.S., C.C., C.L.B., V.A.L., J.A.O., K.B.C., K.V.K., N.C., M.P.M., B.S., G.M., R.N.S., G.A., R.W.C., G.M.H., S.M.R., A.F., K.N.L., C.A.A., The UK-PSC Consortium, The International IBD Genetics Consortium, and The International PSC Study Group collected the samples, performed clinical ascertainment or coordinated sample logistics. All authors read and approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Konstantinos N Lazaridis or Carl A Anderson.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 1

    Quality control summary for the samples in the discovery (GWAS) cohort.

  2. 2.

    Supplementary Table 2

    Summary of post-imputation SNP quality control.

  3. 3.

    Supplementary Table 3

    Summary of samples in the replication cohort.

  4. 4.

    Supplementary Table 4

    Association summary statistics for the 40 variants that showed suggestive evidence of significance in the discovery cohort and were followed up by replication.

  5. 5.

    Supplementary Table 5

    Previously reported genome-wide associations in other immune-mediated diseases.

  6. 6.

    Supplementary Table 6

    SIFT and PolyPhen 2 results.

  7. 7.

    Supplementary Table 7

    GWAVA results and select gene position annotation.

  8. 8.

    Supplementary Table 8

    Prioritized genes for all 18 PSC risk loci.

  9. 9.

    Supplementary Table 9

    Colocalization analysis results in the 18 PSC risk loci.

  10. 10.

    Supplementary Table 10

    Summary statistics of 18 PSC risk loci in PSC, CD, UC and IBD.

  11. 11.

    Supplementary Table 11

    Summary of IBD subphenotypes in the PSC cohort.

  12. 12.

    Supplementary Table 12

    Summary of quality control for 40 variants genotyped by Sequenom in the replication analysis.

  13. 13.

    Supplementary Table 13

    Summary of quality control for samples included in the genetic correlation analysis.

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DOI

https://doi.org/10.1038/ng.3745

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