Article | Published:

Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Nature Genetics volume 48, pages 510518 (2016) | Download Citation

Abstract

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

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Acknowledgements

We thank all patients with ankylosing spondylitis, Crohn's disease, PSC, psoriasis and ulcerative colitis, their families, healthy control individuals and clinicians for their participation in this study. We thank T. Wesse, T. Henke, S. Sedghpour Sabet, R. Vogler, G. Jacobs, I. Urbach, W. Albrecht, V. Pelkonen, K. Holm, H. Dahlen Sollid, B. Woldseth, J.A. Anmarkrud and L. Wenche Torbjørnsen for expert help. F. Braun, W. Kreisel, T. Berg and R. Günther are acknowledged for contributing German patients with PSC. B.A. Lie and the Norwegian Bone Marrow Donor Registry at Oslo University Hospital, Rikshospitalet, in Oslo and the Nord-Trøndelag Health Study (HUNT) are acknowledged for sharing the healthy Norwegian controls. This work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A). This project received infrastructure support from Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 'Inflammation at Interfaces' and the PopGen Biobank. A.F. receives an endowment professorship by the Foundation for Experimental Medicine (Zurich, Switzerland). The Estonian Genome Center at the University of Tartu (EGCUT) received targeted financing from Estonian Research Council grant IUT20-60, the Center of Excellence in Genomics (EXCEGEN) and the University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially V. Soo and S. Smit. Data analyses were carried out in part at the High-Performance Computing Center of the University of Tartu. We acknowledge support from the UK Department of Health via National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre awards to Guy's and St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and to Addenbrooke's Hospital in partnership with the University of Cambridge. The study was supported by the German Federal Ministry of Education and Research (BMBF), within the context of National Genome Research Network 2 (NGFN-2), National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (grants 01GS08144 and 01GS08147). R.K.W. is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO). J.H. was supported by the Swedish Research Council (521-2011-2764). This work is supported in part by funding from the US NIH (1R01AR063759 (S.R.), 5U01GM092691-05 (S.R.), 1UH2AR067677-01 (S.R.), U19AI111224-01 (S.R.) and 1R01DK084960-05 (K.N.L.)) and Doris Duke Charitable Foundation grant 2013097. A.B.J. and S.B. acknowledge funding from the Novo Nordisk Foundation (grant NNF14CC0001) and the H2020 project MedBioinformatics (grant 634143). The study was supported by the Norwegian PSC Research Center. We thank G. Trynka for assistance in setting up GoShifter.

Author information

Author notes

    • David Ellinghaus

    Present address: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • Matthew A Brown
    •  & Andre Franke

    These authors jointly supervised this work.

Affiliations

  1. Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.

    • David Ellinghaus
    • , Jörn Bethune
    • , Matthias Hübenthal
    • , Stefan Schreiber
    • , Eva Ellinghaus
    •  & Andre Franke
  2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Luke Jostins
    • , Sarah L Spain
    •  & Jeffrey C Barrett
  3. Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK.

    • Adrian Cortes
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Adrian Cortes
  5. Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.

    • Buhm Han
  6. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

    • Yu Rang Park
  7. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Soumya Raychaudhuri
    • , Harm-Jan Westra
    •  & Tune H Pers
  8. Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
    •  & Harm-Jan Westra
  9. Division of Rheumatology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
    •  & Harm-Jan Westra
  10. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
    •  & Harm-Jan Westra
  11. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

    • Jennie G Pouget
  12. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

    • Jennie G Pouget
  13. Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Trine Folseraas
    •  & Tom H Karlsen
  14. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Trine Folseraas
    •  & Tom H Karlsen
  15. Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

    • Trine Folseraas
    •  & Tom H Karlsen
  16. Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.

    • Trine Folseraas
    •  & Tom H Karlsen
  17. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Yunpeng Wang
    •  & Anders M Dale
  18. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tonu Esko
    •  & Andres Metspalu
  19. Division of Endocrinology, Boston Children's Hospital, Cambridge, Massachusetts, USA.

    • Tonu Esko
  20. Center for Basic and Translational Obesity Research, Boston Children's Hospital, Cambridge, Massachusetts, USA.

    • Tonu Esko
    •  & Tune H Pers
  21. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.

    • Lude Franke
  22. Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

    • Tune H Pers
  23. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Tune H Pers
  24. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

    • Rinse K Weersma
    •  & Valerie Collij
  25. Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Mauro D'Amato
  26. BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.

    • Mauro D'Amato
  27. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

    • Jonas Halfvarson
  28. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Anders Boeck Jensen
    •  & Søren Brunak
  29. Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany.

    • Wolfgang Lieb
  30. PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany.

    • Wolfgang Lieb
  31. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Franziska Degenhardt
    • , Andreas J Forstner
    •  & Andrea Hofmann
  32. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.

    • Franziska Degenhardt
    • , Andreas J Forstner
    •  & Andrea Hofmann
  33. Department of General Internal Medicine, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel, Germany.

    • Stefan Schreiber
  34. Department of Dermatology, University Hospital, Schleswig-Holstein, Christian Albrechts University of Kiel, Kiel, Germany.

    • Ulrich Mrowietz
    • , Stephan Weidinger
    •  & Michael Weichenthal
  35. 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
  36. Department of Radiology, University of California, San Diego, La Jolla, California, USA.

    • Anders M Dale
  37. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Richard C Trembath
  38. Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA.

    • James T Elder
  39. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA.

    • James T Elder
  40. St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Jonathan N W N Barker
  41. NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

    • Ole A Andreassen
  42. Division of Mental Health and Addiction, Oslo University Hospital, Ullevål, Oslo, Norway.

    • Ole A Andreassen
  43. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA.

    • Dermot P McGovern
  44. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Dermot P McGovern
  45. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • Miles Parkes
  46. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.

    • Matthew A Brown
  47. Institute of Health and Biomedical Innovation (IHBI), Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, Queensland, Australia.

    • Matthew A Brown

Consortia

  1. The International IBD Genetics Consortium (IIBDGC)

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

  2. International Genetics of Ankylosing Spondylitis Consortium (IGAS)

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

  3. International PSC Study Group (IPSCSG)

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

  4. Genetic Analysis of Psoriasis Consortium (GAPC)

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

  5. Psoriasis Association Genetics Extension (PAGE)

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

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Contributions

D.E., L.J., S.L.S., A.C., J.B., B.H., Y.R.P., J.G.P., S.R., Y.W., T.E., H.-J.W., L.F., T.H.P., R.K.W., V.C., O.A.A., A.B.J., S.B. and A.M.D. performed statistical and computational analyses. M.H. performed computational analyses. T.F., A.M., M.D'A., J.H., W.L., F.D., A.J.F., A.H., S.S., U.M., B.D.J., K.N.L., R.C.T., S.W., M.W., E.E., J.T.E., J.N.W.N.B. and M.A.B. were involved in study subject recruitment and assembling phenotypic data. D.E. wrote the draft of the manuscript. D.E., D.P.M., T.H.K., J.C.B., M.P., M.A.B. and A.F. conceived, designed and managed the study. All authors reviewed, edited and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Ellinghaus.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1, 4 and 7–17, Supplementary Figures 1–3 and 7–17, and Supplementary Note.

  2. 2.

    Supplementary Figure 4

    Regional association plots for 244 independent association signals within 169 genome-wide significant non-MHC risk loci.

  3. 3.

    Supplementary Figure 5

    Synthesis-View plots showing the multidisease association signals for 244 independent association signals within 169 genome-wide significant non-MHC risk loci.

  4. 4.

    Supplementary Figure 6

    Pairwise comparisons of variance explained per risk variant between ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis (PS), primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) for a maximum of 244 independent signals from 169 risk loci.

Excel files

  1. 1.

    Supplementary Table 2

    Twenty-seven newly identified single-disease associations with genome-wide significance.

  2. 2.

    Supplementary Table 3

    Summary of 169 non-MHC genome-wide significant susceptibility loci.

  3. 3.

    Supplementary Table 5

    Functional in silico annotations of risk SNPs.

  4. 4.

    Supplementary Table 6

    Analysis of cis-eQTL data from whole peripheral samples of 2,360 unrelated individuals.

About this article

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DOI

https://doi.org/10.1038/ng.3528

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