Contrasting linkage-disequilibrium patterns between cases and controls as a novel association-mapping method
Contrasting linkage-disequilibrium patterns between cases and controls as a novel association-mapping method
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DOI：
10.1086/503710
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发表时间：
2006-05-01
影响因子：
9.8
通讯作者：
Ehm, MG
中科院分区：
文献类型：
--
作者：
Zaykin, DV;Meng, ZL;Ehm, MG
识别和描述潜在疾病易感性、疗效和药物不良反应的遗传变异仍然是一个难题。在候选区域变异分析的重要步骤之一是表征连锁不平衡（LD）。在遗传相关区域，LD的程度在病例组和对照组之间有所不同。通常会为候选区域提供病例和对照组的成对标准化LD测量（例如，）的单独图，以图形方式传达LD的病例-对照差异。然而，观察到的图形差异缺乏统计支持。因此，我们建议使用“LD对比”检验来比较两个样本之间的整个不平衡矩阵。当单倍型阶段未被观察到时，评估LD的常用技术是期望最大化算法，其可能性包含Hardy-Weinberg平衡（HWE）的假设。这种方法提出了一个潜在的问题，在遗传关联的区域，当样本是根据表型选择时，HWE假设可能不成立。在这里，我们提出了一种计算上可行的方法，不假设HWE，以及图形显示和病例和对照样本之间的成对LD矩阵的统计比较。ld对比试验为现有的发现和表征遗传关联的工具提供了有用的补充。虽然当易感性主要由单倍型决定时，单倍型关联测试有望提供更高的功效，但在某些单倍型驱动的疾病模型下，ld对比测试显示出更高的功效。
Identification and description of genetic variation underlying disease susceptibility, efficacy, and adverse reactions to drugs remains a difficult problem. One of the important steps in the analysis of variation in a candidate region is the characterization of linkage disequilibrium (LD). In a region of genetic association, the extent of LD varies between the case and the control groups. Separate plots of pairwise standardized measures of LD (e.g.,) for cases and controls are often presented for a candidate region, to graphically convey case-control differences in LD. However, the observed graphic differences lack statistical support. Therefore, we suggest the "LD contrast" test to compare whole matrices of disequilibrium between two samples. A common technique of assessing LD when the haplotype phase is unobserved is the expectation-maximization algorithm, with the likelihood incorporating the assumption of Hardy-Weinberg equilibrium (HWE). This approach presents a potential problem in that, in the region of genetic association, the HWE assumption may not hold when samples are selected on the basis of phenotypes. Here, we present a computationally feasible approach that does not assume HWE, along with graphic displays and a statistical comparison of pairwise matrices of LD between case and control samples. LD-contrast tests provide a useful addition to existing tools of finding and characterizing genetic associations. Although haplotype association tests are expected to provide superior power when susceptibilities are primarily determined by haplotypes, the LD-contrast tests demonstrate substantially higher power under certain haplotype-driven disease models.