Nature 464, 713-720 (1 April 2010) | doi:10.1038/nature08979; Received 16 October 2009; Accepted 5 March 2010

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

The Wellcome Trust Case Control Consortium

  1. MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  2. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  3. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
  4. The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  5. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
  6. Departments of Health Sciences and Genetics, University of Leicester, 217 Adrian Building, University Road, Leicester LE1 7RH, UK.
  7. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry University of Exeter, Exeter EX1 2LU, UK.
  8. Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 0PT, UK.
  9. National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge CB2 0PT, UK.
  10. Multidisciplinary Cardiovascular Research Centre (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK.
  11. arc Epidemiology Unit, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
  12. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
  13. Department of Medical and Molecular Genetics, King’s College London School of Medicine, 8th Floor Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK.
  14. Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK.
  15. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
  16. IBD Genetics Research Group, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
  17. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
  18. SGDP, The Institute of Psychiatry, King’s College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
  19. Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK.
  20. Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
  21. Department of Psychiatry, University of Birmingham, National Centre for Mental Health, 25 Vincent Drive, Birmingham B15 2FG, UK.
  22. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
  23. Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
  24. Academic Unit of Genetic Medicine, University of Southampton, Southampton SO16 5YA, UK.
  25. Endoscopy Regional Training Unit, Torbay Hospital, Torbay TQ2 7AA, UK.
  26. Academic Unit of Musculoskeletal Disease, University of Leeds, Chapel Allerton Hospital, Leeds, West Yorkshire LS7 4SA, UK.
  27. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK.
  28. Department of Medical Genetics, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester M13 0JH, UK.
  29. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
  30. The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, MaRS Centre–East Tower, 101 College St, Room 14-701, Toronto, Ontario M5G 1L7, Canada.
  31. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala 75185, Sweden.
  32. Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK.
  33. University Hospital Birmingham NHS Foundation Trust, Birmingham B15 2TT, UK.
  34. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Magdalen Road, Exeter EX1 2LU, UK.
  35. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
  36. University of Oxford, Institute of Musculoskeletal Sciences, Botnar Research Centre, Oxford OX3 7LD, UK.
  37. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.
  38. Bone Research Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, UK.
  39. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
  40. Institute of Cellular Medicine, Musculoskeletal Research Group, 4th Floor, Catherine Cookson Building, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  41. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
  42. Centre National de Genotypage, 2 Rue Gaston Cremieux, Evry, Paris 91057, France.
  43. Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
  44. ALSPAC Laboratory, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK.
  45. Division of Nutritional Sciences, King’s College London School of Biomedical and Health Sciences, London SE1 9NH, UK.
  46. NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Chapel Allerton Hospital, Leeds, West Yorkshire LS7 4SA, UK.
  47. Department of General Internal Medicine, Ninewells Hospital and Medical School, Ninewells Avenue, Dundee DD1 9SY, UK.
  48. INSERM UMR915, L’Institut du Thorax, Nantes 44035, France.
  49. Clinical and Academic Rheumatology, Kings College Hospital National Health Service Foundation Trust, Denmark Hill, London SE5 9RS, UK.
  50. University of Toronto, St Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
  51. University of Bath, Claverdon, Norwood House, Room 5.11a, Bath, Somerset BA2 7AY, UK.
  52. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  53. Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK.
  54. School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield S10 2JF, UK.
  55. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Windmill Road, Headington, Oxford OX3 7LD, UK.
  56. UBC Institute of Mental Health, 430-5950 University Boulevard Vancouver, British Columbia V6T 1Z3, Canada.
  57. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK.
  58. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  59. Division of Community Health Sciences, St George’s, University of London, London SW17 0RE, UK.
  60. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia.
  61. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
  62. Genetics of Diabetes, Peninsula College of Medicine and Dentistry, University of Exeter, Barrack Road, Exeter EX2 5DW, UK.
  63. Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
  64. The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.
  65. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
  66. Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.
  67. Lists of authors and their affiliations appear at the end of the paper.
  68. These authors contributed equally to this work.

Correspondence to: Correspondence and requests for materials should be addressed to P.D. (Email:


Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease—IRGM for Crohn’s disease, HLA for Crohn’s disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes—although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.


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