PROJECT SUMMARY/ABSTRACT This proposal is for an MD/PhD student?s individual pre-doctoral fellowship application. Joseph Park, the applicant under consideration, proposes a research training plan with the long-term goal of developing into an independent physician-scientist studying the genetic mechanisms underlying cardiometabolic and other complex diseases using computational, experimental, and translational approaches. Genome-wide association studies (GWAS) have successfully described the roles of common genetic variation on human diseases by analyzing large populations with shared disease traits, but the clinical ontologies of numerous genes remain incompletely described through these phenotype-based methodologies. Additionally, a fundamental problem of genetic association studies remains to be the difficulty of describing the functional consequences of disease- associated variants to their respective gene products (i.e. loss- vs. gain-of-function). The Penn Medicine Biobank, a healthcare system-based database of genotype, whole-exome sequencing, and electronic health record (EHR) data, allows for an unbiased, genotype-first approach to describing the relationships between dysfunctional genes and human disease traits captured in the clinical setting through phenome-wide association studies (PheWAS). Through gene-burden PheWAS tests, the proposed study aims to characterize the clinical manifestations of disease caused by rare, loss-of-function mutations in each gene on a genome- wide scale. Our analyses will enable clinicians to more effectively identify genetic diseases among their patients in the clinical setting. Furthermore, in addition to our interrogation of loss-of-function mutations, our proposed project has the potential to define the roles of known gain-of-function mutations in human disease and identify novel gain-of-function variants relevant to disease, offering a direction for investigators to design follow-up experimental studies in the basic sciences as well as a platform promoting more efficient therapeutic discoveries. And importantly, while conducting the proposed study, Joseph will receive rigorous training in computational biology and statistical genetics during the funding period, promoting his maturation into a successful, independent physician-scientist thoroughly prepared for a clinical career involving the analysis of ?omics? and ?big data?. These goals will be accomplished through the extensive fellowship training plan jointly developed by him and his sponsor, Daniel Rader. Through the mentorship of numerous senior investigators, regular attendance at seminars, conferences, and other opportunities for presentation and interaction with renowned scientists at the University of Pennsylvania, and the collaborative research environment that the Rader laboratory and its physically surrounding organizations promote, Joseph is well-equipped to achieve his career goals through his guaranteed development during the proposed training.