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Abstract

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

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Change history

  • 12 July 2017

    The equation at the end Methods section ‘Establishing a P value threshold’ was corrected.

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Acknowledgements

We thank M. Khan and B. Wong for their assistance in designing illustrations, and K. de Lange for comments on the Supplementary Methods. We received support from the following grants. M.J.D. and R.J.X.: P30DK43351, U01DK062432, R01DK64869, Helmsley grant 2015PG-IBD001 and Crohn’s & Colitis Foundation of America. G.T., C.A.A. and J.C.B: Wellcome Trust grant 098051. M.G.: Fonds de la Recherche Scientifique-FNRS for the FRFS-WELBIO under grant no. WELBIO-CR-2012A-06 (CAUSIBD), BELSPO-IUAP-P7/43-BeMGI, Fédération Wallonie-Bruxelles (ARC IBD@Ulg), and Région Wallonne (CIBLES, FEDER). H.H.: ASHG/Charles J. Epstein Trainee Award. J.L.: Wellcome Trust 098759/Z/12/Z. D.M.: Olle Engkvist Foundation and Swedish Research Council (grants 2010-2976 and 2013-3862). R.K.W.: VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research. J.D.R.: Canada Research Chair, National Institute of Diabetes and Digestive and Kidney Diseases grants DK064869 and DK062432, CIHR GPG-102170 from the Canadian Institutes of Health Research, GPH-129341 from Genome Canada and Génome Québec, and Crohn’s Colitis Canada. J.H.C.: DK062429, DK062422, DK092235, DK106593, and the Sanford J. Grossman Charitable Trust. R.H.D.: Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh, U01DK062420 and R01CA141743. E.D.: Marie-Curie Fellowship. A.-S.G: Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) and Fonds Léon Fredericq fellowships. J.H.: Örebro University Hospital Research Foundation and the Swedish Research Council (grant number 521 2011 2764). C.G.M. and M.P.: National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy’s & St Thomas’ NHS Trust/King’s College London and to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine. D.E.: German Federal Ministry of Education and Research (SysInflame grant 01ZX1306A), DFG Excellence Cluster number 306 ‘Inflammation at Interfaces’. A.F.: Professor of Foundation for Experimental Medicine (Zurich, Switzerland). D.P.B.M.: DK062413, AI067068, U54DE023789-01, 305479 from the European Union, and The Leona M. and Harry B. Helmsley Charitable Trust. Additional acknowledgements for the original data are in the Supplementary Information.

Author information

Author notes

    • Hailiang Huang
    • , Ming Fang
    •  & Luke Jostins

    These authors contributed equally to this work.

    • Hailiang Huang
    • , Michel Georges
    • , Mark J. Daly
    •  & Jeffrey C. Barrett

    These authors jointly supervised this work.

Affiliations

  1. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Hailiang Huang
    • , Kyle Kai-How Farh
    •  & Mark J. Daly
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA

    • Hailiang Huang
    • , Kyle Kai-How Farh
    • , Ramnik J. Xavier
    •  & Mark J. Daly
  3. Unit of Medical Genomics, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-R) Research Center and WELBIO, University of Liège, 4000 Liège, Belgium

    • Ming Fang
    • , François Crins
    • , Valérie Deffontaine
    • , Julia Dmitrieva
    • , Elisa Docampo
    • , Mahmoud Elansary
    • , Ann-Stephan Gori
    • , Edouard Louis
    • , Rob Mariman
    • , Myriam Mni
    • , Yukihide Momozawa
    • , Emilie Théâtre
    •  & Michel Georges
  4. Faculty of Veterinary Medicine, University of Liège, 4000 Liège, Belgium

    • Ming Fang
    • , François Crins
    • , Valérie Deffontaine
    • , Julia Dmitrieva
    • , Elisa Docampo
    • , Mahmoud Elansary
    • , Ann-Stephan Gori
    • , Rob Mariman
    • , Myriam Mni
    • , Yukihide Momozawa
    • , Emilie Théâtre
    •  & Michel Georges
  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington OX3 7BN, UK

    • Luke Jostins
    •  & Adrian Cortes
  6. Christ Church, University of Oxford, St Aldates OX1 1DP, UK

    • Luke Jostins
  7. Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK

    • Maša Umićević Mirkov
    • , Carl A. Anderson
    • , Sarah L. Spain
    • , Gosia Trynka
    •  & Jeffrey C. Barrett
  8. Research Center, Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada

    • Gabrielle Boucher
    • , Philippe Goyette
    •  & John D. Rioux
  9. Focused research unit for Molecular Diagnostic and Clinical Research (MOK), IRS-Center Sonderjylland, Hospital of Southern Jutland, 6200 Åbenrå, Denmark

    • Vibeke Andersen
  10. Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark

    • Vibeke Andersen
  11. Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium

    • Isabelle Cleynen
    •  & Severine Vermeire
  12. Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK

    • Adrian Cortes
  13. Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, 17176 Stockholm, Sweden

    • Mauro D’Amato
  14. Department of Gastrointestinal and Liver Diseases, BioDonostia Health Research Institute, 20014 San Sebastián, Spain

    • Mauro D’Amato
  15. IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain

    • Mauro D’Amato
  16. Illumina, San Diego, California 92122, USA

    • Kyle Kai-How Farh
  17. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany

    • Andre Franke
  18. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden

    • Jonas Halfvarson
  19. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

    • Talin Haritunians
    •  & Dermot P. B. McGovern
  20. Data Science Institute and Lancaster Medical School, Lancaster University, Lancaster LA1 4YG, UK

    • Jo Knight
  21. Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia 6008, Australia

    • Ian C. Lawrance
  22. Harry Perkins Institute for Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, Western Australia 6150, Australia

    • Ian C. Lawrance
  23. Gastrointestinal Unit, Western General Hospital University of Edinburgh, Edinburgh, UK

    • Charlie W. Lees
    •  & Jack Satsangi
  24. Division of Gastroenterology, Centre Hospitalier Universitaire (CHU) de Liège, 4000 Liège, Belgium

    • Edouard Louis
  25. Institute of Livestock and Aquacultural Sciences, Norwegian University of Life Sciences, 1430 Ås, Norway

    • Theo Meuwissen
  26. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Kanagawa 230-0045, Japan

    • Yukihide Momozawa
  27. Inflammatory Bowel Disease Research Group, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK

    • Miles Parkes
  28. Open Targets, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK

    • Sarah L. Spain
  29. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, 9700RB Groningen, The Netherlands

    • Suzanne van Sommeren
    •  & Rinse K. Weersma
  30. Division of Gastroenterology, University Hospital Gasthuisberg, 3000 Leuven, Belgium

    • Severine Vermeire
  31. Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Ramnik J. Xavier
  32. Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • Richard H. Duerr
  33. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA

    • Richard H. Duerr
  34. Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK

    • Christopher G. Mathew
  35. Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2193, South Africa

    • Christopher G. Mathew
  36. Faculté de Médecine, Université de Montréal, Montréal, Québec H3C 3J7, Canada

    • John D. Rioux
  37. Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA

    • Judy H. Cho

Consortia

  1. International Inflammatory Bowel Disease Genetics Consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

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Contributions

Overall project supervision and management: M.J.D. J.C.B., M.G. Fine-mapping algorithms: H.H., M.F., L.J. TFBS analyses: H.H., K.F. Epigenetic analyses: M.U.M., G.T. eQTL dataset generation: E.L., E.T., J.D., E.D., M.E., R.M., M.M., Y.M., V.D., A.G. eQTL analyses: M.F., J.D., L.J., A.C. Variance component analysis: T.M., M.F. Contribution to overall statistical analyses: G.B. Primary drafting of the manuscript: M.J.D., J.C.B, M.G., H.H., L.J. Major contribution to drafting of the manuscript: M.F., M.U.M., J.H.C., D.P.B.M., J.D.R., C.G.M., R.H.D., R.K.W. The remaining authors contributed to the study conception, design, genotyping quality control, and/or writing of the manuscript. All authors saw, had the opportunity to comment on, and approved the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hailiang Huang or Michel Georges or Mark J. Daly or Jeffrey C. Barrett.

Reviewer Information Nature thanks A. Morris, C. Polychronakos, L. Scott, and T. Vyse for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods, Supplementary Notes, a Supplementary Box, the full list of members of the International Inflammatory Bowel Disease Genetics Consortium and acknowledgements for the original data.

Excel files

  1. 1.

    Supplementary Table 1

    This table contains a list of all fine-mapped signals, a list of all variants in fine-mapped signals and Functional annotation for all fine-mapped signals.

  2. 2.

    Supplementary Table 2

    This table shows enrichment for histone marks in various cell lines.

  3. 3.

    Supplementary Table 3

    This table shows test of heterogeneity between the balanced and imbalanced cohorts.

About this article

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DOI

https://doi.org/10.1038/nature22969

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