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

被引：591

作者：

Craddock, Nick ^{[1
]}

Hurles, Matthew E. ^{[2
]}

Cardin, Niall ^{[3
]}

Pearson, Richard D. ^{[4
]}

Plagnol, Vincent ^{[5
]}

Robson, Samuel ^{[2
]}

Vukcevic, Damjan ^{[4
]}

Barnes, Chris ^{[2
]}

Conrad, Donald F. ^{[2
]}

Giannoulatou, Eleni ^{[3
]}

Holmes, Chris ^{[3
]}

Marchini, Jonathan L. ^{[3
]}

Stirrups, Kathy ^{[2
]}

Tobin, Martin D. ^{[6
,7
]}

Wain, Louise V. ^{[6
,7
]}

Yau, Chris ^{[3
]}

Aerts, Jan ^{[2
]}

Ahmad, Tariq ^{[8
]}

Andrews, T. Daniel ^{[2
]}

Arbury, Hazel ^{[2
]}

Attwood, Anthony ^{[2
,9
,10
]}

Auton, Adam ^{[3
]}

Ball, Stephen G. ^{[11
]}

Balmforth, Anthony J. ^{[11
]}

Barrett, Jeffrey C. ^{[2
]}

Barroso, Ines ^{[2
]}

Barton, Anne ^{[12
]}

Bennett, Amanda J. ^{[13
]}

Bhaskar, Sanjeev ^{[2
]}

Blaszczyk, Katarzyna ^{[14
]}

Bowes, John ^{[12
]}

Brand, Oliver J. ^{[15
]}

Braund, Peter S. ^{[16
]}

Bredin, Francesca ^{[17
]}

Breen, Gerome ^{[18
,19
]}

Brown, Morris J. ^{[20
]}

Bruce, Ian N. ^{[12
]}

Bull, Jaswinder ^{[21
]}

Burren, Oliver S. ^{[5
]}

Burton, John ^{[2
]}

Byrnes, Jake ^{[4
]}

Caesar, Sian ^{[22
]}

Clee, Chris M. ^{[2
]}

Coffey, Alison J. ^{[2
]}

Connell, John M. C. ^{[23
]}

Cooper, Jason D. ^{[5
]}

Dominiczak, Anna F. ^{[23
]}

Downes, Kate ^{[5
]}

Drummond, Hazel E. ^{[24
]}

Dudakia, Darshna ^{[21
]}

机构：

[1] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Sch Med, Cardiff CF14 4XN, Wales

[2] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[3] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[5] Univ Cambridge, Cambridge Inst Med Res, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab,Dept Med Ge, Cambridge CB2 0XY, England

[6] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England

[7] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[8] Univ Exeter, Peninsula Coll Med & Dent, Exeter EX1 2LU, Devon, England

[9] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England

[10] Cambridge Ctr, Natl Hlth Serv Blood & Transplant, Cambridge CB2 0PT, England

[11] Univ Leeds, LIGHT, MCRC, Leeds LS2 9JT, W Yorkshire, England

[12] Univ Manchester, Arc Epidemiol Unit, Manchester M13 9PT, Lancs, England

[13] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Med, Oxford OX3 7LJ, England

[14] Kings Coll London, Sch Med, Dept Med & Mol Genet, Guys Hosp, London SE1 9RT, England

[15] Univ Birmingham, Inst Biomed Res, Ctr Endocrinol Diabet & Metab, Birmingham B15 2TT, W Midlands, England

[16] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England

[17] Addenbrookes Hosp, IBD Genet Res Grp, Cambridge CB2 0QQ, England

[18] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland

[19] Kings Coll London, Inst Psychiat, SGDP, London SE5 8AF, England

[20] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England

[21] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England

[22] Univ Birmingham, Natl Ctr Mental Hlth, Dept Psychiat, Birmingham B15 2FG, W Midlands, England

[23] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland

[24] Univ Edinburgh, Western Gen Hosp, Gastrointestinal Unit, Div Med Sci,Sch Mol & Clin Med, Edinburgh EH4 2XU, Midlothian, Scotland

[25] Univ Southampton, Acad Unit Genet Med, Southampton SO16 5YA, Hants, England

[26] Torbay Hosp, Endoscopy Reg Training Unit, Torquay TQ2 7AA, England

[27] Univ Leeds, Chapel Allerton Hosp, Acad Unit Musculoskeletal Dis, Leeds LS7 4SA, W Yorkshire, England

[28] Univ Bristol, MRC, Ctr Causal Analyses Translat Epidemiol, Dept Social Med, Bristol BS8 2BN, Avon, England

[29] Univ Manchester, MAHSC, Dept Med Genet, Manchester M13 0JH, Lancs, England

[30] Royal Victoria Infirm, Sch Neurol Neurobiol & Psychiat, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[31] Hosp Sick Children, MaRS Ctr, Ctr Appl Genom, Toronto, ON M5G 1L7, Canada

[32] Hosp Sick Children, MaRS Ctr, Program Genet & Genom Biol, Toronto, ON M5G 1L7, Canada

[33] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, S-75185 Uppsala, Sweden

[34] Univ Coll London Hosp Trust, Inst Digest Dis, London NW1 2BU, England

[35] Univ Hosp Birmingham NHS Fdn Trust, Birmingham B15 2TT, W Midlands, England

[36] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[37] Harvard Univ, Sch Med, Boston, MA 02115 USA

[38] Univ Oxford, Inst Musculoskeletal Sci, Botnar Res Ctr, Oxford OX3 7LD, England

[39] Barts & London Royal London Hosp, Ctr Diabet & Metab Med, London E1 1BB, England

[40] Univ Aberdeen, Bone Res Grp, Dept Med & Therapeut, Aberdeen AB25 2ZD, Scotland

[41] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol & Barts & London Genome Ctr, London EC1M 6BQ, England

[42] Sch Med, Musculoskeletal Res Grp, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[43] Univ Oxford, Gastroenterol Unit, Radcliffe Infirm, Oxford OX2 6HE, England

[44] Ctr Natl Genotypage, F-91057 Paris, France

[45] Newcastle Univ, Royal Victoria Infirm, Dept Gastroenterol & Hepatol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England

[46] Univ Bristol, Dept Social Med, ALSPAC Lab, Bristol BS8 2BN, Avon, England

[47] Kings Coll London, Sch Biomed & Hlth Sci, Div Nutr Sci, London SE1 9NH, England

[48] Univ Leeds, Chapel Allerton Hosp, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds LS7 4SA, W Yorkshire, England

[49] Univ Dundee, Ninewells Hosp & Med Sch, Dept Gen Internal Med, Dundee DD1 9SY, Scotland

[50] INSERM, UMR915, Inst Thorax, F-44035 Nantes, France

来源：

NATURE | 2010年 / 464卷 / 7289期

基金：

英国惠康基金;

关键词：

COPY-NUMBER VARIATION; LARGE-SCALE; SUSCEPTIBILITY; POLYMORPHISMS; DELETION; HERITABILITY; HEALTH;

D O I：

10.1038/nature08979

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：713 / U86

页数：10

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