To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at 12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

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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., Y.L., C.A.L., C.A.A. and J.C.B. are supported by the Wellcome Trust (098051; 093885/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. H.U. is supported by the Crohn's and Colitis Foundation of America (CCFA) and the Leona M. and Harry B. Helmsley Charitable Trust. 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, and the BRC to the Oxford IBD cohort study, University of Oxford. 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. We are grateful for genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren's Disease consortium and L. Southam for assistance with genotype intensities. This research has been conducted using the UK Biobank Resource.

Author information

Author notes

    • Yang Luo
    •  & Katrina M de Lange

    These authors contributed equally to this work.

    • Jeffrey C Barrett
    •  & Carl A Anderson

    These authors jointly supervised this work.


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

    • Yang Luo
    • , Katrina M de Lange
    • , Loukas Moutsianas
    • , Joshua Randall
    • , Shane McCarthy
    • , Eva Goncalves Serra
    • , Sam Nichols
    • , Martin Pollard
    • , Jeffrey C Barrett
    •  & Carl A Anderson
  2. Division of Genetics and Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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

    • Yang Luo
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, UK.

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

    • Luke Jostins
  6. Precision Medicine Exeter, University of Exeter, Exeter, UK.

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

    • Nicholas A Kennedy
    •  & Tariq Ahmad
  8. Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

    • Christopher A Lamb
  9. Department of Gastroenterology, Torbay Hospital, Torbay, UK.

    • Cathryn Edwards
  10. Department of Medicine, St Mark's Hospital, Harrow, UK.

    • Ailsa Hart
  11. Nottingham Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.

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

    • John C Mansfield
  13. Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK.

    • Craig Mowat
  14. Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK.

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

    • William G Newman
  16. Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, UK.

    • Jack Satsangi
    •  & Charlie W Lees
  17. Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.

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

    • Alison Simmons
  19. Gastroenterology and General Medicine, Norfolk and Norwich University Hospital, Norwich, UK.

    • Mark Tremelling
  20. Department of Paediatrics, University of Oxford, Oxford, UK.

    • Holm Uhlig
  21. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, UK.

    • David C Wilson
  22. Child Life and Health, University of Edinburgh, Edinburgh, UK.

    • David C Wilson
  23. Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
    •  & Miles Parkes
  24. Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, Guy's Hospital, London, UK.

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

    • Christopher G Mathew


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Y.L., K.M.d.L., L.J., L.M., J.C.B. and C.A.A. performed statistical analysis. Y.L., K.M.d.L., L.J., L.M., J.C.L., C.A.L., E.G.S., J.R., M. Pollard, S.N. and S.M. processed the data. T.A., C.E., N.A.K., A.H., C.H., J.C.M., J.C.L., C.M., W.G.N., J.S., A.S., M.T., H.U., D.C.W., N.J.P., C.W.L., M. Parkes and C.G.M. contributed samples and/or materials. Y.L., K.M.d.L., L.M., J.C.L., M. Parkes, C.A.L., N.A.K., J.C.B. and C.A.A. wrote the manuscript. All authors read and approved the final version of the manuscript. J.C.M., M. Parkes, C.W.L., T.A., N.J.P., J.C.B. and C.A.A. conceived and designed experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jeffrey C Barrett or Carl A Anderson.

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