Abstract
Plasma lipid levels are risk factors for cardiovascular disease, a leading cause of death worldwide. While many studies have been conducted in genetic variation underlying lipid levels, they mainly comprise individuals of European ancestry and thus their transferability to non-European populations is unclear. We performed genome-wide (GWAS) and imputed transcriptome-wide association studies of four lipid traits in the Hispanic Community Health Study/Study of Latinos cohort (HCHS/SoL, n = 11,103), replicated top hits in the Multi-Ethnic Study of Atherosclerosis (MESA, n = 3,855), and compared the results to the larger, predominantly European ancestry meta-analysis by the Global Lipids Genetics Consortium (GLGC, n = 196,475). In our GWAS, we found significant SNP associations in regions within or near known lipid genes, but in our admixture mapping analysis, we did not find significant associations between local ancestry and lipid phenotypes. In the imputed transcriptome-wide association study in multiple tissues and in different ethnicities, we found 59 significant gene-tissue-phenotype associations (P < 3.61×10−8) with 14 unique significant genes, many of which occurred across multiple phenotypes, tissues, and ethnicities and replicated in MESA (45/59) and in GLGC (44/59). These include well-studied lipid genes such as SORT1, CETP, and PSRC1, as well as genes that have been implicated in cardiovascular phenotypes, such as CCL22 and ICAM1. The majority (40/59) of significant associations colocalized with expression quantitative trait loci (eQTLs), indicating a possible mechanism of gene regulation in lipid level variation. To fully characterize the genetic architecture of lipid traits in diverse populations, larger studies in non-European ancestry populations are needed.
Highlights
Lipid levels are a major risk factor for cardiovascular disease, the leading cause of death in the United States [1]
The genetic diversity within HCHS/SoL and other Hispanic populations has been extensively described previously and we concentrated on calculating cohort-specific principal components to be used as covariates in our analyses [16,17,18]
Most HCHS/SoL participants included in the analyses reported a self-identified region of ancestry in the Americas, which we included as a covariate in the regression analyses
Summary
Lipid levels are a major risk factor for cardiovascular disease, the leading cause of death in the United States [1]. The authors thank the staff and participants of the HCHS/SOL study for their important contributions. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Funding for SHARe genotyping was provided by NHLBI Contract N02HL-64278. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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