On the identification of disease mutations by the analysis of haplotype similarity and goodness of fit

Abstract

The observation that haplotypes from a particular region of the genome differ between affected and unaffected individuals or between chromosomes transmitted to affected individuals versus those not transmitted is sound evidence for a disease-liability mutation in the region. Tests for differentiation of haplotype distributions often take the form of either Pearson's chi(2) statistic or tests based on the similarity among haplotypes in the different populations. In this article, we show that many measures of haplotype similarity can be expressed in the same quadratic form, and we give the general form of the variance. As we describe, these methods can be applied to either phase-known or phase-unknown data. We investigate the performance of Pearson's chi(2) statistic and haplotype similarity tests through use of evolutionary simulations. We show that both approaches can be powerful, but under quite different conditions. Moreover, we show that the power of both approaches can be enhanced by clustering rare haplotypes from the distributions before performing a test.

Figure 1

Distribution of haplotypes in affected (top) and unaffected (bottom) individuals for four populations. In populations I and II, the disease mutation occurred on a common background; in population III, it occurred on a haplotype so rare that it was not sampled in our simulation of the controls; and in population IV, it occurred on a haplotype that is rare in the normal population. In these bar plots, haplotypes that differ by a single mutation tend to appear adjacent to one another.

Figure 2

Performance of GOF and similarity statistics, in terms of power. The dotted, dashed, dot-dashed, and solid lines display the matching, count, length, and GOF statistics, respectively. The results represent nine separate populations (X-axis) ordered by power, which are connected to facilitate visualization. For panels A–C, the disease mutation occurred on a common background; for panel D, the disease mutation occurred on a rare background. Tests are performed using six-marker haplotypes (A), three-marker haplotypes (B and D) and three-marker genotypes (C).