Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
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拷贝数变异(CNV)在人类遗传多态中占很大比例，已被预测在常见疾病的遗传易感性中发挥重要作用。为了解决这一问题，我们对CNV和八种常见的人类疾病之间的关系进行了一项大规模的直接全基因组研究。使用专门设计的数组，我们在3432个多态CNV中将约19,000个个体分成不同的拷贝数类，其中估计有~50%的常见CNV大于500bp。我们确定了几种导致假阳性关联的生物制品，包括来自血液和细胞系的DNA之间的系统性CNV差异。关联测试和后续复制分析证实了三个CNV与疾病相关的基因座，克罗恩病的IRGM，克罗恩病、类风湿性关节炎和1型糖尿病的HL A，以及2型糖尿病的TSPAN8，尽管在每个病例中，该基因座都已在基于SNP的研究中确定，反映了我们观察到我们的阵列中大多数类型良好的常见CNV都被SNP很好地标记，因此已经通过SNP研究间接探索了这些CNV。我们得出的结论是，可以在现有平台上进行分型的常见CNV不太可能对常见人类疾病的遗传基础做出重大贡献。
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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影响因子：
30.8
作者：
通讯作者：
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Koch, S;Goedde, R;Witte, T
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Witte, T
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Clayton, DG;Walker, NM;Todd, JA
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Todd, JA
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Stone, Jennifer L.;O'Donovan, Michael C.;Gurling, Hugh;Kirov, George K.;Blackwood, Douglas H. R.;Corvin, Aiden;Craddock, Nick J.;Gill, Michael;Hultman, Christina M.;Lichtenstein, Paul;McQuillin, Andrew;Pato, Carlos N.;Ruderfer, Douglas M.;Owen, Michael J.;St Clair, David;Sullivan, Patrick F.;Sklar, Pamela;Purcell, Shaun M.;Scolnick, E. M.;Holmans, P. A.;Georgieva, L.;Nikolov, I.;Norton, N.;Williams, H.;Williams, N. M.;Toncheva, D.;Milanova, V.;Thelander, E. F.;Morris, D. W.;O'Dushlaine, C. T.;Kenny, E.;Waddington, J. L.;Choudhury, K.;Datta, S.;Pimm, J.;Thirumalai, S.;Puri, V.;Krasucki, R.;Lawrence, J.;Quested, D.;Bass, N.;Curtis, D.;Crombie, C.;Fraser, G.;Kwan, S. L.;Muir, W. J.;McGhee, K. A.;Pickard, B.;Malloy, P.;Maclean, A. W.;Van Beck, M.;Visscher, P. M.;Macgregor, S.;Pato, M. T.;Medeiros, H.;Middleton, F.;Carvalho, C.;Morley, C.;Fanous, A.;Conti, D.;Knowles, J. A.;Ferreira, C. P.;Azevedo, M. H.;McCarroll, S. A.;Gates, C.;Daly, M. J.;Sklar, P.
通讯作者：
Sklar, P.
影响因子：
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通讯作者：
Lopez, AD