Does haplotype diversity predict power for association mapping of disease susceptibility?

Many recent studies have established that haplotype diversity in a small region may not be greatly diminished when the number of markers is reduced to a smaller set of "haplotype-tagging" single-nucleotide polymorphisms (SNPs) that identify the most common haplotypes. These studies are motivated by the assumption that retention of haplotype diversity assures retention of power for mapping disease susceptibility by allelic association. Using two bodies of real data, three proposed measures of diversity, and regression-based methods for association mapping, we found no scenario for which this assumption was tenable. We compared the chi-square for composite likelihood and the maximum chi-square for single SNPs in diplotypes, excluding the marker designated as causal. All haplotype-tagging methods conserve haplotype diversity by selecting common SNPs. When the causal marker has a range of allele frequencies as in real data, chi-square decreases faster than under random selection as the haplotype-tagging set diminishes. Selecting SNPs by maximizing haplotype diversity is inefficient when their frequency is much different from the unknown frequency of the causal variant. Loss of power is minimized when the difference between minor allele frequencies of the causal SNP and a closely associated marker SNP is small, which is unlikely in ignorance of the frequency of the causal SNP unless dense markers are used. Therefore retention of haplotype diversity in simulations that do not mirror genomic allele frequencies has no relevance to power for association mapping. TagSNPs that are assigned to bins instead of haplotype blocks also lose power compared with random SNPs. This evidence favours a multi-stage design in which both models and density change adaptively.