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

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PROJECT SUMMARY Hypertension is a major public health burden in the US, due to its high prevalence among adults (~108 million, 45%) and strong association with cardiovascular disease (CVD) and premature mortality. Compared to other racial/ethnic groups, African-Americans have higher hypertension prevalence, higher mean blood pressure (BP), earlier onset of hypertension, and a greater likelihood of developing treatment-resistant hypertension. In addition, rates are increasing among Hispanic/Latinos, who have lower rates of hypertension awareness, treatment, and control. Advances in genomic research create opportunities for precision medicine to improve prevention, diagnosis, and treatment of hypertension. Polygenic risk scores (PRS) that aggregate genetic risk variants into a score help predict disease risk. Growing evidence demonstrates that PRS may add value beyond traditional risk factors for identifying individuals at increased risk for CVD. Despite their promise, however, current PRS are biased in populations historically underrepresented in genetic studies. Despite the increased risk of hypertension in African-American and Hispanic/Latino populations, PRS originally trained on European ancestry (EA) participants may not serve these populations. Indeed, applying EA-derived PRS to racially/ethnic diverse populations has the strong potential to exacerbate longstanding racial/ethnic disparities in CVD and hypertension. Thus, PRS derived in multi-ethnic populations are needed to ensure that all will benefit from genomic research advances regardless of their race/ethnicity or ancestral heritage. The proposed research will: 1) Develop and evaluate PRS for hypertension related traits in the large and racially/ethnically diverse Population Architecture using Genomics and Epidemiology (PAGE) study population, 2) Extend the multi-ethnic PRS through integration of a lifestyle risk factor score (LRS) composed of non-genetic clinical and prognostic data to improve predictive performance of PRS, and 3) Evaluate the clinical significance of hypertension related PRS in electronic health records (EHRs) to improve biologic insight of hypertension-related diseases. These study aims are nested within the parent study, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, R01HL151152, a collaborative effort between the University of North Carolina at Chapel Hill, the Fred Hutchinson Cancer Research Center Seattle, and the University of Colorado Denver, using high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked EHRs, including over 1.5M non-European ancestry participants. Through the proposed Postdoctoral Supplement, Dr. Love will gain training in developing, validating, and assessing the clinical significance of hypertension related PRS in multiethnic populations, lifestyle and genetic determinants of hypertension, and professional development. Skills and findings obtained from the completion of the training and research aims of this proposal will result in scientific presentations and publications, preliminary data to successfully compete for grant funding, and uniquely position Dr. Love for the study of genetic and lifestyle determinants of CVD.