Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-06

AUTHORS

Paul R. Burton, David G. Clayton, Lon R. Cardon, Nick Craddock, Panos Deloukas, Audrey Duncanson, Dominic P. Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Nilesh J. Samani, John A. Todd, Peter Donnelly, Jeffrey C. Barrett, Paul R. Burton, Dan Davison, Peter Donnelly, Doug Easton, David Evans, Hin-Tak Leung, Jonathan L. Marchini, Andrew P. Morris, Chris C. A. Spencer, Martin D. Tobin, Lon R. Cardon, David G. Clayton, Antony P. Attwood, James P. Boorman, Barbara Cant, Ursula Everson, Judith M. Hussey, Jennifer D. Jolley, Alexandra S. Knight, Kerstin Koch, Elizabeth Meech, Sarah Nutland, Christopher V. Prowse, Helen E. Stevens, Niall C. Taylor, Graham R. Walters, Neil M. Walker, Nicholas A. Watkins, Thilo Winzer, John A. Todd, Willem H. Ouwehand, Richard W. Jones, Wendy L. McArdle, Susan M. Ring, David P. Strachan, Marcus Pembrey, Gerome Breen, David St Clair, Sian Caesar, Katherine Gordon-Smith, Lisa Jones, Christine Fraser, Elaine K. Green, Detelina Grozeva, Marian L. Hamshere, Peter A. Holmans, Ian R. Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael C. O'Donovan, Michael J. Owen, Nick Craddock, David A. Collier, Amanda Elkin, Anne Farmer, Richard Williamson, Peter McGuffin, Allan H. Young, I. Nicol Ferrier, Stephen G. Ball, Anthony J. Balmforth, Jennifer H. Barrett, D. Timothy Bishop, Mark M. Iles, Azhar Maqbool, Nadira Yuldasheva, Alistair S. Hall, Peter S. Braund, Paul R. Burton, Richard J. Dixon, Massimo Mangino, Suzanne Stevens, Martin D. Tobin, John R. Thompson, Nilesh J. Samani, Francesca Bredin, Mark Tremelling, Miles Parkes, Hazel Drummond, Charles W. Lees, Elaine R. Nimmo, Jack Satsangi, Sheila A. Fisher, Alastair Forbes, Cathryn M. Lewis, Clive M. Onnie, Natalie J. Prescott, Jeremy Sanderson, Christopher G. Mathew, Jamie Barbour, M. Khalid Mohiuddin, Catherine E. Todhunter, John C. Mansfield, Tariq Ahmad, Fraser R. Cummings, Derek P. Jewell, John Webster, Morris J. Brown, David G. Clayton, G. Mark Lathrop, John Connell, Anna Dominiczak, Nilesh J. Samani, Carolina A. Braga Marcano, Beverley Burke, Richard Dobson, Johannie Gungadoo, Kate L. Lee, Patricia B. Munroe, Stephen J. Newhouse, Abiodun Onipinla, Chris Wallace, Mingzhan Xue, Mark Caulfield, Martin Farrall, Anne Barton, The Biologics in RA Genetics and Genomics (BRAGGS), Ian N. Bruce, Hannah Donovan, Steve Eyre, Paul D. Gilbert, Samantha L. Hider, Anne M. Hinks, Sally L. John, Catherine Potter, Alan J. Silman, Deborah P. M. Symmons, Wendy Thomson, Jane Worthington, David G. Clayton, David B. Dunger, Sarah Nutland, Helen E. Stevens, Neil M. Walker, Barry Widmer, John A. Todd, Timothy M. Frayling, Rachel M. Freathy, Hana Lango, John R. B. Perry, Beverley M. Shields, Michael N. Weedon, Andrew T. Hattersley, Graham A. Hitman, Mark Walker, Kate S. Elliott, Christopher J. Groves, Cecilia M. Lindgren, Nigel W. Rayner, Nicholas J. Timpson, Eleftheria Zeggini, Mark I. McCarthy, Melanie Newport, Giorgio Sirugo, Emily Lyons, Fredrik Vannberg, Adrian V. S. Hill, Linda A. Bradbury, Claire Farrar, Jennifer J. Pointon, Paul Wordsworth, Matthew A. Brown, Jayne A. Franklyn, Joanne M. Heward, Matthew J. Simmonds, Stephen C. L. Gough, Sheila Seal, Breast Cancer Susceptibility Collaboration (UK), Michael R. Stratton, Nazneen Rahman, Maria Ban, An Goris, Stephen J. Sawcer, Alastair Compston, David Conway, Muminatou Jallow, Melanie Newport, Giorgio Sirugo, Kirk A. Rockett, Dominic P. Kwiatkowski, Suzannah J. Bumpstead, Amy Chaney, Kate Downes, Mohammed J. R. Ghori, Rhian Gwilliam, Sarah E. Hunt, Michael Inouye, Andrew Keniry, Emma King, Ralph McGinnis, Simon Potter, Rathi Ravindrarajah, Pamela Whittaker, Claire Widden, David Withers, Panos Deloukas, Hin-Tak Leung, Sarah Nutland, Helen E. Stevens, Neil M. Walker, John A. Todd, Doug Easton, David G. Clayton, Paul R. Burton, Martin D. Tobin, Jeffrey C. Barrett, David Evans, Andrew P. Morris, Lon R. Cardon, Niall J. Cardin, Dan Davison, Teresa Ferreira, Joanne Pereira-Gale, Ingileif B. Hallgrimsdóttir, Bryan N. Howie, Jonathan L. Marchini, Chris C. A. Spencer, Zhan Su, Yik Ying Teo, Damjan Vukcevic, Peter Donnelly, David Bentley, Matthew A. Brown, Lon R. Cardon, Mark Caulfield, David G. Clayton, Alistair Compston, Nick Craddock, Panos Deloukas, Peter Donnelly, Martin Farrall, Stephen C. L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V. S. Hill, Dominic P. Kwiatkowski, Christopher G. Mathew, Mark I. McCarthy, Willem H. Ouwehand, Miles Parkes, Marcus Pembrey, Nazneen Rahman, Nilesh J. Samani, Michael R. Stratton, John A. Todd, Jane Worthington

ABSTRACT

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined ∼2,000 individuals for each of 7 major diseases and a shared set of ∼3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 × 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn’s disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 × 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research. More... »

PAGES

661-678

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  • Journal

    TITLE

    Nature

    ISSUE

    7145

    VOLUME

    447

    Author Affiliations

  • Department of Health Sciences, Genetic Epidemiology Group, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.
  • Department of Medical Genetics, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
  • Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
  • Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.
  • Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
  • National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge CB2 2PT, UK.
  • Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
  • Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
  • Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  • Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.
  • National Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK.
  • National Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood CM15 8DP, UK.
  • The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun CF72 9WB, UK.
  • The Scottish National Blood Transfusion Service, Ellen’s Glen Road, Edinburgh EH17 7QT, UK.
  • National Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton SO16 5AF, UK.
  • Avon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.
  • Division of Community Health Services, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK.
  • Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
  • University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
  • Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.
  • SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.
  • School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.
  • LIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.
  • IBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
  • Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
  • Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
  • Institute for Digestive Diseases, University College London Hospitals Trust, London, NW1 2BU, UK.
  • Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.
  • Department of Gastroenterology & Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
  • Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
  • Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK.
  • Clinical Pharmacology Unit and the Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK.
  • Centre National de Genotypage, 2, Rue Gaston Cremieux, Evry, Paris 91057, France.
  • BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
  • Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
  • Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
  • arc Epidemiology Research Unit, University of Manchester, Stopford Building, Oxford Rd, Manchester M13 9PT, UK.
  • *Lists of participants and affiliations appear at the end of the paper.
  • Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK.
  • Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU, UK.
  • Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.
  • Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
  • The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Rd, Bristol BS2 8PR, UK.
  • MRC Laboratories, Fajara, The Gambia.
  • Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Qld 4102, Australia.
  • Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7BN, UK.
  • Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  • Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
  • Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK.
  • †Present address: Illumina Cambridge, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex CB10 1XL, UK.
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature05911

    DOI

    http://dx.doi.org/10.1038/nature05911

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1004556449

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17554300


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