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

Craddock, Nick and Hurles, Matthew E. and Cardin, Niall and Pearson, Richard D. and Plagnol, Vincent and Robson, Samuel and Vukcevic, Damjan and Barnes, Chris and Conrad, Donald F. and Giannoulatou, Eleni and Holmes, Chris and Marchini, Jonathan L. and Stirrups, Kathy and Tobin, Martin D. and Wain, Louise V. and Yau, Chris and Aerts, Jan and Ahmad, Tariq and Daniel Andrews, T. and Arbury, Hazel and Attwood, Anthony and Auton, Adam and Ball, Stephen G. and Balmforth, Anthony J. and Barrett, Jeffrey C. and Barroso, Inês and Barton, Anne and Bennett, Amanda J. and Bhaskar, Sanjeev and Blaszczyk, Katarzyna and Bowes, John and Brand, Oliver J. and Braund, Peter S. and Bredin, Francesca and Breen, Gerome and Brown, Morris J. and Bruce, Ian N. and Bull, Jaswinder and Burren, Oliver S. and Burton, John and Byrnes, Jake and Caesar, Sian and Clee, Chris M. and Coffey, Alison J. and Connell, John M. C. and Cooper, Jason D. and Dominiczak, Anna F. and Downes, Kate and Drummond, Hazel E. and Dudakia, Darshna and Dunham, Andrew and Ebbs, Bernadette and Eccles, Diana and Edkins, Sarah and Edwards, Cathryn and Elliot, Anna and Emery, Paul and Evans, David M. and Evans, Gareth and Eyre, Steve and Farmer, Anne and Nicol Ferrier, I. and Feuk, Lars and Fitzgerald, Tomas and Flynn, Edward and Forbes, Alistair and Forty, Liz and Franklyn, Jayne A. and Freathy, Rachel M. and Gibbs, Polly and Gilbert, Paul and Gokumen, Omer and Gordon-Smith, Katherine and Gray, Emma and Green, Elaine and Groves, Chris J. and Grozeva, Detelina and Gwilliam, Rhian and Hall, Anita and Hammond, Naomi and Hardy, Matt and Harrison, Pile and Hassanali, Neelam and Hebaishi, Husam and Hines, Sarah and Hinks, Anne and Hitman, Graham A and Hocking, Lynne and Howard, Eleanor and Howard, Philip and Howson, Joanna M. M. and Hughes, Debbie and Hunt, Sarah and Isaacs, John D. and Jain, Mahim and Jewell, Derek P. and Johnson, Toby and Jolley, Jennifer D. and Jones, Ian R. and Jones, Lisa A. and Kirov, George and Langford, Cordelia F. and Lango-Allen, Hana and Mark Lathrop, G. and Lee, James and Lee, Kate L. and Lees, Charlie and Lewis, Kevin and Lindgren, Cecilia M. and Maisuria-Armer, Meeta and Maller, Julian and Mansfield, John and Martin, Paul and Massey, Dunecan C. O. and McArdle, Wendy L. and McGuffin, Peter and McLay, Kirsten E. and Mentzer, Alex and Mimmack, Michael L. and Morgan, Ann E. and Morris, Andrew P. and Mowat, Craig and Myers, Simon and Newman, William and Nimmo, Elaine R. and O’Donovan, Michael C. and Onipinla, Abiodun and Onyiah, Ifejinelo and Ovington, Nigel R. and Owen, Michael J. and Palin, Kimmo and Parnell, Kirstie and Pernet, David and Perry, John R. B. and Phillips, Anne and Pinto, Dalila and Prescott, Natalie J. and Prokopenko, Inga and Quail, Michael A. and Rafelt, Suzanne and Rayner, Nigel W. and Redon, Richard and Reid, David M. and Renwick, Anthony and Ring, Susan M. and Robertson, Neil and Russell, Ellie and St Clair, David and Sambrook, Jennifer G. and Sanderson, Jeremy D. and Schuilenburg, Helen and Scott, Carol E. and Scott, Richard and Seal, Sheila and Shaw-Hawkins, Sue and Shields, Beverley M. and Simmonds, Matthew J. and Smyth, Debbie J. and Somaskantharajah, Elilan and Spanova, Katarina and Steer, Sophia and Stephens, Jonathan and Stevens, Helen E. and Stone, Millicent A. and Su, Zhan and Symmons, Deborah P. M. and Thompson, John R. and Thomson, Wendy and Travers, Mary E. and Turnbull, Clare and Valsesia, Armand and Walker, Mark and Walker, Neil M. and Wallace, Chris and Warren-Perry, Margaret and Watkins, Nicholas A. and Webster, John and Weedon, Michael N. and Wilson, Anthony G. and Woodburn, Matthew and Wordsworth, B. Paul and Young, Allan H. and Zeggini, Eleftheria and Carter, Nigel P. and Frayling, Timothy M. and Lee, Charles and McVean, Gil and Munroe, Patricia B. and Palotie, Aarno and Sawcer, Stephen J. and Scherer, Stephen W. and Strachan, David P. and Tyler-Smith, Chris and Brown, Matthew A. and Burton, Paul R. and Caulfield, Mark J. and Compston, Alastair and Farrall, Martin and Gough, Stephen C. L. and Hall, Alistair S. and Hattersley, Andrew T. and Hill, Adrian V. S. and Mathew, Christopher G. and Pembrey, Marcus and Satsangi, Jack and Stratton, Michael R. and Worthington, Jane and Deloukas, Panos and Duncanson, Audrey and Kwiatkowski, Dominic P. and McCarthy, Mark I. and Ouwehand, Willem H. and Parkes, Miles and Rahman, Nazneen and Todd, John A. and Samani, Nilesh J. and Donnelly, Peter (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464 (7289). pp. 713-720. ISSN 0028-0836

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Abstract

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 diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough 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. © 2010 Macmillan Publishers Limited. All rights reserved.

Additional Information:The Wellcome Trust Case Control Consortium
Keywords:genetics, copy number variants, Common disease, single nucleotide polymorphism
Subjects:C Biological Sciences > C431 Medical Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:23670
Deposited On:01 Aug 2016 13:54

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