Abstract

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

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Acknowledgements

R.K.W. is supported by a VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research (NWO) and the Broad Medical Research Program of the Broad Foundation (IBD-0318). L.F. is supported by the Netherlands Organization for Scientific Research (NWO), through NWO VENI grant 916.10.135 and NWO VIDI grant 917.14.374. The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007–2013) under grant agreement 259867. T.B.K. is supported by Centre of Excellence grant BT/01/COE/07/UDSC/2008 from the Department of Biotechnology of the government of India (New Delhi, India). The collection of Iranian samples has been supported by the Tehran University of Medical Sciences, Iran. UK case collections were supported by the National Association for Colitis and Crohn's Disease, the Wellcome Trust, the Medical Research Council UK and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy's and St Thomas' NHS Trust/King's College London and to Addenbrooke's Hospital/University of Cambridge School of Clinical Medicine. A.P.M. is supported by the Wellcome Trust under award WT098017. J.Z.L., T.S., J.C.B. and C.A.A. are supported by the Wellcome Trust (098051).

Author information

Author notes

    • Jimmy Z Liu
    •  & Suzanne van Sommeren

    These authors contributed equally to this work.

    • Michiaki Kubo
    • , Carl A Anderson
    •  & Rinse K Weersma

    These authors jointly supervised this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Jimmy Z Liu
    • , Tejas Shah
    • , Jeffrey C Barrett
    •  & Carl A Anderson
  2. Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Suzanne van Sommeren
    • , Rudi Alberts
    •  & Rinse K Weersma
  3. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Suzanne van Sommeren
    • , Lude Franke
    •  & Harm-Jan Westra
  4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Hailiang Huang
    • , Stephan Ripke
    •  & Mark J Daly
  5. Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong.

    • Siew C Ng
    •  & Joseph J Y Sung
  6. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.

    • Atsushi Takahashi
  7. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
    •  & Miles Parkes
  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

    • Luke Jostins
  9. Digestive Disease Research Institute, Shariati Hospital, Tehran, Iran.

    • Shifteh Abedian
    • , Hossein Poustchi
    • , Homayon Vahedi
    •  & Reza Malekzadeh
  10. Department of Gastroenterology and Hepatology, Yonsei University College of Medicine, Seoul, Korea.

    • Jae Hee Cheon
    •  & Won Ho Kim
  11. Icahn School of Medicine, Mount Sinai Hospital, New York, New York, USA.

    • Judy Cho
  12. Department of Gastroenterology, Emam Hospital, Tehran, Iran.

    • Naser E Daryani
  13. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.

    • Yuta Fuyuno
    • , Keiko Yamazaki
    •  & Michiaki Kubo
  14. Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK.

    • Ailsa Hart
  15. National Institute of Immunology, New Delhi, India.

    • Ramesh C Juyal
  16. Department of Genetics, University of Delhi South Campus, New Delhi, India.

    • Garima Juyal
    •  & Thelma B K
  17. Department of Biostatistics, University of Liverpool, Liverpool.

    • Andrew P Morris
  18. Manchester Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester, UK.

    • William G Newman
  19. Department of Medicine, Dayanand Medical College and Hospital, Ludhiana, India.

    • Vandana Midha
    •  & Ajit Sood
  20. Department of Gastroenterology and Hepatology, St. Mary's Hospital, London, UK.

    • Timothy R Orchard
  21. Department of Gastroenterology and Hepatology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

    • Suk-Kyun Yang
  22. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.

    • Andre Franke
  23. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Behrooz Z Alizadeh

Consortia

  1. International Multiple Sclerosis Genetics Consortium

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

  2. International IBD Genetics Consortium

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

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Contributions

Study design: J.Z.L., S.v.S., H.H., A.P.M., J.C.B., B.Z.A., M.P., T.B.K., M.J.D., A.F., C.A.A. and R.K.W. Collection of samples and clinical information: S.C.N., J.C.L., S.A., J.H.C., N.E.D., Y.F., A.H., R.C.J., G.J., W.H.K., H.P., W.G.N., V.M., T.R.O., H.V., A.S., J.J.Y.S., R.M., K.Y., S.-K.Y., M.K., T.B.K., A.F. and R.K.W. Quality control and genotype calling: J.Z.L., S.v.S., B.Z.A., H.H., L.J., T.S. and C.A.A. Statistical analyses: J.Z.L., S.v.S., H.H., A.T., L.J., R.A., S.R., H.-J.W., L.F., C.A.A. and R.K.W. Writing of the manuscript: J.Z.L., S.v.S., H.H., J.C.L., J.C., B.Z.A., M.P., C.A.A. and R.K.W.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carl A Anderson or Rinse K Weersma.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6 and 8–11, Supplementary Tables 4, 8, 10, 11 and 12, and Supplementary Note

  2. 2.

    Supplementary Figure 7

    Regional plots for the 38 novel IBD loci.

Excel files

  1. 1.

    Supplementary Table 1

    Association statistics from the trans-ancestry meta-analysis for all previously identified and novel loci.

  2. 2.

    Supplementary Table 2

    Minimal P values for association within each of the 231 IBD loci for each separate ancestral cohort.

  3. 3.

    Supplementary Table 3

    Heterogeneity of effect of associations among the four ancestry cohorts.

  4. 4.

    Supplementary Table 5

    Association results for the current analysis for all previously reported variants associated with non-European IBD.

  5. 5.

    Supplementary Table 6

    Functional Annotation 38 Novel SNPs - Expression Quantitative Trait Loci (eQTL) for the 38 novel IBD risk loci.

  6. 6.

    Supplementary Table 7

    ENCODE annotation of the 38 novel IBD risk SNPs.

  7. 7.

    Supplementary Table 9

    Functional annotation - GRAIL and DAPPLE results.

About this article

Publication history

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DOI

https://doi.org/10.1038/ng.3359

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