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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 269–273 (2017)Cite this article

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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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Figure 1: Odds ratios (and their 95% confidence intervals) for PSC, UC and CD across the six PSC-associated SNPs demonstrating strong evidence for a shared causal variant (maximum posterior probability > 0.8).
Figure 2: Genome-wide genetic correlation between PSC (and its subphenotypes), CD and UC.

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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

  1. Sun-Gou Ji and Brian D Juran: These authors contributed equally to this work.

  2. Konstantinos N Lazaridis and Carl A Anderson: These authors jointly directed this work.

Authors and 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. Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, 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. Division of Cancer Medicine, Norwegian PSC Research Center, 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. Department of Transplantation Medicine, Division of Cancer, Section of Gastroenterology, 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. Department of Medicine, Snyder Institute for Chronic Diseases, 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. Department of General, Liver and Internal Medicine Unit, 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. Department of Hepatology, AP-HP Hôpital Saint Antoine, 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. Department of Public Health and Primary Care, NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK

    Carmel Moore, Willem H Ouwehand, David J Roberts & John Danesh

  39. Department of Public Health and Primary Care, INTERVAL Coordinating Centre, 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

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  1. Sun-Gou Ji
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Consortia

The UK-PSC Consortium

The International IBD Genetics Consortium

The International PSC Study Group

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.

Corresponding authors

Correspondence to Konstantinos N Lazaridis or Carl A Anderson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

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

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Note (PDF 16839 kb)

Supplementary Table 1

Quality control summary for the samples in the discovery (GWAS) cohort. (XLSX 9 kb)

Supplementary Table 2

Summary of post-imputation SNP quality control. (XLSX 8 kb)

Supplementary Table 3

Summary of samples in the replication cohort. (XLSX 9 kb)

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. (XLSX 17 kb)

Supplementary Table 5

Previously reported genome-wide associations in other immune-mediated diseases. (XLSX 8 kb)

Supplementary Table 6

SIFT and PolyPhen 2 results. (XLSX 9 kb)

Supplementary Table 7

GWAVA results and select gene position annotation. (XLSX 336 kb)

Supplementary Table 8

Prioritized genes for all 18 PSC risk loci. (XLSX 12 kb)

Supplementary Table 9

Colocalization analysis results in the 18 PSC risk loci. (XLSX 16 kb)

Supplementary Table 10

Summary statistics of 18 PSC risk loci in PSC, CD, UC and IBD. (XLSX 14 kb)

Supplementary Table 11

Summary of IBD subphenotypes in the PSC cohort. (XLSX 9 kb)

Supplementary Table 12

Summary of quality control for 40 variants genotyped by Sequenom in the replication analysis. (XLSX 8 kb)

Supplementary Table 13

Summary of quality control for samples included in the genetic correlation analysis. (XLSX 9 kb)

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Ji, SG., Juran, B., Mucha, S. et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet 49, 269–273 (2017). https://doi.org/10.1038/ng.3745

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