The extent of linkage disequilibrium in four populations with distinct demographic histories

The design and feasibility of whole-genome-association studies are critical ly dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empir ical data exist. The authors have determined the extent of LD among 38 bial lelic markers with minor allele frequencies >.1, since these are most compa rable to the common disease-susceptibility polymorphisms that association s tudies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chr omosome 22q13.3-which have been extensively mapped. These markers were exam ined in similar to1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Fi nns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse rela tionship was found between LD and distance in each genomic region and in ea ch population. Mean D' is .68 for marker pairs <5 kb apart and is .24 for p airs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of ma rker pairs at distances <5 kb display sufficient LD (<Delta> > .3) to be us eful in association studies. Results of the present study, if representativ e of the whole genome, suggest that a whole-genome scan searching for commo n disease-susceptibility alleles would require markers spaced less than or equal to5 kb apart.