PROJECT SUMMARY Epidemiological studies have suggested a bidirectional relationship between dental disease and systemic conditions such as diabetes and cardiovascular disease (CVD), with the chronic inflammatory state caused by dental infections attributed as a plausible contributing factor to systemic disease pathogenesis. Despite research progress, the results of these studies are controversial. Among the hindering factors impeding progress in the field is the lack of integrated dental, medical, and genomic data thereby leaving much to be learned about the host biological mechanisms contributing to dental and systemic disease relationships. In previous studies, we have shown the importance of combining genetic and epidemiological association analysis to advance knowledge on dental and systemic disease relationships. Further, we’ve shown that variation in dental-disease associated loci were significantly associated with increased risk for >30 systemic disease phecodes. In this application, we will test the hypothesis that a potential shared genetic etiology may contribute to the interconnectedness between dental and systemic disease and propose a large-scale study with integrated participant data for more conclusive findings and to move the field forward. We will leverage and integrate high- quality clinical (dental and medical), genomic, and demographic data available from >200,000 participants in the All of Us Research Program to identify host factors most likely contributing to a combined phenotype of dental + systemic disease. We will identify gene variants associated with each combined phenotype and determine whether polygenic risk can increase risk to a combined phentoype. This study represents a major advance in the field by creating a roadmap for integrating clinical and genomic data from a large and diverse population to elucidate the contributions of host predisposing factors to dental + systemic disease phenotypes. Data generated through this proposal will be available in the All of Us Researcher Workbench. This proposal addresses NIDCR’s Strategic Priorities #1 Integrate Oral and General Health, and #2 Precision Dental Medicine.