A general test of association for quantitative traits in nuclear families
A general test of association for quantitative traits in nuclear families
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DOI：
10.1086/302698
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发表时间：
2000-01-01
影响因子：
9.8
通讯作者：
Cookson, WOC
中科院分区：
文献类型：
--
作者：
Abecasis, GR;Cardon, LR;Cookson, WOC
高分辨率定位是识别复杂疾病基因的重要一步。在远交群体中，连锁不平衡预计将在短距离内运作，并可能提供一个强大的精细定位工具。在这里，我们建立在最近开发的方法连锁不平衡映射的数量性状构建一个通用的方法，可以容纳任何规模的核心家庭，有或没有父母的信息。方差分量被用来构建一个测试，利用所有可用的后代的信息，但不存在偏见的连锁或家族性。一个排列测试描述的情况下，方差分量的最大似然估计有偏。模拟研究被用来调查这种方法的功率和错误率，并突出的情况下，违反多元正态假设保证排列测试：功率和水平的连锁不平衡，这个测试之间的关系表明，该方法非常适合密集的地图分析。权力和家庭结构之间的关系进行了研究，这些结果适用于复杂疾病的研究设计，特别是对于父母通常无法获得的迟发性疾病。当父母的基因型是可用的，权力并不取决于在每个家庭的后代的数量很大。当父母的基因型不可用时，功率降低，但当每个家庭有四个或更多的后代进行基因分型时，功率的损失可以忽略不计。最后，它表明，当兄弟姐妹可用，基因型的总数，以实现可比的权力是较小的，如果父母没有基因型。
High-resolution mapping is an important step in the identification of complex disease genes. In outbred populations, linkage disequilibrium is expected to operate over short distances and could provide a powerful fine-mapping tool. Here we build on recently developed methods for linkage-disequilibrium mapping of quantitative traits to construct a general approach that can accommodate nuclear families of any size, with or without parental information. Variance components are used to construct a test that utilizes information from all available offspring but that is not biased in the presence of linkage or familiality. A permutation test is described for situations in which maximum-likelihood estimates of the variance components are biased. Simulation studies are used to investigate power and error rates of this approach and to highlight situations in which violations of multivariate normality assumptions warrant the permutation test: The relationship between power and the level of linkage disequilibrium for this test suggests that the method is well suited to the analysis of dense maps. The relationship between power and family structure is investigated, and these results are applicable to study design in complex disease, especially for late-onset conditions for which parents are usually not available. When parental genotypes are available, power does not depend greatly on the number of offspring in each family. Power decreases when parental genotypes are not available, but the loss in power is negligible when four or more offspring per family are genotyped. Finally, it is shown that, when siblings are available, the total number of genotypes required in order to achieve comparable power is smaller if parents are not genotyped.