Schaid D J, Rowland C
Departments of Health Sciences Research and Medical Genetics, Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA.
Am J Hum Genet. 1998 Nov;63(5):1492-506. doi: 10.1086/302094.
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.
检测基因标记与复杂疾病之间的关联可能是朝着确定疾病遗传基础迈出的关键第一步。通过选择患病病例的父母作为对照可以避免产生误导性的关联，但父母的可获得性常常将这种设计限制于早发性疾病。另外，同胞对照提供了一种有效的设计。本文提出了一种通用的多变量评分统计量，用于检测多等位基因遗传标记位点与患病状态之间的关联；这种通用方法适用于使用父母作为对照、同胞作为对照，甚至适用于基因型不符合哈迪-温伯格比例的无关对照，或者适用于合并这些不同设计的任何组合的设计。这种多变量评分统计量的优点在于，当多个标记等位基因与患病状态相关联时，它往往是最具效力的方法。为了规划这类研究，我们提出了计算样本量和检验效能的方法，同时考虑了不同的同胞家庭规模、确定标准和风险遗传模型。结果表明，同胞对照的检验效能低于父母对照，并且可以通过增加每个同胞家庭中患病同胞的数量或未患病对照同胞的数量来提高同胞对照的检验效能。样本量结果表明，对于具有显性效应的标记以及具有隐性效应的常见等位基因，使用同胞对照通过单标记位点或全基因组筛查来检验关联将是可行的。本文给出的结果将对计划使用同胞作为对照进行研究的研究者有用。
