Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations

Abstract

Single-nucleotide polymorphisms (SNPs) may be extremely important for deciphering the impact of genetic variation on complex human diseases. The ultimate value of SNPs for linkage and association mapping studies depends in part on the distribution of SNP allele frequencies and intermarker linkage disequilibrium (LD) across populations. Limited information is available about these distributions on a genomewide scale, particularly for LD. Using 114 SNPs from 33 genes, we compared these distributions in five American populations (727 individuals) of African, European, Chinese, Hispanic, and Japanese descent. The allele frequencies were highly correlated across populations but differed by >20% for at least one pair of populations in 35% of SNPs. The correlation in LD was high for some pairs of populations but not for others (e.g., Chinese American or Japanese American vs. any other population). Regardless of population, average minor-allele frequencies were significantly higher for SNPs in noncoding regions (20%-25%) than for SNPs in coding regions (12%-16%). Interestingly, we found that intermarker LD may be strongest with pairs of SNPs in which both markers are nonconservative substitutions, compared to pairs of SNPs where at least one marker is a conservative substitution. These results suggest that population differences and marker location within the gene may be important factors in the selection of SNPs for use in the study of complex disease with linkage or association mapping methods.

Figure 1

Comparison of allele frequencies and LD among populations. The upper triangle corresponds to the allele frequencies (0), and the lower triangle corresponds to the LD measure, d (×). The correlation is indicated in the lower right corner of each graph. The P value for the correlation was <.0001 in all cases.

Figure 2

P values for the intermarker LD measure, d. Each graph represents a single population: African American (A), European American (B), Hispanic American (C), Chinese American (D), and Japanese American (E). Colors indicate the following categories: pink, significant P value for test of LD (P⩽.001); yellow, low power to detect LD (P>.05 and q_min < .05 or minor alleles in repulsion phase); green, high power to detect LD but LD not detected (q_min > .05, P>.05, minor alleles in coupling phase); and black, no variability for at least one locus, so unable to test for LD (q_min = 0). Pairwise LD shown only for markers within the same gene. The label above each group of SNPs indicates the gene.