Impact of Physical Activity, Sleep, and Genetic Background on Cardiovascular Risk in the All of Us Program

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 analysis, electronic health record cohorts, sleep
research, and use of Fitbit data. The results of this work will provide an initial step toward personalization of
activity and sleep guidance that incorporates genetic background.

Grant Number: 5R21HL172038-02
NIH Institute/Center: NIH
Principal Investigator: Evan Brittain