A joint association test for multiple SNPs in genetic case-control studies.
A joint association test for multiple SNPs in genetic case-control studies.
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DOI：
10.1002/gepi.20368
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发表时间：
2009-02
影响因子：
2.1
通讯作者：
Zeng, Zhao-Bang
中科院分区：
文献类型：
--
作者：
Wang, Tao;Jacob, Howard;Ghosh, Soumitra;Wang, Xujing;Zeng, Zhao-Bang
对于一组密集的遗传标记，例如小候选区域内高连锁不平衡的单核苷酸多态性 (SNP)，用于测试疾病表型和标记集之间关联的基于单倍型的方法在降低数据复杂性和提高统计功效方面具有吸引力。然而，由于潜在疾病变异的状态未知，全面的关联测试可能需要考虑 SNP 的各种组合，这通常会导致严重的多重测试问题。在本文中，我们提出了一种潜在变量方法来测试病例对照研究中多个紧密连锁的 SNP 的关联。首先，我们将潜在变量引入外显率模型中，以表征假定的疾病易感位点（DSL），该位点可能由标记等位基因、标记子集的单倍型或标记之间假定位点的等位基因组成。接下来，通过使用回顾性可能性来调整病例对照抽样确定并适当处理 Hardy-Weinberg 平衡约束，我们开发了一种基于期望最大化（EM）的算法来拟合外显率模型并同时估计 DSL 和标记的联合单倍型频率。通过潜在变量来描述 DSL 的灵活作用，似然比统计量可以为标记集提供联合关联测试，而不需要对多个单倍型的测试进行调整。我们的模拟结果还表明，与经典的单倍型关联方法相比，潜变量方法在某些情况下可能具有更高的功效。
For a dense set of genetic markers such as single nucleotide polymorphisms (SNPs) on high linkage disequilibrium within a small candidate region, a haplotype-based approach for testing association between a disease phenotype and the set of markers is attractive in reducing the data complexity and increasing the statistical power. However, due to unknown status of the underlying disease variant, a comprehensive association test may require consideration of various combinations of the SNPs, which often leads to severe multiple testing problems. In this paper, we propose a latent variable approach to test for association of multiple tightly linked SNPs in case-control studies. First, we introduce a latent variable into the penetrance model to characterize a putative disease susceptible locus (DSL) that may consist of a marker allele, a haplotype from a subset of the markers, or an allele at a putative locus between the markers. Next, through using of a retrospective likelihood to adjust for the case-control sampling ascertainment and appropriately handle the Hardy-Weinberg equilibrium constraint, we develop an expectation-maximization (EM)-based algorithm to fit the penetrance model and estimate the joint haplotype frequencies of the DSL and markers simultaneously. With the latent variable to describe a flexible role of the DSL, the likelihood ratio statistic can then provide a joint association test for the set of markers without requiring an adjustment for testing of multiple haplotypes. Our simulation results also reveal that the latent variable approach may have improved power under certain scenarios comparing with classical haplotype association methods.
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影响因子：
2.1
作者：
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影响因子：
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DOI：
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