Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to play 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 500bp. 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, though in each case the locus had previously been identified in SNP-based studies, reflecting our observation that the majority of common CNVs which 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 which can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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The authors of this manuscript are: Nick Craddock * 1 , Matthew E Hurles * 2 , Niall Cardin 3 , Richard D Pearson 4 , Vincent Plagnol 5 , Samuel Robson 2 , Damjan Vukcevic 4 , Chris Barnes 2 , Donald F Conrad 2 , Eleni Giannoulatou 3 , Chris Holmes 3 , Jonathan L Marchini 3 , Kathy Stirrups 2 , Martin D Tobin 6 , Louise V Wain 6 , Chris Yau 3 , Jan Aerts 2 , Tariq Ahmad 7 , T Daniel Andrews 2 , Hazel Arbury 2 , Anthony Attwood 2 8 9 , Adam Auton 3 , Stephen G Ball 10 , Anthony J Balmforth 10 , Jeffrey C Barrett 2 , Inês Barroso 2 , Anne Barton 11 , Amanda J Bennett 12 , Sanjeev Bhaskar 2 , Katarzyna Blaszczyk 13 , John Bowes 11 , Oliver J Brand 14 , Peter S Braund 15 , Francesca Bredin 16 , Gerome Breen 17 18 , Morris J Brown 19 , Ian N Bruce 11 , Jaswinder Bull 20 , Oliver S Burren 5 , John Burton 2 , Jake Byrnes 4 , Sian Caesar 21 , Chris M Clee 2 , Alison J Coffey 2 , John MC Connell 22 , Jason D Cooper 5 , Anna F Dominiczak 22 , Kate Downes 5 , Hazel E Drummond 23 , Darshna Dudakia 20 , Andrew Dunham 2 , Bernadette Ebbs 20 , Diana Eccles 24 , Sarah Edkins 2 , Cathryn Edwards 25 , Anna Elliot 20 , Paul Emery 26 , David M Evans 27 , Gareth Evans 28 , Steve Eyre 11 , Anne Farmer 18 , I Nicol Ferrier 29 , Lars Feuk 30 31 , Tomas Fitzgerald 2 , Edward Flynn 11 , Alistair Forbes 32 , Liz Forty 1 , Jayne A Franklyn 14 33 , Rachel M Freathy 34 , Polly Gibbs 20 , Paul Gilbert 11 , Omer Gokumen 35 , Katherine Gordon-Smith 1 21 , Emma Gray 2 , Elaine Green 1 , Chris J Groves 12 , Detelina Grozeva 1 , Rhian Gwilliam 2 , Anita Hall 20 , Naomi Hammond 2 , Matt Hardy 5 , Pile Harrison 36 , Neelam Hassanali 12 , Husam Hebaishi 2 , Sarah Hines 20 , Anne Hinks 11 , Graham A Hitman 37 , Lynne Hocking 38 , Eleanor Howard 2 , Philip Howard 39 , Joanna MM Howson 5 , Debbie Hughes 20 , Sarah Hunt 2 , John D Isaacs 40 , Mahim Jain 4 , Derek P Jewell 41 , Toby Johnson 39 , Jennifer D Jolley 8 9 , Ian R Jones 1 , Lisa A Jones 21 , George Kirov 1 , Cordelia F Langford 2 , Hana Lango-Allen 34 , G Mark Lathrop 42 , James Lee 16 , Kate L Lee 39 , Charlie Lees 23 , Kevin Lewis 2 , Cecilia M Lindgren 4 12 , Meeta Maisuria-Armer 5 , Julian Maller 4 , John Mansfield 43 , Paul Martin 11 , Dunecan C O Massey 16 , Wendy L McArdle 44 , Peter McGuffin 18 , Kirsten E McLay 2 , Alex Mentzer 45 , Michael L Mimmack 2 , Ann E Morgan 46 , Andrew P Morris 4 , Craig Mowat 47 , Simon Myers 3 , William Newman 28 , Elaine R Nimmo 23 , Michael C O'Donovan 1 , Abiodun Onipinla 39 , Ifejinelo Onyiah 2 , Nigel R Ovington 5 , Michael J Owen 1 , Kimmo Palin 2 , Kirstie Parnell 34 , David Pernet 20 , John RB Perry 34 , Anne Phillips 47 , Dalila Pinto 30 , Natalie J Prescott 13 , Inga Prokopenko 4 12 , Michael A Quail 2 , Suzanne Rafelt 15 , Nigel W Rayner 4 12 , Richard Redon 2 48 , David M Reid 38 , Anthony Renwick 20 , Susan M Ring 44 , Neil Robertson 4 12 , Ellie Russell 1 , David St Clair 17 , Jennifer G Sambrook 8 9 , Jeremy D Sanderson 45 , Helen Schuilenburg 5 , Carol E Scott 2 , Richard Scott 20 , Sheila Seal 20 , Sue Shaw-Hawkins 39 , Beverley M Shields 34 , Matthew J Simmonds 14 , Debbie J Smyth 5 , Elilan Somaskantharajah 2 , Katarina Spanova 20 , Sophia Steer 49 , Jonathan Stephens 8 9 , Helen E Stevens 5 , Millicent A Stone 50 51 , Zhan Su 3 , Deborah PM Symmons 11 , John R Thompson 6 , Wendy Thomson 11 , Mary E Travers 12 , Clare Turnbull 20 , Armand Valsesia 2 , Mark Walker 52 , Neil M Walker 5 , Chris Wallace 5 , Margaret Warren-Perry 20 , Nicholas A Watkins 8 9 , John Webster 53 , Michael N Weedon 34 , Anthony G Wilson 54 , Matthew Woodburn 5 , B Paul Wordsworth 55 , Allan H Young 29 56 , Eleftheria Zeggini 2 4 , Nigel P Carter 2 , Timothy M Frayling 34 , Charles Lee 35 , Gil McVean 3 , Patricia B Munroe 39 , Aarno Palotie 2 , Stephen J Sawcer 57 , Stephen W Scherer 30 58 , David P Strachan 59 , Chris Tyler-Smith 2 , Matthew A Brown 55 60 , Paul R Burton 6 , Mark J Caulfield 39 , Alastair Compston 57 , Martin Farrall 61 , Stephen CL Gough 14 33 , Alistair S Hall 10 , Andrew T Hattersley 34 62 , Adrian VS Hill 4 , Christopher G Mathew 13 , Marcus Pembrey 63 , Jack Satsangi 23 , Michael R Stratton 2 20 , Jane Worthington 11 , Panos Deloukas 2 , Audrey Duncanson 64 , Dominic P Kwiatkowski 2 4 , Mark I McCarthy 4 12 65 , Willem H Ouwehand 2 8 9 , Miles Parkes 16 , Nazneen Rahman 20 , John A Todd 5 , Nilesh J Samani 15 66 , Peter Donnelly 4 3 .
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