Leveraging the HapMap correlation structure in association studies.
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.
Zaitlen
Noah
N
Bioinformatics Program, University of California-San Diego, La Jolla, CA, USA.
Kang
Hyun Min
HM
Eskin
Eleazar
E
Halperin
Eran
E
D030541:Databases, Genetic; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012984:Software
D005819:Genetic Markers