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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).

  2. 2.

    et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830–832 (2007).

  3. 3.

    et al. A genome-wide association study identifies 2 susceptibility loci for Crohn's disease in a Japanese population. Gastroenterology 144, 781–788 (2013).

  4. 4.

    et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011).

  5. 5.

    et al. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet. 8, e1002559 (2012).

  6. 6.

    et al. A genome-wide association study identifies a novel locus at 6q22.1 associated with ulcerative colitis. Hum. Mol. Genet. 23, 6927–6934 (2014).

  7. 7.

    et al. Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 63, 80–87 (2014).

  8. 8.

    et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510–518 (2016).

  9. 9.

    et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

  10. 10.

    et al. Searching for missing heritability: designing rare variant association studies. Proc. Natl. Acad. Sci. USA 111, E455–E464 (2014).

  11. 11.

    et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat. Genet. 43, 1066–1073 (2011).

  12. 12.

    et al. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet. 9, e1003723 (2013).

  13. 13.

    et al. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability. Nature 498, 232–235 (2013).

  14. 14.

    et al. Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes. PLoS Genet. 11, e1004955 (2015).

  15. 15.

    et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518, 102–106 (2015).

  16. 16.

    et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).

  17. 17.

    et al. Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nat. Neurosci. 19, 571–577 (2016).

  18. 18.

    et al. Association mapping of inflammatory bowel disease loci to single variant resolution. Preprint at bioRxiv (2015).

  19. 19.

    et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

  20. 20.

    , , , & Low-coverage sequencing: implications for design of complex trait association studies. Genome Res. 21, 940–951 (2011).

  21. 21.

    CONVERGE Consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588–591 (2015).

  22. 22.

    et al. Genome-wide association analyses based on whole-genome sequencing in Sardinia provide insights into regulation of hemoglobin levels. Nat. Genet. 47, 1264–1271 (2015).

  23. 23.

    UK10K Consortium. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).

  24. 24.

    et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

  25. 25.

    & Improving the accuracy and efficiency of identity-by-descent detection in population data. Genetics 194, 459–471 (2013).

  26. 26.

    et al. Large multiallelic copy number variations in humans. Nat. Genet. 47, 296–303 (2015).

  27. 27.

    et al. The genetic architecture of type 2 diabetes. Nature 536, 41–47 (2016).

  28. 28.

    et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

  29. 29.

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  30. 30.

    et al. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat. Genet. 41, 1330–1334 (2009).

  31. 31.

    Efficient haplotype matching and storage using the positional Burrows–Wheeler transform (PBWT). Bioinformatics 30, 1266–1272 (2014).

  32. 32.

    et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. (2017).

  33. 33.

    et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat. Med. 21, 1018–1027 (2015).

  34. 34.

    , , & Effects of forskolin on Kupffer cell production of interleukin-10 and tumor necrosis factor α differ from those of endogenous adenylyl cyclase activators: possible role for adenylyl cyclase 9. Infect. Immun. 73, 7290–7296 (2005).

  35. 35.

    et al. Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice. J. Immunol. 185, 335–344 (2010).

  36. 36.

    , & Zymosan activates protein kinase A via adenylyl cyclase VII to modulate innate immune responses during inflammation. Mol. Immunol. 54, 14–22 (2013).

  37. 37.

    et al. Higher TNFα responses in young males compared to females are associated with attenuation of monocyte adenylyl cyclase expression. Hum. Immunol. 76, 427–430 (2015).

  38. 38.

    , , & Capturing adenylyl cyclases as potential drug targets. Nat. Rev. Drug Discov. 8, 321–335 (2009).

  39. 39.

    et al. Subtle stratification confounds estimates of heritability from rare variants. Preprint at bioRxiv (2016).

  40. 40.

    , , & GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

  41. 41.

    et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and Immunochip data. Hum. Mol. Genet. 23, 4710–4720 (2014).

  42. 42.

    et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506, 185–190 (2014).

  43. 43.

    et al. Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic. Bioinformatics 30, 2179–2188 (2014).

  44. 44.

    et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).

  45. 45.

    , , & Cyclic AMP dysregulates intestinal epithelial cell restitution through PKA and RhoA. Inflamm. Bowel Dis. 18, 1081–1091 (2012).

  46. 46.

    et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

  47. 47.

    et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat. Neurosci. 19, 1433–1441 (2016).

  48. 48.

    et al. Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

  49. 49.

    et al. The UCSC Genome Browser Database: update 2006. Nucleic Acids Res. 34, D590–D598 (2006).

  50. 50.

    , & METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

  51. 51.

    & Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

  52. 52.

    & MultiBLUP: improved SNP-based prediction for complex traits. Genome Res. 24, 1550–1557 (2014).

Download references


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


  1. Search for Yang Luo in:

  2. Search for Katrina M de Lange in:

  3. Search for Luke Jostins in:

  4. Search for Loukas Moutsianas in:

  5. Search for Joshua Randall in:

  6. Search for Nicholas A Kennedy in:

  7. Search for Christopher A Lamb in:

  8. Search for Shane McCarthy in:

  9. Search for Tariq Ahmad in:

  10. Search for Cathryn Edwards in:

  11. Search for Eva Goncalves Serra in:

  12. Search for Ailsa Hart in:

  13. Search for Chris Hawkey in:

  14. Search for John C Mansfield in:

  15. Search for Craig Mowat in:

  16. Search for William G Newman in:

  17. Search for Sam Nichols in:

  18. Search for Martin Pollard in:

  19. Search for Jack Satsangi in:

  20. Search for Alison Simmons in:

  21. Search for Mark Tremelling in:

  22. Search for Holm Uhlig in:

  23. Search for David C Wilson in:

  24. Search for James C Lee in:

  25. Search for Natalie J Prescott in:

  26. Search for Charlie W Lees in:

  27. Search for Christopher G Mathew in:

  28. Search for Miles Parkes in:

  29. Search for Jeffrey C Barrett in:

  30. Search for Carl A Anderson in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11, Supplementary Tables 1–17 and Supplementary Note

About this article

Publication history






Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing