ABSTRACT Excess body fat, referred to as “adiposity”, is a major contributor to heart disease, the leading cause of death worldwide. Anti-obesity medications (AOMs) designed to reduce excess body fat not only help with weight loss but also significantly decrease the risk of heart disease. However, it is unknown whether this reduction in risk is solely due to weight loss or if AOMs influence other contributing risk factors, such as elevated lipid levels (e.g., cholesterol and triglycerides), which are strongly linked to heart disease and adiposity. In this research proposal, we will evaluate how adiposity alters the biological mechanisms regulating blood lipid levels by leveraging the genetic nature of lipids and adiposity, and large-scale datasets with clinical and multi- omics data—genomics, transcriptomics, and proteomics—to (1) measure interaction effects between adiposity and genetic DNA variants on lipid levels; (2) evaluate how genetically determined volumes of adipose tissue affect lifetime trajectories of lipid levels and heart disease risk; and (3) examine how risk factors in addition to lipid levels, such as high blood pressure and hyperglycemia, mediate the relationship between AOMs and heart disease. Completing these research aims will assist in identifying key biological pathways at the adiposity-lipid intersection and provide insight into whether a risk reduction of heart disease by AOMs is due to mechanisms beyond weight loss. This project will be led by Dr. Dron, a computational geneticist with expertise in lipid and lipoprotein metabolism, clinical and population cohorts, and disease risk assessment. Dr. Dron has developed a comprehensive plan to complete the above research aims and further her career development by expanding upon her current expertise with training in adipose biology, obesity, and advanced statistical modeling techniques. This supports her goal of becoming an independent researcher using genetic-based approaches to investigate new ways to enhance heart disease prediction, prevention, and treatment by better understanding the biological relationship and interaction between adiposity and heart disease risk factors. Dr. Dron’s exceptional advisory team will directly support her career development. Her primary mentor, Dr. Pradeep Natarajan, is a prominent leader in cardiovascular genomics. The additional members of Dr. Dron’s advisory team include scientists with diverse experiences in biostatistics, causal inference models, adiposity, obesity, AOMs, and multi-omic analyses of complex traits. Dr. Dron’s outstanding advisory team and training plan, coupled with the collaborative environment and extensive resources for innovative genetic research at the Center for Genomic Medicine and Broad Institute of MIT and Harvard, will facilitate her transition into an independent research career.