Abstract

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).

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Acknowledgements

The authors wish to thank all PSC cases and healthy controls for their participation. We also thank K. Cloppenborg-Schmidt, I. Urbach, I. Pauselis, T. Wesse, T. Henke, R. Vogler, B. Stade, T. Vennegerts, P.R. Berg, H.D. Sollid and B. Woldseth for expert technical help. We are grateful to M.K. Viken and M. Nothnagel for helpful discussions. We acknowledge B.A. Lie and the Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet for contributing the healthy Norwegian control population. We acknowledge F. Braun, W. Kreisel, T. Berg and R. Günther for contributing German PSC cases. We acknowledge A. Strasser for generating and kindly providing the Bcl2l11−/− mouse model. We greatly acknowledge A. Kaser for managing the Bcl2l11−/− liver histology assessment and for helpful discussions on the functional implications of all findings. The study was supported by The Norwegian PSC research center, the German Federal Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN), the PopGen biobank, the Integrated Research and Treatment Center–Transplantation (reference number: 01EO0802), the Palumbo Charitable Trust, the Musette and Allen Morgan Jr. Foundation for the Study of PSC, PSC Partners Seeking a Cure and the Mayo Clinic College of Medicine. The project received infrastructure support through the Norwegian Functional Genomics Programme (FUGE) through the 'CIGENE' platform, the Research Computing Services at the University of Oslo and the Deutsche Forschungsgemeinschaft (DFG) excellence cluster 'Inflammation at Interfaces'. The Kooperative Gesundheitsforschung in der Region Augsburg (KORA) research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). This research was also supported within the Munich Center of Health Sciences (MC Health) as part of Ludwig-Maximilians-Universität (LMU) innovativ.

Author information

Author notes

    • Espen Melum
    •  & Andre Franke

    These authors contributed equally to this work.

    • Stefan Schreiber
    •  & Tom H Karlsen

    These authors jointly directed this work.

Affiliations

  1. Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Espen Melum
    • , Kirsten Muri Boberg
    • , Johannes Roksund Hov
    • , Kristian Holm
    • , Erik Schrumpf
    •  & Tom H Karlsen
  2. Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Espen Melum
    •  & Johannes Roksund Hov
  3. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

    • Andre Franke
    • , Eva Ellinghaus
    • , Tobias Balschun
    • , David Ellinghaus
    • , Michael Wittig
    •  & Stefan Schreiber
  4. 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Christoph Schramm
    •  & Martina Sterneck
  5. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

    • Tobias J Weismüller
    • , Jochen Wedemeyer
    •  & Michael P Manns
  6. Integrated Research and Treatment Center-Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.

    • Tobias J Weismüller
    • , Jochen Wedemeyer
    •  & Michael P Manns
  7. Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.

    • Daniel Nils Gotthardt
    • , Peter Sauer
    •  & Adolf Stiehl
  8. Academic Teaching Hospital Feldkirch, Feldkirch, Austria.

    • Felix A Offner
  9. 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
  10. Centre for Molecular Biology and Neuroscience (CMBN) and Institute of Medical Microbiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Jon K Laerdahl
  11. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.

    • Verena Labi
    •  & Andreas Villunger
  12. Section of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.

    • Einar Björnsson
    •  & Björn Lindkvist
  13. Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Rinse K Weersma
  14. Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Liesbet Henckaerts
    •  & Severine Vermeire
  15. 1st Department of Medicine, University of Mainz, Mainz, Germany.

    • Andreas Teufel
  16. Department of Medicine 2, Grosshadern, University of Munich, Munich, Germany.

    • Christian Rust
  17. Department of Gastroenterology and Hepatology, Karolinska University Hospital Huddinge, Stockholm, Sweden.

    • Annika Bergquist
  18. Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Euijung Ryu
  19. Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Robert J Porte
  20. Institute of Epidemiology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
    •  & H-Erich Wichmann
  21. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany.

    • H-Erich Wichmann
  22. Klinikum Grosshadern, Munich, Germany.

    • H-Erich Wichmann
  23. Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Pieter Stokkers
    • , Cyriel Y Ponsioen
    •  & Ulrich Beuers
  24. Department of Human Genetics, University Hospital of Heidelberg, Heidelberg, Germany.

    • Heiko Runz
  25. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Cisca Wijmenga
  26. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.

    • Stefan Schreiber

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Contributions

E.M. performed data analysis. A.F. and T.H.K. supervised data analysis and coordinated project contributions. E.E., T.B., D.E., J.R.H. and E.R. helped with data analysis. F.A.O., V.L. and A.V. performed the Bcl2l11−/− animal work and liver histology assessments. J.K.L. performed in silico analysis of chromosome 2q13 transcripts. M.W. and K.H. were responsible for in-house conversion and database management of genome-wide association study data. C.S., T.J.W., D.N.G., B.D.J., E.B., R.K.W., L.H., A.T., C.R., K.M.B., C.G., H.-E.W., A.B., P. Sauer, J.W., B.L., R.J.P., P. Stokkers, C.Y.P., H.R., A.S., C.W., M.S., S.V., U.B., E.S., K.N.L., M.P.M. and S.S. provided the case populations and healthy controls. S.S., A.F., T.H.K. and E.M. designed the experiment. E.M. and T.H.K. drafted the manuscript. All authors revised the manuscript and approved of the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tom H Karlsen.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1 and 2, Supplementary Figures 1–5 and Supplementary Methods

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DOI

https://doi.org/10.1038/ng.728

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