Extent and distribution of linkage disequilibrium in three genomic regions

Abstract

The positional cloning of genes underlying common complex diseases relies on the identification of linkage disequilibrium (LD) between genetic markers and disease. We have examined 127 polymorphisms in three genomic regions in a sample of 575 chromosomes from unrelated individuals of British ancestry. To establish phase, 800 individuals were genotyped in 160 families. The fine structure of LD was found to be highly irregular. Forty-five percent of the variation in disequilibrium measures could be explained by physical distance. Additional factors, such as allele frequency, type of polymorphism, and genomic location, explained <5% of the variation. Nevertheless, disequilibrium was occasionally detectable at 500 kb and was present for over one-half of marker pairs separated by <50 kb. Although these findings are encouraging for the prospects of a genomewide LD map, they suggest caution in interpreting localization due to allelic association.

Figure 1

Distribution of LD in three genomic regions. A, Raw disequilibrium matrix. B, Adjusted for physical distance. Red, green, and blue represent strong disequilibrium (D′ ⩾.8), moderate (D′ ∼.5), and weak (D′ ∼0) disequilibrium, respectively (Abecasis and Cookson 2000).

Figure 2

A, LD (D′) and physical distance for markers derived from three genomic regions. D′ for marker pairs separated by <1 Mb is shown. B, Moving averages of D′ and physical distance in three genomic regions. Data from chromosome 2 are shown in red, from chromosome 13 in blue, and from chromosome 14 in black. C, Frequency of useful D′ (<.33) and physical distance in three genomic regions. Data from chromosome 2 are shown in red, from chromosome 13 in blue, and from chromosome 14 in black.