Genetically indistinguishable SNPs and their influence on inferring the location of disease-associated variants

As part of a recent high-density linkage disequilibrium (LD) study of chromosome 20, we obtained genotypes for ∼30,000 SNPs at a density of 1 SNP/2 kb on four different population samples (47 CEPH founders; 91 UK unrelateds [unrelated white individuals of western European ancestry]; 97 African Americans; 42 East Asians). We observed that ∼50% of SNPs had at least one genetically indistinguishable partner; i.e., for every individual considered, their genotype at the first locus was identical to their genotype at the second locus, or in LD terms, the SNPs were in “perfect” LD (r 2 = 1.0). These “genetically indistinguishable SNPs” (giSNPs) formed into clusters of varying size. The larger the cluster, the greater the tendency to be located within genes and to overlap with giSNP clusters in other population samples. As might be expected for this map density, many giSNPs were located close to one another, thus reflecting local regions of undetected recombination or haplotype blocks. However, ∼1/3 of giSNP clusters had intermingled, non-indistinguishable SNPs with incomplete LD (D and r 2 <1), sometimes spanning hundreds of kilobases, comprising up to 70 indistinguishable markers and overlapping multiple haplotype blocks. These long-range, nonconsecutive giSNPs have implications for disease gene localization by allelic association as evidence for association at one locus will be indistinguishable from that at another locus, even though both loci may be situated far apart. We describe the distribution of giSNPs on this map of chromosome 20 and illustrate the potential impact they can have on association mapping.