Testing for population subdivision and association in four case-control studies
Testing for population subdivision and association in four case-control studies
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DOI：
10.1086/341719
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发表时间：
2002-08-01
影响因子：
9.8
通讯作者：
Seielstad, M
中科院分区：
文献类型：
--
作者：
Ardlie, KG;Lunetta, KL;Seielstad, M
人群结构被认为是导致文献中报道的许多不可复制的疾病标志物关联的原因，但很少有实际的病例对照研究评估了结构的存在。在这里，我们检查了4个中度病例对照样本，包括3，472个个体，以确定是否存在可检测的人群细分。这四个群体样本包括：500名美国人。S.白人和236名非洲裔美国人患有高血压; S.白人和500名患有2型糖尿病的波兰白人，所有人都有匹配的对照组。对两个糖尿病人群的PPARg Pro 12 Ala多态性进行分型，以复制这种得到充分支持的相关性（Altshirt et al. 2000）。在四个样本中，我们使用9个STR和35个SNP标记的病例对照等位基因频率χ 2统计量的总和来测试结构（Pritchard和Rosenberg 1999）。我们发现只有非洲裔美国人样本中的人口结构证据不足，但进一步细化样本，仅包括美国-出生的父母和祖父母，消除了分层。我们的例子提供了对影响关联研究重复性的因素的深入了解，并表明在世界性的美国，仔细匹配的，中等规模的病例对照样本。S.欧洲人群不太可能包含会导致假阳性关联数量显著膨胀的结构水平。我们探讨的作用，权力之间的研究，由于样本量和风险等位基因频率差异的极端差异，可能会在复制问题。
Population structure has been presumed to cause many of the unreplicated disease-marker associations reported in the literature, yet few actual case-control studies have been evaluated for the presence of structure. Here, we examine four moderate case-control samples, comprising 3,472 individuals, to determine if detectable population subdivision is present. The four population samples include: 500 U. S. whites and 236 African Americans with hypertension; and 500 U. S. whites and 500 Polish whites with type 2 diabetes, all with matched control subjects. Both diabetes populations were typed for the PPARg Pro12Ala polymorphism, to replicate this well-supported association (Altshuler et al. 2000). In each of the four samples, we tested for structure, using the sum of the case-control allele frequency chi(2) statistics for 9 STR and 35 SNP markers (Pritchard and Rosenberg 1999). We found weak evidence for population structure in the African American sample only, but further refinement of the sample, to include only individuals with U.S.-born parents and grandparents, eliminated the stratification. Our examples provide insight into the factors affecting the replication of association studies and suggest that carefully matched, moderate-sized case-control samples in cosmopolitan U. S. and European populations are unlikely to contain levels of structure that would result in significantly inflated numbers of false-positive associations. We explore the role that extreme differences in power among studies, due to sample size and risk-allele frequency differences, may play in the replication problem.