Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • 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 269–273 (2017)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Boonstra, K. et al. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm. Bowel Dis. 18, 2270–2276 (2012).

    Article  Google Scholar 

  2. Tischendorf, J.J.W., Hecker, H., Krüger, M., Manns, M.P. & Meier, P.N. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am. J. Gastroenterol. 102, 107–114 (2007).

    Article  Google Scholar 

  3. Karlsen, T.H. & Kaser, A. Deciphering the genetic predisposition to primary sclerosing cholangitis. Semin. Liver Dis. 31, 188–207 (2011).

    Article  CAS  Google Scholar 

  4. Karlsen, T.H., Schrumpf, E. & Boberg, K.M. Update on primary sclerosing cholangitis. Dig. Liver Dis. 42, 390–400 (2010).

    Article  CAS  Google Scholar 

  5. Bergquist, A. et al. Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis. Clin. Gastroenterol. Hepatol. 6, 939–943 (2008).

    Article  Google Scholar 

  6. de Vries, A.B., Janse, M., Blokzijl, H. & Weersma, R.K. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J. Gastroenterol. 21, 1956–1971 (2015).

    Article  Google Scholar 

  7. Melum, E. et al. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci. Nat. Genet. 43, 17–19 (2011).

    Article  CAS  Google Scholar 

  8. Ellinghaus, D. et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 58, 1074–1083 (2013).

    Article  CAS  Google Scholar 

  9. Folseraas, T. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J. Hepatol. 57, 366–375 (2012).

    Article  CAS  Google Scholar 

  10. Karlsen, T.H. et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 138, 1102–1111 (2010).

    Article  Google Scholar 

  11. Liu, J.Z. et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat. Genet. 45, 670–675 (2013).

    Article  CAS  Google Scholar 

  12. Srivastava, B. et al. Fine mapping and replication of genetic risk loci in primary sclerosing cholangitis. Scand. J. Gastroenterol. 47, 820–826 (2012).

    Article  CAS  Google Scholar 

  13. 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

  14. UK 10K Consortium. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

  15. Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    Article  CAS  Google Scholar 

  16. Kumar, P., Henikoff, S. & Ng, P.C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    Article  CAS  Google Scholar 

  17. Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  Google Scholar 

  18. Ritchie, G.R.S., Dunham, I., Zeggini, E. & Flicek, P. Functional annotation of noncoding sequence variants. Nat. Methods 11, 294–296 (2014).

    Article  CAS  Google Scholar 

  19. Battle, A. et al. Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals. Genome Res. 24, 14–24 (2014).

    Article  CAS  Google Scholar 

  20. Westra, H.J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).

    Article  CAS  Google Scholar 

  21. Fairfax, B.P. et al. Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles. Nat. Genet. 44, 502–510 (2012).

    Article  CAS  Google Scholar 

  22. Zhang, M.Q. Statistical features of human exons and their flanking regions. Hum. Mol. Genet. 7, 919–932 (1998).

    Article  CAS  Google Scholar 

  23. Lappalainen, T. et al. Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501, 506–511 (2013).

    Article  CAS  Google Scholar 

  24. Jin, Y. et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat. Genet. 44, 676–680 (2012).

    Article  CAS  Google Scholar 

  25. Barrett, J.C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  Google Scholar 

  26. Liu, J.Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).

    Article  CAS  Google Scholar 

  27. Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).

    Article  Google Scholar 

  28. Stuart, P.E. et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am. J. Hum. Genet. 97, 816–836 (2015).

    Article  CAS  Google Scholar 

  29. Bowes, J. et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat. Commun. 6, 6046 (2015).

    Article  CAS  Google Scholar 

  30. Lee, S.H., Yang, J., Goddard, M.E., Visscher, P.M. & Wray, N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism–derived genomic relationships and restricted maximum likelihood. Bioinformatics 28, 2540–2542 (2012).

    Article  CAS  Google Scholar 

  31. Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

    Article  CAS  Google Scholar 

  32. Bulik-Sullivan, B.K. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).

    Article  CAS  Google Scholar 

  33. Goyette, P. et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat. Genet. 47, 172–179 (2015).

    Article  CAS  Google Scholar 

  34. Ellinghaus, D. et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510–518 (2016).

    Article  CAS  Google Scholar 

  35. Chapman, R.W.G. et al. Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology. Gut 21, 870–877 (1980).

    Article  CAS  Google Scholar 

  36. Yimam, K.K. & Bowlus, C.L. Diagnosis and classification of primary sclerosing cholangitis. Autoimmun. Rev. 13, 445–450 (2014).

    Article  CAS  Google Scholar 

  37. Mailman, M.D. et al. The NCBI dbGaP database of genotypes and phenotypes. Nat. Genet. 39, 1181–1186 (2007).

    Article  CAS  Google Scholar 

  38. Bellenguez, C., Strange, A., Freeman, C., Donnelly, P. & Spencer, C.C. A robust clustering algorithm for identifying problematic samples in genome-wide association studies. Bioinformatics 28, 134–135 (2012).

    Article  CAS  Google Scholar 

  39. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  40. Delaneau, O., Zagury, J.F. & Marchini, J. Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 (2013).

    Article  CAS  Google Scholar 

  41. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  Google Scholar 

  42. Pirinen, M., Donnelly, P. & Spencer, C.C.A. Efficient computation with a linear mixed model on large-scale data sets with applications to genetic studies. Ann. Appl. Stat. 7, 369–390 (2013).

    Article  Google Scholar 

  43. Olson, J.E. et al. The Mayo Clinic Biobank: a building block for individualized medicine. Mayo Clin. Proc. 88, 952–962 (2013).

    Article  Google Scholar 

  44. Moore, C. et al. The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial. Trials 15, 363 (2014).

    Article  Google Scholar 

  45. Gaffney, D.J. Global properties and functional complexity of human gene regulatory variation. PLoS Genet. 9, e1003501 (2013).

    Article  CAS  Google Scholar 

  46. GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  47. Fairfax, B.P. et al. Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression. Science 343, 1246949 (2014).

    Article  Google Scholar 

  48. Lee, M.N. et al. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014).

    Article  Google Scholar 

  49. Fortune, M.D. et al. Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. Nat. Genet. 47, 839–846 (2015).

    Article  CAS  Google Scholar 

  50. Lee, S.H., Wray, N.R., Goddard, M.E. & Visscher, P.M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).

    Article  Google Scholar 

  51. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nat. Genet. 42, 565–569 (2010).

    Article  CAS  Google Scholar 

Download references

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

Authors
  1. Sun-Gou Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian D Juran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sören Mucha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Trine Folseraas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luke Jostins
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Espen Melum
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Natsuhiko Kumasaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elizabeth J Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Erik M Schlicht
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jimmy Z Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tejas Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Javier Gutierrez-Achury
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kirsten M Boberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Annika Bergquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Severine Vermeire
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Bertus Eksteen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter R Durie
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Martti Farkkila
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Tobias Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Christoph Schramm
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Martina Sterneck
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Tobias J Weismüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Daniel N Gotthardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. David Ellinghaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Felix Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Andreas Teufel
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Mattias Laudes
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Wolfgang Lieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Gunnar Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Ulrich Beuers
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Rinse K Weersma
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Cisca Wijmenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Hanns-Ulrich Marschall
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Piotr Milkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Albert Pares
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Kimmo Kontula
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Olivier Chazouillères
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Pietro Invernizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Elizabeth Goode
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Kelly Spiess
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Carmel Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. Jennifer Sambrook
    View author publications

    You can also search for this author in PubMed Google Scholar

  43. Willem H Ouwehand
    View author publications

    You can also search for this author in PubMed Google Scholar

  44. David J Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  45. John Danesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  46. Annarosa Floreani
    View author publications

    You can also search for this author in PubMed Google Scholar

  47. Aliya F Gulamhusein
    View author publications

    You can also search for this author in PubMed Google Scholar

  48. John E Eaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  49. Stefan Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  50. Catalina Coltescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  51. Christopher L Bowlus
    View author publications

    You can also search for this author in PubMed Google Scholar

  52. Velimir A Luketic
    View author publications

    You can also search for this author in PubMed Google Scholar

  53. Joseph A Odin
    View author publications

    You can also search for this author in PubMed Google Scholar

  54. Kapil B Chopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  55. Kris V Kowdley
    View author publications

    You can also search for this author in PubMed Google Scholar

  56. Naga Chalasani
    View author publications

    You can also search for this author in PubMed Google Scholar

  57. Michael P Manns
    View author publications

    You can also search for this author in PubMed Google Scholar

  58. Brijesh Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  59. George Mells
    View author publications

    You can also search for this author in PubMed Google Scholar

  60. Richard N Sandford
    View author publications

    You can also search for this author in PubMed Google Scholar

  61. Graeme Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  62. Daniel J Gaffney
    View author publications

    You can also search for this author in PubMed Google Scholar

  63. Roger W Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

  64. Gideon M Hirschfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  65. Mariza de Andrade
    View author publications

    You can also search for this author in PubMed Google Scholar

  66. Simon M Rushbrook
    View author publications

    You can also search for this author in PubMed Google Scholar

  67. Andre Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  68. Tom H Karlsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  69. Konstantinos N Lazaridis
    View author publications

    You can also search for this author in PubMed Google Scholar

  70. Carl A Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing