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.
| Original language | English |
|---|---|
| Pages (from-to) | 713-720 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 464 |
| Issue number | 7289 |
| DOIs | |
| Publication status | Published - 1 Apr 2010 |
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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., ... 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), 713-720. https://doi.org/10.1038/nature08979
Craddock, Nick ; Hurles, Matthew E. ; Cardin, Niall et al. / 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. 713-720.
@article{ff9c25a29c26471288c2ec1098c6dff9,
title = "Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls",
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.",
author = "Nick Craddock and Hurles, {Matthew E.} and Niall Cardin and Pearson, {Richard D.} and Vincent Plagnol and Samuel Robson and Damjan Vukcevic and Chris Barnes and Conrad, {Donald F.} and Eleni Giannoulatou and Chris Holmes and Marchini, {Jonathan L.} and Kathy Stirrups and Tobin, {Martin D.} and Wain, {Louise V.} and Chris Yau and Jan Aerts and Tariq Ahmad and Andrews, {T. Daniel} and Hazel Arbury and Anthony Attwood and Adam Auton and Ball, {Stephen G.} and Balmforth, {Anthony J.} and Barrett, {Jeffrey C.} and In{\^e}s Barroso and Anne Barton and Bennett, {Amanda J.} and Sanjeev Bhaskar and Katarzyna Blaszczyk and John Bowes and Brand, {Oliver J.} and Braund, {Peter S.} and Francesca Bredin and Gerome Breen and Brown, {Morris J.} and Bruce, {Ian N.} and Jaswinder Bull and Burren, {Oliver S.} and John Burton and Jake Byrnes and Sian Caesar and Clee, {Chris M.} and Coffey, {Alison J.} and Connell, {John M.C.} and Cooper, {Jason D.} and Dominiczak, {Anna F.} and Kate Downes and Drummond, {Hazel E.} and Darshna Dudakia and Andrew Dunham and Bernadette Ebbs and Diana Eccles and Sarah Edkins and Cathryn Edwards and Anna Elliot and Paul Emery and Evans, {David M.} and Gareth Evans and Steve Eyre and Anne Farmer and Ferrier, {I. Nicol} and Lars Feuk and Tomas Fitzgerald and Edward Flynn and Alistair Forbes and Liz Forty and Franklyn, {Jayne A.} and Freathy, {Rachel M.} and Polly Gibbs and Paul Gilbert and Omer Gokumen and Katherine Gordon-Smith and Emma Gray and Elaine Green and Groves, {Chris J.} and Detelina Grozeva and Rhian Gwilliam and Anita Hall and Naomi Hammond and Matt Hardy and Pile Harrison and Neelam Hassanali and Husam Hebaishi and Sarah Hines and Anne Hinks and Hitman, {Graham A.} and Lynne Hocking and Eleanor Howard and Philip Howard and Howson, {Joanna M.M.} and Debbie Hughes and Sarah Hunt and Isaacs, {John D.} and Mahim Jain and Jewell, {Derek P.} and Toby Johnson and Jolley, {Jennifer D.} and Jones, {Ian R.} and Jones, {Lisa A.} and George Kirov and Langford, {Cordelia F.} and Hana Lango-Allen and Lathrop, {G. Mark} and James Lee and Lee, {Kate L.} and Charlie Lees and Kevin Lewis and Lindgren, {Cecilia M.} and Meeta Maisuria-Armer and Julian Maller and John Mansfield and Paul Martin and Massey, {Dunecan C.O.} and McArdle, {Wendy L.} and Peter McGuffin and McLay, {Kirsten E.} and Alex Mentzer and Mimmack, {Michael L.} and Morgan, {Ann E.} and Morris, {Andrew P.} and Craig Mowat and Simon Myers and William Newman and Nimmo, {Elaine R.} and O'Donovan, {Michael C.} and Abiodun Onipinla and Ifejinelo Onyiah and Ovington, {Nigel R.} and Owen, {Michael J.} and Kimmo Palin and Kirstie Parnell and David Pernet and Perry, {John R.B.} and Anne Phillips and Dalila Pinto and Prescott, {Natalie J.} and Inga Prokopenko and Quail, {Michael A.} and Suzanne Rafelt and Rayner, {Nigel W.} and Richard Redon and Reid, {David M.} and Anthony Renwick and Ring, {Susan M.} and Neil Robertson and Ellie Russell and Clair, {David St} and Sambrook, {Jennifer G.} and Sanderson, {Jeremy D.} and Helen Schuilenburg and Scott, {Carol E.} and Richard Scott and Sheila Seal and Sue Shaw-Hawkins and Shields, {Beverley M.} and Simmonds, {Matthew J.} and Smyth, {Debbie J.} and Elilan Somaskantharajah and Katarina Spanova and Sophia Steer and Jonathan Stephens and Stevens, {Helen E.} and Stone, {Millicent A.} and Zhan Su and Symmons, {Deborah P.M.} and Thompson, {John R.} and Wendy Thomson and Travers, {Mary E.} and Clare Turnbull and Armand Valsesia and Mark Walker and Walker, {Neil M.} and Chris Wallace and Margaret Warren-Perry and Watkins, {Nicholas A.} and John Webster and Weedon, {Michael N.} and Wilson, {Anthony G.} and Matthew Woodburn and Wordsworth, {B. Paul} and Young, {Allan H.} and Eleftheria Zeggini and Carter, {Nigel P.} and Frayling, {Timothy M.} and Charles Lee and Gil McVean and Munroe, {Patricia B.} and Aarno Palotie and Sawcer, {Stephen J.} and Scherer, {Stephen W.} and Strachan, {David P.} and Chris Tyler-Smith and Brown, {Matthew A.} and Burton, {Paul R.} and Caulfield, {Mark J.} and Alastair Compston and Martin Farrall and Gough, {Stephen C.L.} and Hall, {Alistair S.} and Hattersley, {Andrew T.} and Hill, {Adrian V.S.} and Mathew, {Christopher G.} and Marcus Pembrey and Jack Satsangi and Stratton, {Michael R.} and Jane Worthington and Panos Deloukas and Audrey Duncanson and Kwiatkowski, {Dominic P.} and McCarthy, {Mark I.} and Ouwehand, {Willem H.} and Miles Parkes and Nazneen Rahman and Todd, {John A.} and Samani, {Nilesh J.} and Peter Donnelly",
year = "2010",
month = apr,
day = "1",
doi = "10.1038/nature08979",
language = "English",
volume = "464",
pages = "713--720",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7289",
}
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, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Feuk, L, Fitzgerald, T, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Freathy, RM, Gibbs, P, Gilbert, P, Gokumen, O, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Onyiah, I, Ovington, NR, Owen, MJ, Palin, K, Parnell, K, Pernet, D, Perry, JRB, Phillips, A, Pinto, D, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Redon, R, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Russell, E, Clair, DS, Sambrook, JG, Sanderson, JD, Schuilenburg, H, Scott, CE, Scott, R, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stone, MA, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Travers, ME, Turnbull, C, Valsesia, A, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Young, AH, Zeggini, E, Carter, NP, Frayling, TM, Lee, C, McVean, G, Munroe, PB, Palotie, A, Sawcer, SJ, Scherer, SW, Strachan, DP, Tyler-Smith, C, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Deloukas, P, Duncanson, A, Kwiatkowski, DP, McCarthy, MI, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ & Donnelly, P 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. 713-720. 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 et al.
In: Nature, Vol. 464, No. 7289, 01.04.2010, p. 713-720.
Research output: Contribution to journal › Article › peer-review
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, Inês
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 - Drummond, Hazel E.
AU - Dudakia, Darshna
AU - Dunham, Andrew
AU - Ebbs, Bernadette
AU - Eccles, Diana
AU - Edkins, Sarah
AU - Edwards, Cathryn
AU - Elliot, Anna
AU - Emery, Paul
AU - Evans, David M.
AU - Evans, Gareth
AU - Eyre, Steve
AU - Farmer, Anne
AU - Ferrier, I. Nicol
AU - Feuk, Lars
AU - Fitzgerald, Tomas
AU - Flynn, Edward
AU - Forbes, Alistair
AU - Forty, Liz
AU - Franklyn, Jayne A.
AU - Freathy, Rachel M.
AU - Gibbs, Polly
AU - Gilbert, Paul
AU - Gokumen, Omer
AU - Gordon-Smith, Katherine
AU - Gray, Emma
AU - Green, Elaine
AU - Groves, Chris J.
AU - Grozeva, Detelina
AU - Gwilliam, Rhian
AU - Hall, Anita
AU - Hammond, Naomi
AU - Hardy, Matt
AU - Harrison, Pile
AU - Hassanali, Neelam
AU - Hebaishi, Husam
AU - Hines, Sarah
AU - Hinks, Anne
AU - Hitman, Graham A.
AU - Hocking, Lynne
AU - Howard, Eleanor
AU - Howard, Philip
AU - Howson, Joanna M.M.
AU - Hughes, Debbie
AU - Hunt, Sarah
AU - Isaacs, John D.
AU - Jain, Mahim
AU - Jewell, Derek P.
AU - Johnson, Toby
AU - Jolley, Jennifer D.
AU - Jones, Ian R.
AU - Jones, Lisa A.
AU - Kirov, George
AU - Langford, Cordelia F.
AU - Lango-Allen, Hana
AU - Lathrop, G. Mark
AU - Lee, James
AU - Lee, Kate L.
AU - Lees, Charlie
AU - Lewis, Kevin
AU - Lindgren, Cecilia M.
AU - Maisuria-Armer, Meeta
AU - Maller, Julian
AU - Mansfield, John
AU - Martin, Paul
AU - Massey, Dunecan C.O.
AU - McArdle, Wendy L.
AU - McGuffin, Peter
AU - McLay, Kirsten E.
AU - Mentzer, Alex
AU - Mimmack, Michael L.
AU - Morgan, Ann E.
AU - Morris, Andrew P.
AU - Mowat, Craig
AU - Myers, Simon
AU - Newman, William
AU - Nimmo, Elaine R.
AU - O'Donovan, Michael C.
AU - Onipinla, Abiodun
AU - Onyiah, Ifejinelo
AU - Ovington, Nigel R.
AU - Owen, Michael J.
AU - Palin, Kimmo
AU - Parnell, Kirstie
AU - Pernet, David
AU - Perry, John R.B.
AU - Phillips, Anne
AU - Pinto, Dalila
AU - Prescott, Natalie J.
AU - Prokopenko, Inga
AU - Quail, Michael A.
AU - Rafelt, Suzanne
AU - Rayner, Nigel W.
AU - Redon, Richard
AU - Reid, David M.
AU - Renwick, Anthony
AU - Ring, Susan M.
AU - Robertson, Neil
AU - Russell, Ellie
AU - Clair, David St
AU - Sambrook, Jennifer G.
AU - Sanderson, Jeremy D.
AU - Schuilenburg, Helen
AU - Scott, Carol E.
AU - Scott, Richard
AU - Seal, Sheila
AU - Shaw-Hawkins, Sue
AU - Shields, Beverley M.
AU - Simmonds, Matthew J.
AU - Smyth, Debbie J.
AU - Somaskantharajah, Elilan
AU - Spanova, Katarina
AU - Steer, Sophia
AU - Stephens, Jonathan
AU - Stevens, Helen E.
AU - Stone, Millicent A.
AU - Su, Zhan
AU - Symmons, Deborah P.M.
AU - Thompson, John R.
AU - Thomson, Wendy
AU - Travers, Mary E.
AU - Turnbull, Clare
AU - Valsesia, Armand
AU - Walker, Mark
AU - Walker, Neil M.
AU - Wallace, Chris
AU - Warren-Perry, Margaret
AU - Watkins, Nicholas A.
AU - Webster, John
AU - Weedon, Michael N.
AU - Wilson, Anthony G.
AU - Woodburn, Matthew
AU - Wordsworth, B. Paul
AU - Young, Allan H.
AU - Zeggini, Eleftheria
AU - Carter, Nigel P.
AU - Frayling, Timothy M.
AU - Lee, Charles
AU - McVean, Gil
AU - Munroe, Patricia B.
AU - Palotie, Aarno
AU - Sawcer, Stephen J.
AU - Scherer, Stephen W.
AU - Strachan, David P.
AU - Tyler-Smith, Chris
AU - Brown, Matthew A.
AU - Burton, Paul R.
AU - Caulfield, Mark J.
AU - Compston, Alastair
AU - Farrall, Martin
AU - Gough, Stephen C.L.
AU - Hall, Alistair S.
AU - Hattersley, Andrew T.
AU - Hill, Adrian V.S.
AU - Mathew, Christopher G.
AU - Pembrey, Marcus
AU - Satsangi, Jack
AU - Stratton, Michael R.
AU - Worthington, Jane
AU - Deloukas, Panos
AU - Duncanson, Audrey
AU - Kwiatkowski, Dominic P.
AU - McCarthy, Mark I.
AU - Ouwehand, Willem H.
AU - Parkes, Miles
AU - Rahman, Nazneen
AU - Todd, John A.
AU - Samani, Nilesh J.
AU - Donnelly, Peter
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 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=77950405093&partnerID=8YFLogxK
U2 - 10.1038/nature08979
DO - 10.1038/nature08979
M3 - Article
SN - 0028-0836
VL - 464
SP - 713
EP - 720
JO - Nature
JF - Nature
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):713-720. doi: 10.1038/nature08979
