PROJECT SUMMARY Cardiovascular disease and its risk factors are major contributors to health burden and early death. Physical activity and sleep patterns are important behaviors that are causally tied to cardiovascular morbidity and mortality. Additionally, an individual’s genetic predisposition contributes to either increased or decreased risk of these conditions. The extent to which modifiable activity and sleep behaviors combine with genetic background to influence cardiovascular risk is not known. This is an important knowledge gap because contemporary physical activity recommendations do not account for genetic variability. The All of Us Research Program offers a unique combination of long-term activity and sleep data from wearable devices, whole-genome sequencing, and clinical outcomes from patients seeking care. These data sources provide an opportunity to understand how behaviors interact with genetic factors to contribute to incident disease risk. We hypothesize that increased physical activity and improved sleep will be necessary to mitigate excess genetic risk. Physical activity and sleep duration and quality can be quantified and tracked by wearables that are now widely used by the public. These devices enable high quality, longitudinal collection of these measures to integrate to inform impact on disease. Genetic risk is a significant contributor to cardiovascular disease and an important factor to consider when quantifying the role of modifiable behaviors. Genetic background represents a risk floor upon which behavior and environment interact to determine disease onset and severity. It is currently unclear to what degree behaviors such as physical activity and sleep might need to be adjusted to the specific genetic background of the individual. In preliminary work using All of Us data, we performed a phenome-wide association study of the association between step counts and incident chronic disease. Over 5.9 million person-days of monitoring, cardiovascular risk factors (obesity, diabetes, hypertension, and major depression) emerged among 1,700 phenotypes as most strongly associated with lower step counts. We now propose to extend our work to measure the impact of underlying genetic risk and activity and sleep patterns on cardiovascular risk. Aim 1 will quantify the interaction of genetic risk and physical activity on modifying incident cardiovascular risk factors using polygenic risk scores for obesity, hypertension, dyslipidemia, diabetes, and depression. Secondary analyses will examine the impact of genetic risk on cardiovascular outcomes. Aim 2 will assess the impact of sleep duration on incident cardiovascular risk factors with and without integration of genetic risk. Our investigative team is uniquely qualified to maximally leverage the available sources of data in All of Us to quantify the combined impact of sleep, activity, and genetics on cardiovascular risk. We have collective expertise in cardiovascular disease, genomic an...