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

2010; Nature Portfolio; Volume: 464; Issue: 7289 Linguagem: Inglês

10.1038/nature08979

1476-4687

Nick Craddock, Matthew E. Hurles, Niall J. Cardin, Richard D. Pearson, Vincent Plagnol, Samuel C. Robson, Damjan Vukcevic, C. Barnes, Donald F. Conrad, Eleni Giannoulatou, Christopher Holmes, Jonathan Marchini, Kathy Stirrups, Martin D. Tobin, Louise V. Wain, Christopher Yau, Jan Aerts, Tariq Ahmad, T. Daniel Andrews, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev S. Bhaskar, Katarzyna Błaszczyk, John Bowes, Stephan Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Matthew A. Brown, Ian N Bruce, Jaswinder Bull, Oliver S. Burren, John H. Burton, Jake Byrnes, Sian Caesar, Chris M. Clee, Alison J. Coffey, John Connell, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, D. Gareth Evans, Stephen Eyre, Anne Farmer, I. Nicol Ferrier, Lars Feuk, Tomas Fitzgerald, Edward Flynn, Alastair Forbes, Liz Forty, Jayne A. Franklyn, Rachel M. Freathy, Polly Gibbs, Paul Gilbert, Omer Gokumen, Katherine Gordon‐Smith, Emma Gray, Elaine Green, Chris Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pille Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, G. A. Hitman, Lynne J. Hocking, Eleanor Howard, Philip Howard, Joanna M. M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian Jones, Lisa Jones, George Kirov, Cordelia F. Langford, Hana Lango Allen, G.M. Lathrop, James Lee, Kate Lee, Charlie W. Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Paul Martin, Dunecan Massey, Wendy L. McArdle, Peter McGuffin, Kirsten McLay, Alexander J. Mentzer, Michael L. Mimmack, Ann W. Morgan, Andrew P. Morris, Craig Mowat, Simon Myers, William G. Newman, Elaine R. Nimmo, Michael O’Donovan, Abiodun Onipinla, Ifejinelo Onyiah, Nigel Ovington, Michael J. Owen, Kimmo Palin, Kirstie Parnell, David Pernet, John R. B. Perry, Anne Phillips, Dalila Pinto, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, Richard Redon, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy Sanderson, Helen Schuilenburg, Carol Scott, Richard Scott, Sheila Seal, Sue Shaw‐Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Millicent Stone, Zhan Su, Deborah Symmons, J. Thompson, Wendy Thomson, Mary E. Travers, Clare Turnbull, Armand Valsesia, Mark Walker, Neil Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B P Wordsworth, Allan H. Young, Eleftheria Zeggini, Nigel P. Carter, Timothy M. Frayling, Charles Lee, Gil McVean, Patricia B. Munroe, Aarno Palotie, Stephen Sawcer, Stephen W. Scherer, David P. Strachan, Chris Tyler‐Smith, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, A. Compston, Martin Farrall, Stephen Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V. S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Panos Deloukas, Audrey Duncanson, Dominic Kwiatkowski, Mark I. McCarthy, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Peter Donnelly,

Genetic Associations and Epidemiology

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 500 base 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. Copy number variations or CNVs are a common form of genetic variation between individuals, caused by genomic rearrangements, either inherited or due to de novo mutation. A major collaborative effort using tiling oligonucleotide microarrays and HapMap samples has generated a comprehensive working map of 11,700 CNVs in the human genome. About half of these were also genotyped in individuals of different ancestry — European, African or East Asian. Thirty loci with CNVs that are candidates for influencing disease susceptibility were identified. Published online last October, this vast data set is a landmark in terms of completeness and spatial resolution, and as John Armour wrote in News & Views , is likely to stand as a definitive resource for years to come. This resource is the main focus of a new genome-wide association study, from the Wellcome Trust Case Control Consortium, of the links between common CNVs and eight common human diseases. Providing a wealth of technical insights to inform future study design and analysis, the Wellcome study also implies that common CNVs that can be genotyped using existing platforms are unlikely to have a major role in the genetic basis of common diseases. Copy number variants (CNVs) account for a major proportion of human genetic diversity and may contribute to genetic susceptibility to disease. Here, a large, genome-wide study of association between common CNVs and eight common human diseases is presented. The study provides a wealth of technical insights that will inform future study design and analysis. The results also indicate that common CNVs that can be 'typed' on existing platforms are unlikely to contribute much to the genetic basis of common diseases.