Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program

Abstract

Association studies of candidate genes with complex traits have generally used one or a few single nucleotide polymorphisms (SNPs), although variation in the extent of linkage disequilibrium (LD) within genes markedly influences the sensitivity and precision of association studies. The extent of LD and the underlying haplotype structure for most candidate genes are still unavailable. We sampled 193 blacks (African-Americans) and 160 whites (European-Americans) and estimated the intragenic LD and the haplotype structure in four genes of the renin-angiotensin system. We genotyped 25 SNPs, with all but one of the pairs spaced between 1 and 20 kb, thus providing resolution at small scale. The pattern of LD within a gene was very heterogeneous. Using a robust method to define haplotype blocks, blocks of limited haplotype diversity were identified at each locus; between these blocks, LD was lost owing to the history of recombination events. As anticipated, there was less LD among blacks, the number of haplotypes was substantially larger, and shorter haplotype segments were found, compared with whites. These findings have implications for candidate-gene association studies and indicate that variation between populations of European and African origin in haplotype diversity is characteristic of most genes.

Figures

Figure 1.

Comparison of LD between blacks and whites based on D‘ and r2. (A) |D‘| for blacks. (B) |D‘| for whites. (C) r2 for blacks. (D) r2 for whites. In blacks, both D‘ and r2 decay as the distance increases, although considerable variation is observed. In whites, the decay of D‘ values demarcated by the ellipse are apparently owing to the effects of rare minor allele frequency (ACE A7941G, f(G) = 0.05). The rare minor allele frequency (AGTR1 A44221G, f(G) = 0.05) is also associated with D‘ values of 1, as indicated in the circle. Excluding the D‘ values in the ellipse and the circle leads to a slower decay of the D‘ value in whites as the distance increases than that in blacks. Similarly, the low r2 values in the ellipse among whites are caused by the minor alleles being rare. These r2 values are derived from at least one SNP with an allele frequency <0.15. After excluding these values, r2 decays as the distance increases.

Figure 1.

Comparison of LD between blacks and whites based on D‘ and r2. (A) |D‘| for blacks. (B) |D‘| for whites. (C) r2 for blacks. (D) r2 for whites. In blacks, both D‘ and r2 decay as the distance increases, although considerable variation is observed. In whites, the decay of D‘ values demarcated by the ellipse are apparently owing to the effects of rare minor allele frequency (ACE A7941G, f(G) = 0.05). The rare minor allele frequency (AGTR1 A44221G, f(G) = 0.05) is also associated with D‘ values of 1, as indicated in the circle. Excluding the D‘ values in the ellipse and the circle leads to a slower decay of the D‘ value in whites as the distance increases than that in blacks. Similarly, the low r2 values in the ellipse among whites are caused by the minor alleles being rare. These r2 values are derived from at least one SNP with an allele frequency <0.15. After excluding these values, r2 decays as the distance increases.

Figure 1.

Comparison of LD between blacks and whites based on D‘ and r2. (A) |D‘| for blacks. (B) |D‘| for whites. (C) r2 for blacks. (D) r2 for whites. In blacks, both D‘ and r2 decay as the distance increases, although considerable variation is observed. In whites, the decay of D‘ values demarcated by the ellipse are apparently owing to the effects of rare minor allele frequency (ACE A7941G, f(G) = 0.05). The rare minor allele frequency (AGTR1 A44221G, f(G) = 0.05) is also associated with D‘ values of 1, as indicated in the circle. Excluding the D‘ values in the ellipse and the circle leads to a slower decay of the D‘ value in whites as the distance increases than that in blacks. Similarly, the low r2 values in the ellipse among whites are caused by the minor alleles being rare. These r2 values are derived from at least one SNP with an allele frequency <0.15. After excluding these values, r2 decays as the distance increases.

Figure 1.

Comparison of LD between blacks and whites based on D‘ and r2. (A) |D‘| for blacks. (B) |D‘| for whites. (C) r2 for blacks. (D) r2 for whites. In blacks, both D‘ and r2 decay as the distance increases, although considerable variation is observed. In whites, the decay of D‘ values demarcated by the ellipse are apparently owing to the effects of rare minor allele frequency (ACE A7941G, f(G) = 0.05). The rare minor allele frequency (AGTR1 A44221G, f(G) = 0.05) is also associated with D‘ values of 1, as indicated in the circle. Excluding the D‘ values in the ellipse and the circle leads to a slower decay of the D‘ value in whites as the distance increases than that in blacks. Similarly, the low r2 values in the ellipse among whites are caused by the minor alleles being rare. These r2 values are derived from at least one SNP with an allele frequency <0.15. After excluding these values, r2 decays as the distance increases.