Patterns of population differentiation of candidate genes for cardiovascular disease

Abstract

Background: The basis for ethnic differences in cardiovascular disease (CVD) susceptibility is not fully understood. We investigated patterns of population differentiation (FST) of a set of genes in etiologic pathways of CVD among 3 ethnic groups: Yoruba in Nigeria (YRI), Utah residents with European ancestry (CEU), and Han Chinese (CHB) + Japanese (JPT). We identified 37 pathways implicated in CVD based on the PANTHER classification and 416 genes in these pathways were further studied; these genes belonged to 6 biological processes (apoptosis, blood circulation and gas exchange, blood clotting, homeostasis, immune response, and lipoprotein metabolism). Genotype data were obtained from the HapMap database.

Results: We calculated FST for 15,559 common SNPs (minor allele frequency > or = 0.10 in at least one population) in genes that co-segregated among the populations, as well as an average-weighted FST for each gene. SNPs were classified as putatively functional (non-synonymous and untranslated regions) or non-functional (intronic and synonymous sites). Mean FST values for common putatively functional variants were significantly higher than FST values for nonfunctional variants. A significant variation in FST was also seen based on biological processes; the processes of 'apoptosis' and 'lipoprotein metabolism' showed an excess of genes with high FST. Thus, putative functional SNPs in genes in etiologic pathways for CVD show greater population differentiation than non-functional SNPs and a significant variance of FST values was noted among pairwise population comparisons for different biological processes.

Conclusion: These results suggest a possible basis for varying susceptibility to CVD among ethnic groups.

Figure 1

(a) Mean F_ST in pairwise population comparisons in the observed data. (b) Distribution of F_ST values in HapMap data set. (c) Mean F_ST in pairwise population comparisons in the simulated data. (d) Distribution of F_ST values in the simulated data set. YRI, Yoruba in Ibadan, Nigeria; CEU, Utah residents with ancestry from northern and western Europe, CHB, Han Chinese in Beijing, China, and JPT, Japanese in Tokyo, Japan

Figure 2

Mean F_ST values for SNPs of different categories, conditioned on MAF. YRI, Yoruba in Ibadan, Nigeria; CEU, Utah residents with ancestry from northern and western Europe, CHB, Han Chinese in Beijing, China, and JPT, Japanese in Tokyo, Japan

Figure 3

Boxplots of F_ST according to biological processes. Points in the box are the mean F_ST values. Outliers are not shown. P values were calculated by Kruskal-Wallis test. YRI, Yoruba in Ibadan, Nigeria; CEU, Utah residents with ancestry from northern and western Europe, CHB, Han Chinese in Beijing, China, and JPT, Japanese in Tokyo, Japan

Figure 4

Mean and 95% upper limits of F_ST distributions. Black, dark grey, and light grey bars represent the mean of F_ST distribution found for the autosomal SNPs analyzed in Akey et al. [18], Izagirre et al. [47], and coalescent simulations, respectively. White bars represent the mean of F_ST in the 'neutral' autosomal loci (14,792 SNPs) from the intergenic regions in this study. The 95% upper limits are placed on top of the mean value of F_ST.

Figure 5

Percentage of genes in different biological processes with significantly high F_ST (empirical P ≤ 0.05) in at least one SNP.

Figure 6

F_ST profile for nine genes with a significantly higher weighted-average F_ST. The X-axis indicates the chromosomal position (kb). See Table 3 for gene names. The average recombination rate (cM/MB) for the genes is: GRB2, 1.78; IKBKB, 0.76; ARHGEF1, 0.81; RIPK1, 2.06; PMVK, 1.07; BCL2L1, 0.86; IL4, 0.94; IL6, 1.10; F2, 0.66.