Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease1,2,3,4,5,6,7,8, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

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Acknowledgements

We thank all individuals who contributed samples to the study. This work was co-funded by the Wellcome Trust (098051) and the Medical Research Council, UK (MR/J00314X/1). Case collections were supported by Crohn's and Colitis UK. K.M.d.L., L.M., C.A.L., Y.L., D.R., J.G.-A., N.J.P., C.A.A. and J.C.B. are supported by the Wellcome Trust (098051; 093885/Z/10/Z; 094491/Z/10/Z). K.M.d.L. is supported by a Woolf Fisher Trust scholarship. C.A.L. is a clinical lecturer funded by the NIHR. We thank A. Stanton for coordinating the patient recruitment at Guy's and St. Thomas'. We acknowledge support from the UK Department of Health via NIHR comprehensive Biomedical Research Centre awards to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London and to Addenbrooke's Hospital, Cambridge, in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen, and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website.

Author information

Author notes

    • Katrina M de Lange
    • , Loukas Moutsianas
    •  & James C Lee

    These authors contributed equally to this work.

    • Carl A Anderson
    •  & Jeffrey C Barrett

    These authors jointly directed this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Katrina M de Lange
    • , Loukas Moutsianas
    • , Yang Luo
    • , Daniel L Rice
    • , Javier Gutierrez-Achury
    • , Sun-Gou Ji
    • , Carl A Anderson
    •  & Jeffrey C Barrett
  2. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
    •  & Miles Parkes
  3. Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

    • Christopher A Lamb
  4. Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Yang Luo
  5. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Yang Luo
  6. Precision Medicine Exeter, University of Exeter, Exeter, UK.

    • Nicholas A Kennedy
    • , Graham Heap
    •  & Tariq Ahmad
  7. IBD Pharmacogenetics, Royal Devon and Exeter Foundation Trust, Exeter, UK.

    • Nicholas A Kennedy
    • , Graham Heap
    •  & Tariq Ahmad
  8. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

    • Luke Jostins
  9. Christ Church, University of Oxford, St Aldates, UK.

    • Luke Jostins
  10. Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.

    • Elaine R Nimmo
    • , Jack Satsangi
    •  & Charlie W Lees
  11. Department of Gastroenterology, Torbay Hospital, Torbay, UK.

    • Cathryn Edwards
  12. Department of Child Life and Health, University of Edinburgh, Edinburgh, UK.

    • Paul Henderson
    •  & David C Wilson
  13. Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.

    • Paul Henderson
  14. Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.

    • Craig Mowat
  15. Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, Department of Gastroenterology, London, UK.

    • Jeremy Sanderson
  16. Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.

    • Alison Simmons
    •  & Holm Uhlig
  17. Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Alison Simmons
  18. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.

    • David C Wilson
  19. Gastroenterology and General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.

    • Mark Tremelling
  20. Department of Medicine, St. Mark's Hospital, Harrow, UK.

    • Ailsa Hart
  21. Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Natalie J Prescott
  22. Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.

    • Christopher G Mathew
  23. Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.

    • William G Newman
  24. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.

    • William G Newman
  25. Department of Paediatrics, University of Oxford, Oxford, UK.

    • Holm Uhlig
  26. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.

    • Chris Hawkey
  27. Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, UK.

    • John C Mansfield

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Contributions

K.M.d.L., L.M., Y.L., L.J., D.L.R., C.A.A. and S.-G.J. performed statistical analysis. K.M.d.L., L.M., Y.L., L.J., J.C.L., J.G.-A., S.-G.J., C.A.L., N.A.K. and C.A.A. analyzed the data. G.H., E.R.N., C.E., C.M., A.S., D.C.W., M.T., A.H., C.G.M., M.P., W.G.M., C.W.L., H.U., C.H., N.J.P., T.A., J.C.M., J. Satsangi, J. Sanderson and P.H. contributed samples and/or materials. C.A.A., J.C.B., K.M.d.L., L.M., J.C.L., C.G.M., M.P., C.A.L., N.A.K., Y.L. and P.H. wrote the manuscript. J.C.B., C.A.A., J.C.M., M.P., C.W.L., T.A. and N.J.P. conceived and designed experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carl A Anderson or Jeffrey C Barrett.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

Excel files

  1. 1.

    Supplementary Table 1

    GWAS, sequencing and summary statistic data sets included in this study.

  2. 2.

    Supplementary Table 2

    Meta-analysis association statistics at all 241 known and novel loci.

  3. 3.

    Supplementary Table 3

    Fine-mapping summary statistics for 65 loci where fine-mapping was attempted.

  4. 4.

    Supplementary Table 4

    Enrichment of known IBD loci for genes associated with Mendelian disorders of inflammation and immunity.

  5. 5.

    Supplementary Table 5

    Colocalization between meta-analysis association statistics and monocyte stimulus response eQTLs.

  6. 6.

    Supplementary Table 6

    IBD-associated loci containing genes in immune pathways related to classes of approved therapeutics.

  7. 7.

    Supplementary Table 7

    Overlap of 25 novel IBD-associated loci with known eQTL signals.