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Patterns of population differentiation of candidate genes for cardiovascular disease.

Kullo IJ, Ding K - BMC Genet. (2007)

Bottom Line: Mean FST values for common putatively functional variants were significantly higher than FST values for nonfunctional variants.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.These results suggest a possible basis for varying susceptibility to CVD among ethnic groups.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. kullo.iftikhar@mayo.edu

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.

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Related in: MedlinePlus

Mean and 95% upper limits of FST distributions. Black, dark grey, and light grey bars represent the mean of FST 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 FST 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 FST.
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Figure 4: Mean and 95% upper limits of FST distributions. Black, dark grey, and light grey bars represent the mean of FST 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 FST 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 FST.

Mentions: The HapMap data provides a genome-wide empirical distribution of FST against which significance of FST values can be evaluated, rather than based on theoretical computer simulations [33]. SNPs distant from genes are good candidates for neutral mutations since genes and their regulatory elements are more likely to be under selection than non-coding DNA [34]. We acquired the empirical 'neutral' distribution of FST values from 289 intergenic regions across the autosomal genome (14,792 SNPs) and 17 intergenic regions across the X chromosome (372 SNPs) without considering the effect of MAF. For autosomal chromosomes, the 95% upper limits of FST values were: YRI vs. CEU (= 0.602); YRI vs. CHB + JPT (= 0.640); and CEU vs. CHB + JPT (= 0.466) (Figure 4). The 95% upper limits of FST values were higher for chromosome X – 0.729 (YRI vs. CEU), 0.828 (YRI vs. CHB + JPT), and 0.707 (CEU vs. CHB + JPT), respectively.


Patterns of population differentiation of candidate genes for cardiovascular disease.

Kullo IJ, Ding K - BMC Genet. (2007)

Mean and 95% upper limits of FST distributions. Black, dark grey, and light grey bars represent the mean of FST 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 FST 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 FST.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1937006&req=5

Figure 4: Mean and 95% upper limits of FST distributions. Black, dark grey, and light grey bars represent the mean of FST 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 FST 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 FST.
Mentions: The HapMap data provides a genome-wide empirical distribution of FST against which significance of FST values can be evaluated, rather than based on theoretical computer simulations [33]. SNPs distant from genes are good candidates for neutral mutations since genes and their regulatory elements are more likely to be under selection than non-coding DNA [34]. We acquired the empirical 'neutral' distribution of FST values from 289 intergenic regions across the autosomal genome (14,792 SNPs) and 17 intergenic regions across the X chromosome (372 SNPs) without considering the effect of MAF. For autosomal chromosomes, the 95% upper limits of FST values were: YRI vs. CEU (= 0.602); YRI vs. CHB + JPT (= 0.640); and CEU vs. CHB + JPT (= 0.466) (Figure 4). The 95% upper limits of FST values were higher for chromosome X – 0.729 (YRI vs. CEU), 0.828 (YRI vs. CHB + JPT), and 0.707 (CEU vs. CHB + JPT), respectively.

Bottom Line: Mean FST values for common putatively functional variants were significantly higher than FST values for nonfunctional variants.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.These results suggest a possible basis for varying susceptibility to CVD among ethnic groups.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. kullo.iftikhar@mayo.edu

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.

Show MeSH
Related in: MedlinePlus