Cardiovascular disease (CVD) and its risk factors impose major societal burdens and are leading causes of
morbidity, mortality, and disability. Precision medicine is uniquely positioned to address CVD and its risk factors,
enabled by decades of investigation and billions of dollars of investment that have established their strong
underlying genetic basis. Polygenic risk scores (PRS), the aggregation of risk variants into a single score,
provides one such example. Research on PRS in CVD has transitioned from estimation to examining the clinical
utility; i.e., determining when and how PRS adoption will occur and how similarly conceived
environmental/lifestyle risk scores (ERS) can be used clinically in concert with PRS. However, the majority of
participants included in large-scale CVD research have been of European ancestry (EA), limiting the global
translation of genetic associations into clinical and public health applications relevant for all populations.
The PAGE consortium and others have demonstrated that EA-derived PRS are not directly translatable to
racially/ethnically diverse populations. Statistical tools for PRS estimation and interpretation are founded on
strong assumptions that are violated, and create bias, in the context of population structure that characterizes
racially/ethnically diverse populations. These research gaps will exacerbate long-standing racial/ethnic
disparities in CVD and its risk factors, underscoring the need for research that enables all groups to reap the
benefits of PRS-enabled personalized prevention.
In this revised application, we address the limitations previously identified in our original application by leveraging
high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked
electronic health records, capturing CVD and its risk factors. Through this effort, we will include over 1.5M non-
European ancestry participants to develop and validate PRS for CVD-associated traits in racially/ethnically
diverse populations. We will create the methods, resources, and best practices for the clinical and public health
communities. This research will permit adoption and application of PRS for the detection, intervention, and
treatment of CVD risk factors. Our ultimate goal is to reduce and prevent the burden of CVD in all populations.
Our Specific Aims are (1) Creation of unbiased PRS: Develop and evaluate CVD PRS in combination with ERS
in the large and racially/ethnically diverse PAGE study; and (2) Validation, calibration and dissemination:
Externally validate and improve upon risk score models in biobanks and translate risk score models for improved
access and understanding for the medical community.
We will build the next generation of methods, resources, and best-practices to empower appropriate
development of PRS and subsequent prediction and clinical interrogation in CVD. Deliberate focus on non-EA
populations will ensure that they are not the last to benefit in the new era of genomic medicine.