Assessing Clinical Utility of Polygenic Risk Scores in Ancestrally Diverse Real-World Cohorts

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

Project Summary The long-term goal of this project is to assess the utility of trans-ancestry polygenic risk scores (PRSs) in real-world, ancestrally diverse cohorts to predict health outcomes in clinical settings. PRSs represent a numerical summary of an individuals’ genetic risk for a trait or disease based on combined effects of genetic variants across the human genome. A PRS has many potential benefits such as efficient disease screening/prediction and therapeutic prevention/intervention and may be useful in saving many lives and resources. However, the application of PRS for risk prediction in clinical settings alongside non-genetic risk factors such as lifestyle and environmental risk factors remains largely unknown, especially in underrepresented populations, yet may be of added benefit. A better understanding of PRS utility for clinical risk prediction, and limitations of PRS in diverse, real-world populations is needed to realize the potential benefits of the applications of PRS across all populations. This proposal encompasses a training and research plan to develop the candidate’s expertise in genetic epidemiology research. The specific aims are to 1a) Investigate the association of trans-ancestry blood pressure (BP) PRS with hypertension incidence and progression in individuals across their life course, 1b) Investigate the association of trans-ancestry BP PRS with incidence of BP-related health outcomes including stroke, cardiovascular disease (CVD), dementia, kidney disease, heart failure and all-cause mortality in ancestrally diverse individuals (F99 dissertation research); and 2) Assess clinical utility of trans-ancestry prostate cancer PRS for predicting prostate cancer incidence and aggressiveness, incorporating prostate serum antigen (PSA) level trajectories and other clinical risk factors (K00 postdoctoral direction). This proposed project will generate new knowledge and provide training for the candidate’s advancement to become an independent investigator focused on genetic epidemiology of complex polygenic diseases and traits in ancestrally diverse populations. The research is relevant to NHGRI’s bold predictions by 2030, number 6 “The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts” and number 9: “Individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics.”