Linkage disequilibrium in maps of SNPs and other markers

Abstract

One strategy for detection of disease genes is to exploit linkage disequilibrium in the hope that in candidate regions there will be detectable association between disease and marker alleles. Maps of single nucleotide polymorphisms (SNPs) will be used for this purpose but a recent simulation suggests that a useful level of linkage disequilibrium is unlikely to extend beyond an average distance of 3 Kb in the general population. This implies that very high marker densities will be required to detect disease: SNP associations. The evidence from published data comprising 877 SNP pairs is presented. For comparison, associations between other pairs of markers, principally microsatellites, are examined in a large sample of haplotypes from the fragile X (FRAX) region in Xq27–28. Association ρ is estimated from haplotype frequencies and the decline in linkage disequilibrium with distance is described using the model originally described by Malecot. The evidence from SNP pairs suggest that linkage disequilibrium extends to at least 263 Kb in random haplotypes, but with a considerable amount of variation particularly at small distances. For microsatellites in the FRAX region disequilibrium extends to at least 435 Kb. This suggests that a genome scan with markers spaced every 100 Kb would be powerful (30 000 markers per genome). Higher densities might be required in some genomic regions and presumably will be required to determine causal SNPs.