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

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
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.
Genetics
0028-0836
713-720
Craddock, Nick
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Hurles, Matthew E.
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Cardin, Niall
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Pearson, Richard D.
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Plagnol, Vincent
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Robson, Samuel
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Vukcevic, Damjan
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Barnes, Chris
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Conrad, Donald F.
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Giannoulatou, Eleni
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Holmes, Chris
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Marchini, Jonathan L.
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Aerts, Jan
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Daniel Andrews, T.
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Arbury, Hazel
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Attwood, Anthony
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Balmforth, Anthony J.
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Barton, Anne
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Bhaskar, Sanjeev
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Blaszczyk, Katarzyna
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Bowes, John
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Brand, Oliver J.
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Braund, Peter S.
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Bredin, Francesca
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Breen, Gerome
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Brown, Morris J.
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Bruce, Ian N.
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Bull, Jaswinder
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Burren, Oliver S.
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Burton, John
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Byrnes, Jake
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Caesar, Sian
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Clee, Chris M.
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Coffey, Alison J.
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Connell, John M.C.
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Cooper, Jason D.
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Dominiczak, Anna F.
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Eccles, Diana
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Martin, Paul
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Walker, Mark
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The Wellcome Trust Case Control Consortium
Craddock, Nick
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Hurles, Matthew E.
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Cardin, Niall
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Pearson, Richard D.
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Plagnol, Vincent
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Robson, Samuel
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Vukcevic, Damjan
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Barnes, Chris
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Conrad, Donald F.
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Giannoulatou, Eleni
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Holmes, Chris
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Marchini, Jonathan L.
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Stirrups, Kathy
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Tobin, Martin D.
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Wain, Louise V.
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Yau, Chris
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Aerts, Jan
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Ahmad, Tariq
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Daniel Andrews, T.
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Arbury, Hazel
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Attwood, Anthony
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Auton, Adam
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Ball, Stephen G.
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Balmforth, Anthony J.
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Barrett, Jeffrey C.
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Barroso, Inês
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Barton, Anne
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Bennett, Amanda J.
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Bhaskar, Sanjeev
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Blaszczyk, Katarzyna
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Bowes, John
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Brand, Oliver J.
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Braund, Peter S.
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Bredin, Francesca
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Breen, Gerome
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Brown, Morris J.
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Bruce, Ian N.
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Bull, Jaswinder
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Burren, Oliver S.
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Burton, John
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Byrnes, Jake
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Caesar, Sian
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Clee, Chris M.
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Coffey, Alison J.
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Connell, John M.C.
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Cooper, Jason D.
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Dominiczak, Anna F.
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Eccles, Diana
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Martin, Paul
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Walker, Mark
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Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M.C., Cooper, Jason D., Dominiczak, Anna F., Eccles, Diana, Martin, Paul and Walker, Mark , The Wellcome Trust Case Control Consortium (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464 (7289), 713-720. (doi:10.1038/nature08979).

Record type: Article

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 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.

Full text not available from this repository.

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Published date: 1 April 2010
Keywords: Genetics

Identifiers

Local EPrints ID: 151137
URI: https://eprints.soton.ac.uk/id/eprint/151137
ISSN: 0028-0836
PURE UUID: 7a01010e-1da5-4baf-89f3-1bb5048fd11d
ORCID for Chris Holmes: ORCID iD orcid.org/0000-0001-9021-3760

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Date deposited: 07 May 2010 15:44
Last modified: 03 Dec 2019 01:46

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Contributors

Author: Nick Craddock
Author: Matthew E. Hurles
Author: Niall Cardin
Author: Richard D. Pearson
Author: Vincent Plagnol
Author: Samuel Robson
Author: Damjan Vukcevic
Author: Chris Barnes
Author: Donald F. Conrad
Author: Eleni Giannoulatou
Author: Chris Holmes ORCID iD
Author: Jonathan L. Marchini
Author: Kathy Stirrups
Author: Martin D. Tobin
Author: Louise V. Wain
Author: Chris Yau
Author: Jan Aerts
Author: Tariq Ahmad
Author: T. Daniel Andrews
Author: Hazel Arbury
Author: Anthony Attwood
Author: Adam Auton
Author: Stephen G. Ball
Author: Anthony J. Balmforth
Author: Jeffrey C. Barrett
Author: Inês Barroso
Author: Anne Barton
Author: Amanda J. Bennett
Author: Sanjeev Bhaskar
Author: Katarzyna Blaszczyk
Author: John Bowes
Author: Oliver J. Brand
Author: Peter S. Braund
Author: Francesca Bredin
Author: Gerome Breen
Author: Morris J. Brown
Author: Ian N. Bruce
Author: Jaswinder Bull
Author: Oliver S. Burren
Author: John Burton
Author: Jake Byrnes
Author: Sian Caesar
Author: Chris M. Clee
Author: Alison J. Coffey
Author: John M.C. Connell
Author: Jason D. Cooper
Author: Anna F. Dominiczak
Author: Diana Eccles
Author: Paul Martin
Author: Mark Walker

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