PROJECT SUMMARY For the past 6 years, my independent laboratory has leveraged new approaches in human genomics and pioneered new types of post-genomic functional studies?empowered by genome-editing technologies?to elucidate novel mechanisms that drive cardiovascular diseases. My laboratory has characterized the roles of specific genes involved in lipid metabolism, coronary heart disease, and diabetes, as well yielding insights into how noncoding DNA variation influences the functions of these genes. Going forward, my research will take advantage of recent advances in disease modeling and therapeutic genome editing?advances in which my laboratory played a part?to tackle two exemplary translational challenges in the cardiovascular field: (1) the use of therapeutic genome editing to prevent coronary heart disease, the leading cause of death worldwide; and (2) the use of genome editing to empower high-throughput functional annotation of variants of uncertain significance detected in patients by clinical sequencing.