Zhang Shuanglin, Sha Qiuying, Chen Huann-Sheng, Dong Jianping, Jiang Renfang
Department of Mathematical Sciences, Michigan Technological University, Houghton, MI 49931, USA.
Am J Hum Genet. 2003 Sep;73(3):566-79. doi: 10.1086/378205. Epub 2003 Aug 15.
Studies using haplotypes of multiple tightly linked markers are more informative than those using a single marker. However, studies based on multimarker haplotypes have some difficulties. First, if we consider each haplotype as an allele and use the conventional single-marker transmission/disequilibrium test (TDT), then the rapid increase in the degrees of freedom with an increasing number of markers means that the statistical power of the conventional tests will be low. Second, the parental haplotypes cannot always be unambiguously reconstructed. In the present article, we propose a haplotype-sharing TDT (HS-TDT) for linkage or association between a disease-susceptibility locus and a chromosome region in which several tightly linked markers have been typed. This method is applicable to both quantitative traits and qualitative traits. It is applicable to any size of nuclear family, with or without ambiguous phase information, and it is applicable to any number of alleles at each of the markers. The degrees of freedom (in a broad sense) of the test increase linearly as the number of markers considered increases but do not increase as the number of alleles at the markers increases. Our simulation results show that the HS-TDT has the correct type I error rate in structured populations and that, in most cases, the power of HS-TDT is higher than the power of the existing single-marker TDTs and haplotype-based TDTs.
使用多个紧密连锁标记的单倍型进行的研究比使用单个标记的研究提供的信息更多。然而，基于多标记单倍型的研究存在一些困难。首先，如果我们将每个单倍型视为一个等位基因，并使用传统的单标记传递/不平衡检验（TDT），那么随着标记数量的增加，自由度会迅速增加，这意味着传统检验的统计效力会很低。其次，亲代单倍型并不总是能够明确重建。在本文中，我们提出了一种单倍型共享TDT（HS-TDT），用于疾病易感基因座与已分型多个紧密连锁标记的染色体区域之间的连锁或关联分析。该方法适用于数量性状和质量性状。它适用于任何规模的核心家庭，无论是否有模糊的相位信息，并且适用于每个标记的任何数量的等位基因。检验的自由度（广义上）随着所考虑标记数量的增加而线性增加，但不会随着标记上等位基因数量的增加而增加。我们的模拟结果表明，HS-TDT在结构化群体中具有正确的I型错误率，并且在大多数情况下，HS-TDT的效力高于现有的单标记TDT和基于单倍型的TDT。
