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.

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

“…Previously, we have examined the lipid concentrations in this cohort to characterize overlapping genetic architecture. 21 Here we apply the proposed XP-BLUP method to predict lipid concentrations. For LDL, HDL, and TG, the total estimated heritability on the training set is 0.33, 0.28, and 0.26, respectively.…”

“…Previously we have shown that complex traits genetic architecture overlaps substantially between ethnicities and that harnessing trans-ethnic information leads to substantial improvement in our ability to discover trait loci that are relevant in minority populations. 21,22 Therefore, we reason that trait prediction in minority populations may also benefit from integrating much larger GWAS data generated from populations of European descent. Our proposed approach, termed cross-population BLUP (XP-BLUP), is a multiple-component LMM model designed specifically to address the need for efficient prediction in minority populations.…”

Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36

“…Earlier genetic studies linked CD36 to fasting lipids (21, 48), MetS (22,(49)(50)(51), and stroke risk (44). However, information related to the role of the gene in postprandial lipid metabolism, which plays an important role in etiology of MetS and cardiovascular disease, remains limited.…”

Genetic meta-analysis of 15,901 African Americans identifies variation in EXOC3L1 is associated with HDL concentration

“…Genetic variants generally appear to exert similar effects across ethnicities if tested in a suffi ciently powered cohort, but differences in allele frequency and regional linkage disequilibrium (LD) between ethnicities allows for the identifi cation of novel contributors to lipid metabolism (3)(4)(5). While efforts to identify additional variants associated with blood lipids in African-American populations have been successful ( 3,(6)(7)(8), the identifi cation of novel genetic loci in nonEuropean populations has been hampered by inadequate power due to limited sample size and genotyping platform designs made for optimal SNP coverage of European populations ( 3,9 ).…”

“…There was no sample overlap between the WHI and WHI-SHARe genotyping initiatives. Further details of the populations, genotyping, and quality control analysis have been published elsewhere ( 6,8 ). All participants provided informed written consent.…”