Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata
Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata
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DOI：
10.1086/510257
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发表时间：
2006-12-01
影响因子：
9.8
通讯作者：
Hildebrandt, Michelle A. T.
中科院分区：
文献类型：
--
作者：
Schaid, Daniel J.;Batzler, Anthony J.;Hildebrandt, Michelle A. T.
检测标记基因型频率与 Hardy-Weinberg 平衡 (HWE) 的偏离是几乎所有人类遗传分析中至关重要的第一步。当样本按多个种族群体分层时，重要的是允许标记等位基因频率在各层中存在差异。在这种情况下，通常通过在每个层内使用精确测试，然后使用最小 P 值作为全局测试来测试 HWE。这种方法没有考虑多重测试，并且由于它没有结合各层的信息，因此它不具有最佳功效。已经提出了几种结合地层信息的近似方法，但大多数方法都对地层求和，以衡量偏离 HWE 的程度；如果偏离方向不同，则求和可以减少偏离 HWE 的总体证据。精确的分层测试更有吸引力，因为它使用各层基因型配置的概率作为全局偏离 HWE 的证据。我们开发了双等位标记（例如单核苷酸多态性 (SNP)）的 HWE 精确分层测试，以及 Hardy-Weinberg 不平衡同质性的精确测试。通过将我们的方法应用于来自 Perlegen 和 HapMap 的数据（总共超过 500 万个 SNP 基因型，具有 3 到 4 个分层，分层大小从 23 到 60 个受试者不等），我们表明，精确分层检验提供的结果比通过分层上的最小精确检验 P 值或对偏离 HWE 的测量进行求和的近似分层检验所获得的结果更稳健和更有力。因此，我们的新方法应该对由多个种族组成的样本有用。
Detecting departures from Hardy-Weinberg equilibrium (HWE) of marker-genotype frequencies is a crucial first step in almost all human genetic analyses. When a sample is stratified by multiple ethnic groups, it is important to allow the marker-allele frequencies to differ over the strata. In this situation, it is common to test for HWE by using an exact test within each stratum and then using the minimum P value as a global test. This approach does not account for multiple testing, and, because it does not combine information over strata, it does not have optimal power. Several approximate methods to combine information over strata have been proposed, but most of them sum over strata a measure of departure from HWE; if the departures are in different directions, then summing can diminish the overall evidence of departure from HWE. An exact stratified test is more appealing because it uses the probability of genotype configurations across the strata as evidence for global departures from HWE. We developed an exact stratified test for HWE for diallelic markers, such as single-nucleotide polymorphisms (SNPs), and an exact test for homogeneity of Hardy-Weinberg disequilibrium. By applying our methods to data from Perlegen and HapMap - a combined total of more than five million SNP genotypes, with three to four strata and strata sizes ranging from 23 to 60 subjects - we illustrate that the exact stratified test provides more-robust and more-powerful results than those obtained by either the minimum of exact test P values over strata or approximate stratified tests that sum measures of departure from HWE. Hence, our new methods should be useful for samples composed of multiple ethnic groups.