Use of parents, sibs and unrelated controls for detection of associations between genetic markers and disease
Use of parents, sibs and unrelated controls for detection of associations between genetic markers and disease
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DOI：
10.1086/302094
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发表时间：
1998-11-01
影响因子：
9.8
通讯作者：
Rowland, C
中科院分区：
文献类型：
--
作者：
Schaid, DJ;Rowland, C
检测遗传标记和复杂疾病之间的关联可能是识别疾病遗传基础的关键第一步。通过选择患病病例的父母作为对照，可以避免误导性的关联，但父母的可用性往往限制了这种设计，以早发性疾病。或者，同胞对照提供了有效的设计。提出了一种通用的多变量得分统计量，用于检测多等位基因遗传标记位点与情感状态之间的关联;这种通用方法适用于使用亲本作为对照、同胞作为对照、或甚至其基因型不符合Hardy-Weinberg比例的无关对照或汇集这些不同设计的任何组合的设计，这种多变量评分统计的好处是，当多个标记等位基因与情感状态相关时，它往往是最强大的方法。为了计划这些类型的研究，我们提出了计算样本量和功效的方法，允许不同的同胞关系大小，确定标准和遗传风险模型。结果表明，同胞对照比亲本对照具有更低的能力，并且同胞对照的能力可以通过增加每个同胞关系中受影响同胞的数量或未受影响对照同胞的数量来增加。样本量结果表明，通过使用单标记基因座或全基因组筛选，使用同胞对照来测试关联，对于具有显性效应的标记和具有隐性效应的常见等位基因来说是可行的。研究结果将有助于研究者计划使用同胞作为对照的研究。
Detecting the association between genetic markers and complex diseases can be a critical first step toward identification of the genetic basis of disease. Misleading associations can be avoided by choosing as controls the parents of diseased cases, but the availability of parents often Limits this design to early-onset: disease. Alternatively, sib controls offer a valid design. A general multivariate score statistic is presented, to detect the association between a multiallelic genetic marker locus and affection status; this general approach is applicable to designs that use parents as controls, sibs as controls, or even unrelated controls whose genotypes do not fit Hardy-Weinberg proportions or that pool any combination of these different designs, The benefit of this multivariate score statistic is that it will tend to be the most powerful method when multiple marker alleles are associated with affection status. To plan these types of studies, we present methods to compute sample size and power, allowing for varying sibship sizes, ascertainment criteria, and genetic models of risk. The results indicate that sib controls have less power than parental controls and that the power of sib controls can be increased by increasing either the number of affected sibs per sibship or the number of unaffected control sibs, The sample-size results indicate that the use of sib controls to test for associations, by use of either a single-marker locus or a genomewide screen, will be feasible for markers that have a dominant effect and for common alleles having a recessive effect. The results presented will be useful for investigators planning studies using sibs as controls.