| Summary: | Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are well known independent risk factors for cardiovascular disease. Other lipoproteins, such as Lp(a), are also emerging, independent risk factors as increasing epidemiologic evidence suggests. Lipid-associated single-nucleotide polymorphisms (SNPs) are being discovered in genome-wide association studies (GWAS) in samples of European descent, but little data exist in other populations. Therefore, there is a strong need to characterize the effect sizes and allele frequencies of these GWAS-identified variants in a diverse, population-based cohort. Also, despite the ever-growing number of loci detected by GWAS, the proportion of trait variation explained is collectively small. To investigate this missing heritability, it is important to continue to identify novel variants that are associated with lipid levels and to explore gene-environment interactions, which may also contribute to trait variation.
The primary objective of this work was to identify and characterize common genetic variants that explain a proportion of the inter-individual variability in lipids levels, including LDL-C, HDL-C, TG, and Lp(a) levels. To achieve this goal, I selected a set of SNPs associated with lipid levels from the literature and demonstrated that the majority of associations replicate and generalize in a diverse, independent cohort. An additional GWAS of children was used to discover a novel variants associated with LDL-C, HDL-C, and TG. I also performed a candidate gene study and determined that common variants in LPA were associated with Lp(a) levels. Lastly, I identified several environmental modifiers of replicated variants associated with LDL-C, HDL-C, and TG.
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