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

Nick Craddock, Matthew E. Hurles, Niall Cardin, Richard D. Pearson, Vincent Plagnol, Samuel Robson, Damjan Vukcevic, Chris Barnes, Donald F. Conrad, Eleni Giannoulatou, Chris Holmes, Jonathan L. Marchini, Kathy Stirrups, Martin D. Tobin, Louise V. Wain, Chris Yau, Jan Aerts, Tariq Ahmad, T. Daniel Andrews, Hazel Arbury & 31 others Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Jeffrey C. Barrett, Ines Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Chris M. Clee, Alison J. Coffey, John M. C. Connell, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Andrew P. Morris, Craig Mowat, Wellcome Trust Case Control

    Research output: Contribution to journalArticle

    559 Citations (Scopus)

    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 similar to 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.

    Original languageEnglish
    Pages (from-to)713-U86
    Number of pages10
    JournalNature
    Volume464
    Issue number7289
    DOIs
    Publication statusPublished - 1 Apr 2010

    Keywords

    • COPY-NUMBER VARIATION
    • LARGE-SCALE
    • SUSCEPTIBILITY
    • POLYMORPHISMS
    • DELETION
    • CCL3L1
    • SCHIZOPHRENIA
    • DUPLICATIONS
    • HERITABILITY
    • PSORIASIS

    Cite this

    Craddock, N., Hurles, M. E., Cardin, N., Pearson, R. D., Plagnol, V., Robson, S., ... Wellcome Trust Case Control (2010). Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464(7289), 713-U86. https://doi.org/10.1038/nature08979
    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 ; Andrews, T. Daniel ; Arbury, Hazel ; Attwood, Anthony ; Auton, Adam ; Ball, Stephen G. ; Balmforth, Anthony J. ; Barrett, Jeffrey C. ; Barroso, Ines ; 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. ; Downes, Kate ; Morris, Andrew P. ; Mowat, Craig ; Wellcome Trust Case Control. / Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. In: Nature. 2010 ; Vol. 464, No. 7289. pp. 713-U86.
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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 similar to 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.",
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    Craddock, N, Hurles, ME, Cardin, N, Pearson, RD, Plagnol, V, Robson, S, Vukcevic, D, Barnes, C, Conrad, DF, Giannoulatou, E, Holmes, C, Marchini, JL, Stirrups, K, Tobin, MD, Wain, LV, Yau, C, Aerts, J, Ahmad, T, Andrews, TD, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Clee, CM, Coffey, AJ, Connell, JMC, Cooper, JD, Dominiczak, AF, Downes, K, Morris, AP, Mowat, C & Wellcome Trust Case Control 2010, 'Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls', Nature, vol. 464, no. 7289, pp. 713-U86. https://doi.org/10.1038/nature08979

    Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. / 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; Andrews, T. Daniel; Arbury, Hazel; Attwood, Anthony; Auton, Adam; Ball, Stephen G.; Balmforth, Anthony J.; Barrett, Jeffrey C.; Barroso, Ines; 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.; Downes, Kate; Morris, Andrew P.; Mowat, Craig; Wellcome Trust Case Control.

    In: Nature, Vol. 464, No. 7289, 01.04.2010, p. 713-U86.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

    AU - Craddock, Nick

    AU - Hurles, Matthew E.

    AU - Cardin, Niall

    AU - Pearson, Richard D.

    AU - Plagnol, Vincent

    AU - Robson, Samuel

    AU - Vukcevic, Damjan

    AU - Barnes, Chris

    AU - Conrad, Donald F.

    AU - Giannoulatou, Eleni

    AU - Holmes, Chris

    AU - Marchini, Jonathan L.

    AU - Stirrups, Kathy

    AU - Tobin, Martin D.

    AU - Wain, Louise V.

    AU - Yau, Chris

    AU - Aerts, Jan

    AU - Ahmad, Tariq

    AU - Andrews, T. Daniel

    AU - Arbury, Hazel

    AU - Attwood, Anthony

    AU - Auton, Adam

    AU - Ball, Stephen G.

    AU - Balmforth, Anthony J.

    AU - Barrett, Jeffrey C.

    AU - Barroso, Ines

    AU - Barton, Anne

    AU - Bennett, Amanda J.

    AU - Bhaskar, Sanjeev

    AU - Blaszczyk, Katarzyna

    AU - Bowes, John

    AU - Brand, Oliver J.

    AU - Braund, Peter S.

    AU - Bredin, Francesca

    AU - Breen, Gerome

    AU - Brown, Morris J.

    AU - Bruce, Ian N.

    AU - Bull, Jaswinder

    AU - Burren, Oliver S.

    AU - Burton, John

    AU - Byrnes, Jake

    AU - Caesar, Sian

    AU - Clee, Chris M.

    AU - Coffey, Alison J.

    AU - Connell, John M. C.

    AU - Cooper, Jason D.

    AU - Dominiczak, Anna F.

    AU - Downes, Kate

    AU - Morris, Andrew P.

    AU - Mowat, Craig

    AU - Wellcome Trust Case Control

    PY - 2010/4/1

    Y1 - 2010/4/1

    N2 - 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 similar to 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.

    AB - 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 similar to 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.

    KW - COPY-NUMBER VARIATION

    KW - LARGE-SCALE

    KW - SUSCEPTIBILITY

    KW - POLYMORPHISMS

    KW - DELETION

    KW - CCL3L1

    KW - SCHIZOPHRENIA

    KW - DUPLICATIONS

    KW - HERITABILITY

    KW - PSORIASIS

    U2 - 10.1038/nature08979

    DO - 10.1038/nature08979

    M3 - Article

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    SP - 713-U86

    JO - Nature

    JF - Nature

    SN - 0028-0836

    IS - 7289

    ER -

    Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010 Apr 1;464(7289):713-U86. https://doi.org/10.1038/nature08979