Score tests for association between traits and haplotypes when linkage phase is ambiguous
Score tests for association between traits and haplotypes when linkage phase is ambiguous
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DOI：
10.1086/338688
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发表时间：
2002-02-01
影响因子：
9.8
通讯作者：
Poland, GA
中科院分区：
文献类型：
--
作者：
Schaid, DJ;Rowland, CM;Poland, GA
发现与性状相关的基因的关键步骤是发现性状与一个或多个单倍型之间的关联。单倍型分析还可以提供关于基因功能的关键信息;然而，当对不相关的受试者进行采样时，单倍型通常是模糊的，因为沿着染色体沿着测量的位点的连锁相位未知。在病例对照研究中，一种解释这种模糊性的流行方法使用依赖于单倍型频率的可能性，以便可以在病例和对照之间比较单倍型频率;然而，这种传统方法仅限于二元性状（病例与对照），并且它没有提供测试特定单倍型的统计学显著性的方法。为了解决这些局限性，我们开发了新的方法来测试单倍型和各种各样的性状，包括二元，序数和数量性状之间的统计关联。我们的方法允许调整非遗传协变量，这在分析遗传复杂性状时可能至关重要。此外，我们的方法提供了几种不同的全球关联测试，以及单倍型特异性测试，这在尝试了解许多不同单倍型的作用方面提供了有意义的优势。统计数据可以快速计算，使得评估许多单倍型和性状之间的关联成为可能。为了说明我们的新方法的使用，它们被应用到单倍型（由人类白细胞抗原复合物的基因组成）与麻疹疫苗接种的体液免疫反应的关联的研究。有限的模拟也展示了我们的方法的有效性，以及如何使用我们的方法提供指导方针。
A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.