Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care

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ABSTRACT This supplement will expand on the currently funded grant R01 HL151152 entitled “Polygenic Risk Scores (PRS) for Diverse Populations - Bridging Research and Clinical Care” through a focused polygenic risk scores analysis of hypertension (HTN) and related traits, an incorporation of All of Us diverse data, and incorporation of lifestyle effects, which were not prioritized in the original R01 application. Cardiovascular disease (CVD) and its risk factors impose major societal burdens and are leading causes of morbidity, mortality, and disability. Recent reports documenting a slowing or reversal of four decades of declining CVD mortality rates motivate an innovative transformation of CVD prevention, diagnosis, and treatment. Genomic research, a cornerstone of precision medicine, offers such a transformation through the application of PRS, the aggregation of risk variants into a single score. However, the vast majority of participants included in the PRS research to-date have been of European ancestry (EA). We have demonstrated that EA-derived PRS are not generalizable to racially and ethnically diverse populations, as EA-derived PRS predict CVD and CVD risk factors with much greater accuracy in EA than in all other race and ethnicity groups. This lack of generalizability reflects differential prediction accuracy and unpredictable bias in the context of population structure that characterizes racially and ethnically diverse populations. Despite these limitations, efforts to commercialize and provide to patients EA- derived PRS are underway, even though the application of EA-derived PRS to diverse populations has the strong potential to exacerbate longstanding racial and ethnic disparities in CVD and CVD risk factors. Research that enables estimation, validation, calibration, and contextualization of PRS in racially and ethnically diverse populations is needed to ensure that all populations reap the benefits of precision medicine. We will utilize data from the Population and Architecture using Genetics and Epidemiology (PAGE) study and aim to fully integrate the All of Us Research Program for independent validation. We propose (i) the creation of unbiased PRS for HTN-related traits (systolic and diastolic blood pressure and HTN) in the ancestrally diverse PAGE study population. The PRS will be validated in the All of Us Research Program; (ii) Contextualization/Performance across key lifestyle factors: Develop and evaluate a lifestyle risk score (LRS) composed of non-genetic clinical and prognostic data to improve predictive performance of PRS. The PRS+LRS will be validated in the All of Us Research Program; and (iii) Clinical Characterization: Evaluate the clinical significance of HTN-related PRS to improve biologic insight of HTN-related diseases using the All of Us research program to prioritize functional follow-up on genes and pathways with greatest clinical impact. We will conduct phenome-wide association (PheWAS) analyses to validate expected hypertension-related associations and detect novel phenotypic associations of potential clinical impact.