Leveraging the HapMap correlation structure in association studies

Am J Hum Genet. 2007 Apr;80(4):683-91. doi: 10.1086/513109. Epub 2007 Mar 2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Databases, Genetic
  • Gene Frequency
  • Genetic Markers / genetics*
  • Genomics / methods*
  • Genotype
  • Haplotypes / genetics*
  • Humans
  • Models, Genetic*
  • Oligonucleotide Array Sequence Analysis / methods*
  • Polymorphism, Single Nucleotide / genetics*
  • Software*

Substances

  • Genetic Markers