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

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      The Wellcome Trust Case Control Consortium
      Nature

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          Abstract

          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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          Most cited references23

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          Individual Comparisons by Ranking Methods

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            Global variation in copy number in the human genome.

            Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
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              Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

              Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                1 April 2010
                1 April 2010
                01 October 2010
                : 464
                : 7289
                : 713-720
                Author notes
                Correspondence and requests for materials should be sent to PD ( peter.donnelly@ 123456well.ox.ac.uk ).
                [*]

                Full list of authors and affiliations appears at the end of the paper.

                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 .

                Author contributions

                The author contributions are detailed in SoM section 12.

                [*]

                These authors contributed equally.

                Article
                UKMS29060
                10.1038/nature08979
                2892339
                20360734
                7aa1142f-35b1-4b25-8df9-58bd3358fca8

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                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 083948 || WT
                Funded by: Medical Research Council :
                Award ID: G0701810(85517) || MRC_
                Funded by: Arthritis Research UK :
                Award ID: 17552 || ARC_
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