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

Craddock, N., Hurles, M. E., Cardin, N., Pearson, R. D., Plagnol, V., Robson, S., Vukcevic, D., Barnes, C., Conrad, D. F., Giannoulatou, E., Holmes, C., Marchini, J. L., Stirrups, K., Tobin, M. D., Wain, L. V., Yau, C., Aerts, J., Ahmad, T., Andrews, T. D., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Clee, C. M., Coffey, A. J., Connell, J. M. C., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Feuk, L., Fitzgerald, T., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Freathy, R. M., Gibbs, P., Gilbert, P., Gokumen, O., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Martin, P., Massey, D. C. O., McArdle, W. L., McGuffin, P., McLay, K. E., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Onyiah, I., Ovington, N. R., Owen, M. J., Palin, K., Parnell, K., Pernet, D., Perry, J. R. B., Phillips, A., Pinto, D., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Redon, R., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Schuilenburg, H., Scott, C. E., Scott, R., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stone, M. A., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Travers, M. E., Turnbull, C., Valsesia, A., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Young, A. H., Zeggini, E., Carter, N. P., Frayling, T. M., Lee, C., McVean, G., Munroe, P. B., Palotie, A., Sawcer, S. J., Scherer, S. W., Strachan, D. P., Tyler-Smith, C., Brown, Matthew A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., & Donnelly, P. (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.

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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.

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ID Code: 89403
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :407
Export Date: 21 September 2015
Correspondence Address: Donnelly, P.; Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom; email:
Keywords: artifact, blood, diabetes, disease prevalence, DNA, genetic analysis, genome, polymorphism, public health, article, bipolar disorder, breast cancer, controlled study, copy number variant, coronary artery disease, Crohn disease, DNA determination, gene locus, genetic association, genetic polymorphism, genetic susceptibility, human, hypertension, insulin dependent diabetes mellitus, major clinical study, non insulin dependent diabetes mellitus, priority journal, rheumatoid arthritis, single nucleotide polymorphism, Arthritis, Rheumatoid, Case-Control Studies, Diabetes Mellitus, Disease, DNA Copy Number Variations, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Pilot Projects, Polymorphism, Single Nucleotide, Quality Control
DOI: 10.1038/nature08979
ISSN: 0028-0836
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © 2010 Macmillan Publishers Limited
Deposited On: 22 Oct 2015 23:30
Last Modified: 22 Aug 2016 01:05

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