The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases.
The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases.
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DOI：
10.1371/journal.pone.0076295
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Alda M
中科院分区：
文献类型：
--
作者：
Manchia M;Cullis J;Turecki G;Rouleau GA;Uher R;Alda M
表型错误分类（病例之间）已被证明会降低遗传研究中检测关联的能力。然而，可以想象的是，复杂性状在个体遗传易感性和疾病病理生理学方面是异质的，并且异质性的影响比表型错误的影响更大。尽管异质性是一个直观清晰的概念，但它对常见疾病遗传学研究的影响却很少受到关注。在这里，我们研究表型和遗传异质性对全基因组关联研究（GWAS）统计功效的影响。我们首先对模拟基因型和表型数据进行了研究。接下来，我们分析了 Wellcome Trust 病例对照联盟 (WTCCC) 的 1 型糖尿病 (DM) 1 型 (T1D) 和 2 型糖尿病 (T2D) 数据，使用每种类型糖尿病的不同比例，以检验异质性对之前在 WTCCC 数据中发现的关联强度和统计显着性的影响。在模拟数据和真实数据中，异质性（“非病例”的存在）降低了检测遗传关联的统计能力，并大大降低了对遗传变异造成的风险的估计。这一发现也得到了随后大规模荟萃分析中验证的基因座分析的支持。例如，50% 的异质性会使所需的样本量增加大约三倍。这些结果表明，准确的表型描述对于检测真正的遗传关联可能比增加样本量更重要。
Phenotypic misclassification (between cases) has been shown to reduce the power to detect association in genetic studies. However, it is conceivable that complex traits are heterogeneous with respect to individual genetic susceptibility and disease pathophysiology, and that the effect of heterogeneity has a larger magnitude than the effect of phenotyping errors. Although an intuitively clear concept, the effect of heterogeneity on genetic studies of common diseases has received little attention. Here we investigate the impact of phenotypic and genetic heterogeneity on the statistical power of genome wide association studies (GWAS). We first performed a study of simulated genotypic and phenotypic data. Next, we analyzed the Wellcome Trust Case-Control Consortium (WTCCC) data for diabetes mellitus (DM) type 1 (T1D) and type 2 (T2D), using varying proportions of each type of diabetes in order to examine the impact of heterogeneity on the strength and statistical significance of association previously found in the WTCCC data. In both simulated and real data, heterogeneity (presence of “non-cases”) reduced the statistical power to detect genetic association and greatly decreased the estimates of risk attributed to genetic variation. This finding was also supported by the analysis of loci validated in subsequent large-scale meta-analyses. For example, heterogeneity of 50% increases the required sample size by approximately three times. These results suggest that accurate phenotype delineation may be more important for detecting true genetic associations than increase in sample size.
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DOI：
10.1176/appi.ajp.2010.10091340
发表时间：
2011-03
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Gershon ES;Alliey-Rodriguez N;Liu C
通讯作者：
Liu C
LRTAE：存在表型和/或基因型错误分类错误时，遗传关联与病例/控制数据的统计能力提高。
影响因子：
2.9
作者：
Barral, Sandra;Haynes, Chad;Stone, Millicent;Gordon, Derek
通讯作者：
Gordon, Derek
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
9.8
作者：
Cichon, Sven;Muehleisen, Thomas W.;Noethen, Markus M.
通讯作者：
Noethen, Markus M.
影响因子：
30.8
作者：
Ferreira, Manuel A. R.;O'Donovan, Michael C.;Meng, Yan A.;Jones, Ian R.;Ruderfer, Douglas M.;Jones, Lisa;Fan, Jinbo;Kirov, George;Perlis, Roy H.;Green, Elaine K.;Smoller, Jordan W.;Grozeva, Detelina;Stone, Jennifer;Nikolov, Ivan;Chambert, Kimberly;Hamshere, Marian L.;Nimgaonkar, Vishwajit L.;Moskvina, Valentina;Thase, Michael E.;Caesar, Sian;Sachs, Gary S.;Franklin, Jennifer;Gordon-Smith, Katherine;Ardlie, Kristin G.;Gabriel, Stacey B.;Fraser, Christine;Blumenstiel, Brendan;Defelice, Matthew;Breen, Gerome;Gill, Michael;Morris, Derek W.;Elkin, Amanda;Muir, Walter J.;McGhee, Kevin A.;Williamson, Richard;MacIntyre, Donald J.;MacLean, Alan W.;Clair, David St;Robinson, Michelle;Van Beck, Margaret;Pereira, Ana C. P.;Kandaswamy, Radhika;McQuillin, Andrew;Collier, David A.;Bass, Nicholas J.;Young, Allan H.;Lawrence, Jacob;Ferrier, I. Nicol;Anjorin, Adebayo;Farmer, Anne;Curtis, David;Scolnick, Edward M.;McGuffin, Peter;Daly, Mark J.;Corvin, Aiden P.;Holmans, Peter A.;Blackwood, Douglas H.;Gurling, Hugh M.;Owen, Michael J.;Purcell, Shaun M.;Sklar, Pamela;Craddock, Nick
通讯作者：
Craddock, Nick