Zaitlen Noah, Kang Hyun Min, Eskin Eleazar, Halperin Eran
Bioinformatics Program, University of California-San Diego, La Jolla, CA, USA.
Am J Hum Genet. 2007 Apr;80(4):683-91. doi: 10.1086/513109. Epub 2007 Mar 2.
Recent high-throughput genotyping technologies, such as the Affymetrix 500k array and the Illumina HumanHap 550 beadchip, have driven down the costs of association studies and have enabled the measurement of single-nucleotide polymorphism (SNP) allele frequency differences between case and control populations on a genomewide scale. A key aspect in the efficiency of association studies is the notion of "indirect association," where only a subset of SNPs are collected to serve as proxies for the uncollected SNPs, taking advantage of the correlation structure between SNPs. Recently, a new class of methods for indirect association, multimarker methods, has been proposed. Although the multimarker methods are a considerable advancement, current methods do not fully take advantage of the correlation structure between SNPs and their multimarker proxies. In this article, we propose a novel multimarker indirect-association method, WHAP, that is based on a weighted sum of the haplotype frequency differences. In contrast to traditional indirect-association methods, we show analytically that there is a considerable gain in power achieved by our method compared with both single-marker and multimarker tests, as well as traditional haplotype-based tests. Our results are supported by empirical evaluation across the HapMap reference panel data sets, and a software implementation for the Affymetrix 500k and Illumina HumanHap 550 chips is available for download.
近期的高通量基因分型技术，如Affymetrix 500k芯片和Illumina HumanHap 550芯片，降低了关联研究的成本，并能够在全基因组范围内测量病例组和对照组人群之间的单核苷酸多态性（SNP）等位基因频率差异。关联研究效率的一个关键方面是“间接关联”的概念，即利用SNP之间的相关结构，仅收集一部分SNP作为未收集SNP的代理。最近，已经提出了一类新的间接关联方法——多标记方法。尽管多标记方法是一个相当大的进步，但目前的方法并未充分利用SNP与其多标记代理之间的相关结构。在本文中，我们提出了一种基于单倍型频率差异加权和的新型多标记间接关联方法WHAP。与传统的间接关联方法相比，我们通过分析表明，与单标记和多标记检验以及传统的基于单倍型的检验相比，我们的方法在检验效能上有显著提高。我们的结果得到了HapMap参考面板数据集的实证评估的支持，并且可下载适用于Affymetrix 500k芯片和Illumina HumanHap 550芯片的软件实现。
