Identification of risk-related haplotypes with the use of multiple SNPs from nuclear families
Identification of risk-related haplotypes with the use of multiple SNPs from nuclear families
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DOI：
10.1086/518670
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发表时间：
2007-07-01
影响因子：
9.8
通讯作者：
Weinberg, Clarice R.
中科院分区：
文献类型：
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作者：
Shi, Min;Umbach, David M.;Weinberg, Clarice R.
以家庭为基础的关联研究为人群分层提供了稳健性，并可以深入了解母体介导的和父母的起源影响。通常，此类研究调查覆盖感兴趣的基因或染色体区域的多个标记。我们提出了一种简单而通用的方法来测试疾病性状与多个可能连锁的SNP标记的关联，并随后提名一组“风险单倍型标记等位基因”。“我们的测试，max_Z（2）测试，只使用受影响个体及其父母的基因型，而不要求用户知道或分配单倍型及其阶段。它还适应偶尔缺失的SNP数据。在系谱不平衡检验的精神，我们的程序只需要一个向量的差异与期望值为0下的零假设。当基因型数据完整时，为了提高对一系列替代品的功效，我们还考虑了组合多个检验的方法;在这里，我们将联合收割机max_ Z（2）和Hotelling的T-2结合起来。为了便于发现风险相关的单倍型，我们开发了一个简单的程序提名风险单倍型标记等位基因。我们的程序也可用于研究母体介导的遗传效应和探索印记。我们比较了几个竞争的测试程序的统计能力，通过模拟研究的情况下，父母的黑社会，其双倍型模拟的基础上绘制基于HapMap的已知单倍型的四个基因。在我们的模拟中，max_ Z（2）检验和McIntyre等人提出的max_TDT（transmission/ disequilibrium test）检验的表现几乎相同，但max_Z 2与max_ TDT不同，它直接扩展到母体效应的研究。作为一个例子，我们重新分析数据从以前报道的orofacial裂缝的研究，现在调查胎儿和母亲的影响IRF 6基因。
Family-based association studies offer robustness to population stratification and can provide insight into maternally mediated and parent-of-origin effects. Usually, such studies investigate multiple markers covering a gene or chromosomal region of interest. We propose a simple and general method to test the association of a disease trait with multiple, possibly linked SNP markers and, subsequently, to nominate a set of "risk-haplotype-tagging alleles." Our test, the max_Z(2) test, uses only the genotypes of affected individuals and their parents without requiring the user to either know or assign haplotypes and their phases. It also accommodates sporadically missing SNP data. In the spirit of the pedigree disequilibrium test, our procedure requires only a vector of differences with expected value 0 under the null hypothesis. To enhance power against a range of alternatives when genotype data are complete, we also consider a method for combining multiple tests; here, we combine max_ Z(2) and Hotelling's T-2. To facilitate discovery of risk-related haplotypes, we develop a simple procedure for nominating risk-haplotype-tagging alleles. Our procedures can also be used to study maternally mediated genetic effects and to explore imprinting. We compare the statistical power of several competing testing procedures through simulation studies of case-parents triads, whose diplotypes are simulated on the basis of draws from the HapMap-based known haplotypes of four genes. In our simulations, the max_ Z(2) test and the max_TDT (transmission/ disequilibrium test) proposed by McIntyre et al. perform almost identically, but max_ Z2, unlike max_ TDT, extends directly to the investigation of maternal effects. As an illustration, we reanalyze data from a previously reported orofacial cleft study, to now investigate both fetal and maternal effects of the IRF6 gene.