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 & 197 others Anthony Attwood, Adam Auton, Stephen G Ball, Anthony J Balmforth, Jeffrey C Barrett, Inês 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, Hazel E Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M Evans, Gareth Evans, Steve Eyre, Anne Farmer, I Nicol Ferrier, Lars Feuk, Tomas Fitzgerald, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A Franklyn, Rachel M Freathy, Polly Gibbs, Paul Gilbert, Omer Gokumen, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A Hitman, Lynne Hocking, Eleanor Howard, Philip Howard, Joanna M M Howson, Debbie Hughes, Sarah Hunt, John D Isaacs, Mahim Jain, Derek P Jewell, Toby Johnson, Jennifer D Jolley, Ian R Jones, Lisa A Jones, George Kirov, Cordelia F Langford, Hana Lango-Allen, G Mark Lathrop, James Lee, Kate L Lee, Charlie Lees, Kevin Lewis, Cecilia M Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Paul Martin, Dunecan C O Massey, Wendy L McArdle, Peter McGuffin, Kirsten E McLay, Alex Mentzer, Michael L Mimmack, Ann E Morgan, Andrew P Morris, Craig Mowat, Simon Myers, William Newman, Elaine R Nimmo, Michael C O’Donovan, Abiodun Onipinla, Ifejinelo Onyiah, Nigel R Ovington, Michael J Owen, Kimmo Palin, Kirstie Parnell, David Pernet, John R B Perry, Anne Phillips, Dalila Pinto, Natalie J Prescott, Inga Prokopenko, Michael A Quail, Suzanne Rafelt, Nigel W Rayner, Richard Redon, David M Reid, Anthony Renwick, Susan M Ring, Neil Robertson, Ellie Russell, David St Clair, Jennifer G Sambrook, Jeremy D Sanderson, Helen Schuilenburg, Carol E Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M Shields, Matthew J Simmonds, Debbie J Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E Stevens, Millicent A Stone, Zhan Su, Deborah P M Symmons, John R Thompson, Wendy Thomson, Mary E Travers, Clare Turnbull, Armand Valsesia, Mark Walker, Neil M Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A Watkins, John Webster, Michael N Weedon, Anthony G Wilson, Matthew Woodburn, B Paul Wordsworth, Allan H Young, Eleftheria Zeggini, Nigel P Carter, Timothy M Frayling, Charles Lee, Gil McVean, Patricia B Munroe, Aarno Palotie, Stephen J Sawcer, Stephen W Scherer, David P Strachan, Chris Tyler-Smith, Matthew A Brown, Paul R Burton, Mark J Caulfield, Alastair Compston, Martin Farrall, Stephen C L Gough, Alistair S Hall, Andrew T Hattersley, Adrian V S Hill, Christopher G Mathew, Marcus Pembrey, Jack Satsangi, Michael R Stratton, Jane Worthington, Panos Deloukas, Audrey Duncanson, Dominic P Kwiatkowski, Mark I McCarthy, Willem H Ouwehand, Miles Parkes, Nazneen Rahman, John A Todd, Nilesh J Samani, Peter Donnelly

Research output: Contribution to journalArticle

  • 535 Citations

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.
LanguageEnglish
Pages713-722
Number of pages10
JournalNature
Volume464
Issue number7289
DOIs
StatusPublished - 1 Apr 2010

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Genome-Wide Association Study
Single Nucleotide Polymorphism
Crohn Disease
Medical Genetics
Genetic Polymorphisms
Genetic Predisposition to Disease
Type 1 Diabetes Mellitus
Base Pairing
Artifacts
Type 2 Diabetes Mellitus
Blood Cells
Rheumatoid Arthritis
Cell Line
DNA

Cite this

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

In: Nature, Vol. 464, No. 7289, 01.04.2010, p. 713-722.

Research output: Contribution to journalArticle

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, Daniel Andrews, T, 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, Nicol Ferrier, I, 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, Mark Lathrop, G, 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, St Clair, D, 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. 713-722. DOI: 10.1038/nature08979
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):713-722. Available from, DOI: 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 ; 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 ; Downes, Kate ; Drummond, Hazel E ; Dudakia, Darshna ; Dunham, Andrew ; Ebbs, Bernadette ; Eccles, Diana ; Edkins, Sarah ; Edwards, Cathryn ; Elliot, Anna ; Emery, Paul ; Evans, David M ; Evans, Gareth ; Eyre, Steve ; Farmer, Anne ; Nicol Ferrier, I ; Feuk, Lars ; Fitzgerald, Tomas ; Flynn, Edward ; Forbes, Alistair ; Forty, Liz ; Franklyn, Jayne A ; Freathy, Rachel M ; Gibbs, Polly ; Gilbert, Paul ; Gokumen, Omer ; Gordon-Smith, Katherine ; Gray, Emma ; Green, Elaine ; Groves, Chris J ; Grozeva, Detelina ; Gwilliam, Rhian ; Hall, Anita ; Hammond, Naomi ; Hardy, Matt ; Harrison, Pile ; Hassanali, Neelam ; Hebaishi, Husam ; Hines, Sarah ; Hinks, Anne ; Hitman, Graham A ; Hocking, Lynne ; Howard, Eleanor ; Howard, Philip ; Howson, Joanna M M ; Hughes, Debbie ; Hunt, Sarah ; Isaacs, John D ; Jain, Mahim ; Jewell, Derek P ; Johnson, Toby ; Jolley, Jennifer D ; Jones, Ian R ; Jones, Lisa A ; Kirov, George ; Langford, Cordelia F ; Lango-Allen, Hana ; Mark Lathrop, G ; Lee, James ; Lee, Kate L ; Lees, Charlie ; Lewis, Kevin ; Lindgren, Cecilia M ; Maisuria-Armer, Meeta ; Maller, Julian ; Mansfield, John ; Martin, Paul ; Massey, Dunecan C O ; McArdle, Wendy L ; McGuffin, Peter ; McLay, Kirsten E ; Mentzer, Alex ; Mimmack, Michael L ; Morgan, Ann E ; Morris, Andrew P ; Mowat, Craig ; Myers, Simon ; Newman, William ; Nimmo, Elaine R ; O’Donovan, Michael C ; Onipinla, Abiodun ; Onyiah, Ifejinelo ; Ovington, Nigel R ; Owen, Michael J ; Palin, Kimmo ; Parnell, Kirstie ; Pernet, David ; Perry, John R B ; Phillips, Anne ; Pinto, Dalila ; Prescott, Natalie J ; Prokopenko, Inga ; Quail, Michael A ; Rafelt, Suzanne ; Rayner, Nigel W ; Redon, Richard ; Reid, David M ; Renwick, Anthony ; Ring, Susan M ; Robertson, Neil ; Russell, Ellie ; St Clair, David ; Sambrook, Jennifer G ; Sanderson, Jeremy D ; Schuilenburg, Helen ; Scott, Carol E ; Scott, Richard ; Seal, Sheila ; Shaw-Hawkins, Sue ; Shields, Beverley M ; Simmonds, Matthew J ; Smyth, Debbie J ; Somaskantharajah, Elilan ; Spanova, Katarina ; Steer, Sophia ; Stephens, Jonathan ; Stevens, Helen E ; Stone, Millicent A ; Su, Zhan ; Symmons, Deborah P M ; Thompson, John R ; Thomson, Wendy ; Travers, Mary E ; Turnbull, Clare ; Valsesia, Armand ; Walker, Mark ; Walker, Neil M ; Wallace, Chris ; Warren-Perry, Margaret ; Watkins, Nicholas A ; Webster, John ; Weedon, Michael N ; Wilson, Anthony G ; Woodburn, Matthew ; Wordsworth, B Paul ; Young, Allan H ; Zeggini, Eleftheria ; Carter, Nigel P ; Frayling, Timothy M ; Lee, Charles ; McVean, Gil ; Munroe, Patricia B ; Palotie, Aarno ; Sawcer, Stephen J ; Scherer, Stephen W ; Strachan, David P ; Tyler-Smith, Chris ; Brown, Matthew A ; Burton, Paul R ; Caulfield, Mark J ; Compston, Alastair ; Farrall, Martin ; Gough, Stephen C L ; Hall, Alistair S ; Hattersley, Andrew T ; Hill, Adrian V S ; Mathew, Christopher G ; Pembrey, Marcus ; Satsangi, Jack ; Stratton, Michael R ; Worthington, Jane ; Deloukas, Panos ; Duncanson, Audrey ; Kwiatkowski, Dominic P ; McCarthy, Mark I ; Ouwehand, Willem H ; Parkes, Miles ; Rahman, Nazneen ; Todd, John A ; Samani, Nilesh J ; Donnelly, Peter. / 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. 713-722
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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 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.",
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 {Daniel Andrews}, T 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 {Nicol Ferrier}, I 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 {Mark Lathrop}, G 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 {St Clair}, David 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",
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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 - Daniel Andrews,T

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 - Nicol Ferrier,I

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

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AU - Johnson,Toby

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AU - Jones,Ian R

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AU - Kirov,George

AU - Langford,Cordelia F

AU - Lango-Allen,Hana

AU - Mark Lathrop,G

AU - Lee,James

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AU - Lees,Charlie

AU - Lewis,Kevin

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AU - Maisuria-Armer,Meeta

AU - Maller,Julian

AU - Mansfield,John

AU - Martin,Paul

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AU - McArdle,Wendy L

AU - McGuffin,Peter

AU - McLay,Kirsten E

AU - Mentzer,Alex

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AU - Walker,Mark

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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

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AU - Satsangi,Jack

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AU - Duncanson,Audrey

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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 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.

UR - http://www.scopus.com/inward/record.url?scp=77950405093&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1038/nature08979

U2 - 10.1038/nature08979

DO - 10.1038/nature08979

M3 - Article

VL - 464

SP - 713

EP - 722

JO - Nature

T2 - Nature

JF - Nature

SN - 0028-0836

IS - 7289

ER -