Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations

Abstract

Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.

Figure 1

Enrichment for Small p Values among SNPs that Are Significantly or Suggestively Associated in European GWASs (A and B) High-density lipoprotein (HDL) cholesterol in African Americans (AAs) (A) and in Hispanic Americans (HAs) (B). (C and D) Low-density lipoprotein (LDL) cholesterol in AAs (C) and in HAs (D). (E and F) Triglycerides (TG) in AAs (E) and in HAs (F).

Figure 2

Genetic Effects of Candidate Lipid Variants Are Correlated between African Americans and Hispanic Americans (A–C) SNPs are those with p < 10⁻⁵ in a European GWAS. The x axis represents the estimated allelic effects in African Americans (AAs) and the y axis represents the estimated allelic effects of the corresponding SNPs in Hispanic Americans (HAs). (A) High-density lipoprotein (HDL) cholesterol. (B) Low-density lipoprotein (LDL) cholesterol. (C) Triglycerides (TG). (D) Genetic effects of 92 SNPs representing independent loci; SNPs are the best surrogate index SNPs on Affy 6.0 arrays defined by Telosvich et al. The estimated allelic effects in (D) are in the unit of standard deviation of the phenotype.

Figure 3

Overlap in Genetic Architecture in AAs Genomic regions are ranked by the SNP with the strongest association evidence in a European GWAS. Proportions of the phenotypic variance explained in AAs (y axis) by the top x% of the genome (x axis) are estimated with a mixed effect model. Red points indicates the 95% confidence interval excludes the expected value (magenta line) under the null model that x% randomly selected genome explains h²x% of phenotypic variance, where h² is the variance explained by the entire genome. When the null cannot be excluded, the point estimates are drawn with gray points. (A) High-density lipoprotein (HDL) cholesterol. (B) Low-density lipoprotein (LDL) cholesterol. (C) Triglycerides (TG).