Two-phase designs to follow-up genome-wide association signals with DNA resequencing studies.
Two-phase designs to follow-up genome-wide association signals with DNA resequencing studies.
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DOI：
10.1002/gepi.21708
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发表时间：
2013-04
影响因子：
2.1
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
--
作者：
Schaid, Daniel J.;Jenkins, Gregory D.;Ingle, James N.;Weinshilboum, Richard M.
复杂性状的全基因组关联研究（GWAS）产生了许多单核苷酸多态性（SNP）的关联信号。为了了解潜在的因果遗传变异，通常使用靶向基因组区域的聚焦DNA重测序，但目前重测序的成本限制了重测序研究的样本量。来自大GWAS的信息可用于指导用于重测序的样品的选择，例如靶向基因组区域中的SNP基因型。将GWAS tag-SNPs视为潜在因果变异的不完美替代物，但预期tag-SNPs与因果变异相关，合理的方法是两阶段病例对照设计，GWAS作为第一阶段，重测序研究作为第二阶段。使用基于tag-SNP基因型和病例对照状态的分层抽样，我们探索了两阶段设计相对于随机抽样病例和对照的功效增益，用于重新测序（即，忽略tag-SNP基因型）。模拟结果表明，基于tag-SNP基因型和病例对照状态的分层抽样不太可能比仅基于病例对照状态的分层抽样具有更低的功效，并且有时可以具有更大的功效。功效的增加取决于tag-SNP和因果变体等位基因之间的连锁不平衡的量，以及因果变体的效应大小。因此，两阶段设计提供了一种有效的方法，后续GWAS信号与DNA重测序。
Genome-wide association studies (GWAS) of complex traits have generated many association signals for single nucleotide polymorphisms (SNPs). To understand the underlying causal genetic variant(s), focused DNA resequencing of targeted genomic regions is commonly used, yet the current cost of resequencing limits sample sizes for resequencing studies. Information from the large GWAS can be used to guide choice of samples for resequencing, such as the SNP genotypes in the targeted genomic region. Viewing the GWAS tag-SNPs as imperfect surrogates for the underlying causal variants, yet expecting that the tag-SNPs are correlated with the causal variants, a reasonable approach is a two-phase case-control design, with the GWAS serving as the first-phase and the resequencing study serving as the second-phase. Using stratified sampling based on both tag-SNP genotypes and case-control status, we explore the gains in power of a two-phase design relative to randomly sampling cases and controls for resequencing (i.e., ignoring tag-SNP genotypes). Simulation results show that stratified sampling based on both tag-SNP genotypes and case-control status is not likely to have lower power than stratified sampling based only on case-control status, and can sometimes have substantially greater power. The gain in power depends on the amount of linkage disequilibrium between the tag-SNP and causal variant alleles, as well as the effect size of the causal variant. Hence, the two-phase design provides an efficient approach to follow-up GWAS signals with DNA resequencing.
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影响因子：
1
作者：
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DOI：
10.1111/1467-9876.00165
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