Using genetic variation to study biology of blood lipids & coronary heart disease

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PROJECT SUMMARY / ABSTRACT Cardiovascular disease is the leading cause of death worldwide and elevated blood lipid levels are the strongest risk factor. The goal of this R01 proposal is to continue discovering and characterize genetic variants and genes associated with blood lipid levels using new methods, diverse cohorts, and clinical trials to identify new therapeutic targets and risk mitigation frameworks for lipids and cardiovascular disease. Our research team combines strengths in cardiovascular medicine, statistical genetics, high-throughput genetics and genomics, and development and application of innovative computational and statistical methods. In Aim 1, we will determine genetic variants associated with lipid levels leveraging over 2.5 million multi-ethnic samples. In Aim 2, we will perform phenome-wide scans for lipid-associated alleles and bi-directional multi-phenotype Mendelian randomization in ~1 million individuals. In Aim 3, we will build and evaluate multi-ethic polygenic risk scores for lipid levels in epidemiologic studies and completed clinical trials. In Aim 4 we will create a web- based compute engine to both provide our association results and calculate individual-level polygenic risk scores to facilitate the standardization of scores across studies. This proposal is a renewal of the previous Global Lipids Genetics Consortium (GLGC) award and established collaborative relationships, and will allow for the continued effort and coordination of the consortium. Completion of our aims will provide new insights that have the potential to catalyze breakthroughs in prevention, treatment, and diagnosis of cardiovascular disease and may serve as a model for other large-scale genetic studies.