Capitalizing on admixture in genome-wide association studies: a two-stage testing procedure and application to height in African-Americans
Capitalizing on admixture in genome-wide association studies: a two-stage testing procedure and application to height in African-Americans
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DOI：
10.3389/fgene.2011.00011
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发表时间：
2011-01-01
影响因子：
3.7
通讯作者：
Allison, David B.
中科院分区：
文献类型：
--
作者：
Kang, Guolian;Gao, Guimin;Allison, David B.
随着全基因组关联研究扩展到欧洲血统人群之外，混合物的作用将在持续发现和精细定位影响复杂性状的变异方面变得越来越重要。虽然混合物通常被认为是一个混杂的影响，在关联研究中，方法，如混合物映射已经证明了它的能力，突出疾病的基因组易感性区域。在这项研究中，我们说明了一个强大的两阶段测试策略，旨在揭示性状相关的单核苷酸多态性的祖先等位基因频率分化的存在。在第一阶段，我们进行关联扫描，使用预测的基因型值的基础上，区域混合估计。然后，我们选择一个子集的有前途的标记物列入第二阶段的分析，其中关联之间的观察到的基因型和表型的预测基因型的条件进行测试。我们证明了，在零假设下，在每个阶段使用的检验统计量是正交的，渐近独立的。使用模拟的数据，旨在模仿非洲裔美国人的数量性状的情况下，我们表明，我们的两阶段的程序保持适当的控制家庭明智的错误率，并具有更高的权力下现实的效果大小比一阶段的测试程序，其中所有的标志物进行测试，同时与控制混合物的关联。我们应用所提出的程序，在201个非洲裔美国人的身高基因型在108个祖先信息标记的研究。该两阶段程序鉴定了两个具有统计学意义的标志物rs 1985080（PTHB 1/BBS 9）和rs 952718（ABCA 12）。PTHB 1/BBS 9在成骨细胞中被甲状旁腺激素下调，被认为参与甲状旁腺激素在骨骼中的作用，并可能在身高中发挥作用。ABCA 12是ATP结合盒转运蛋白超家族的成员，其与身高的潜在关系尚不清楚。
As genome-wide association studies expand beyond populations of European ancestry, the role of admixture will become increasingly important in the continued discovery and fine-mapping of variation influencing complex traits. Although admixture is commonly viewed as a confounding influence in association studies, approaches such as admixture mapping have demonstrated its ability to highlight disease susceptibility regions of the genome. In this study, we illustrate a powerful two-stage testing strategy designed to uncover trait-associated single nucleotide polymorphisms in the presence of ancestral allele frequency differentiation. In the first stage, we conduct an association scan by using predicted genotypic values based on regional admixture estimates. We then select a subset of promising markers for inclusion in a second-stage analysis, where association is tested between the observed genotype and the phenotype conditional on the predicted genotype. We prove that, under the null hypothesis, the test statistics used in each stage are orthogonal and asymptotically independent. Using simulated data designed to mimic African-American populations in the case of a quantitative trait, we show that our two-stage procedure maintains appropriate control of the family wise error rate and has higher power under realistic effect sizes than the one-stage testing procedure in which all markers are tested for association simultaneously with control of admixture. We apply the proposed procedure to a study of height in 201 African-Americans genotyped at 108 ancestry informative markers. The two-stage procedure identified two statistically significant markers rs1985080 (PTHB1/BBS9) and rs952718 (ABCA12). PTHB1/BBS9 is downregulated by parathyroid hormone in osteoblastic cells and is thought to be involved in parathyroid hormone action in bones and may play a role in height. ABCA12 is a member of the superfamily of ATP-binding cassette transporters and its potential involvement in height is unclear.