PROJECT SUMMARY In this application we propose to build on our prior work on polygenic risk scores (PRSs) to extend these to diverse ancestry groups. By improving risk stratification, PRSs for common diseases have the potential to transform clinical practice. However, such PRSs must be available for diverse ancestry groups to ensure equitable implementation of genomic medicine and reduce the potential exacerbation of health disparities in the context of genomic medicine. Our application aims to address the critical need to develop PRSs for diverse ancestry groups and will focus on coronary heart disease (CHD) and its risk factors: hypertension, diabetes, obesity and hypercholesterolemia, collectively an enormous health burden world-wide. CHD is the prototypical complex disease for the use of PRSs given available validated risk prediction equations that bin individuals into risk categories and substantial reclassification across these categories by a PRS with consequent therapeutic implications. As part of the PRS Diversity Consortium (PRS-DC), we will develop methods to generate PRSs for populations of diverse ancestry using existing and new datasets with genomic and phenotype data for CHD and its risk factors. We will harmonize data elements across these data sets. The methods we develop will be applicable towards the generation of PRSs for a broad range of common diseases across diverse populations. The investigative team is part of the Mayo eMERGE IV application and will serve as a bridge between the PRS-DC and eMERGE. To generate PRSs for diverse ancestries, we will use data from the eMERGE consortium, Million Veteran’s Program (MVP), the All of US (AoU) program, dbGAP, PRS-DC sites, UK Biobank, and collaborations with several international groups representing the Middle Eastern, South Asian and East Asian cohorts. Our application includes several innovations to enable the use of PRSs for risk stratification and prevention of CHD in individuals belonging to diverse ancestries. Our specific aims are: Specific aim 1. Integrate and harmonize phenotype data from heterogeneous sources to enable cross platform phenotyping and generation of PRSs for common diseases in diverse ancestry groups. Specific aim 2. Develop PRSs for CHD and its major risk factors (hypertension, diabetes, obesity, hypercholesterolemia) in populations of diverse ancestry. Specific aim 3. Develop novel statistical and computational methods to account for diverse genetic ancestry and admixture in models of polygenic risk. Specific aim 4. Develop ‘clinic ready’ PRSs for diverse ancestry groups by creating reference distributions of a PRSCHD and integrate it with clinical information to compute absolute risk estimates.

PROJECT NARRATIVE The goal of our project is to use genotype and phenotype data from a variety of sources, to generate polygenic risk scores (PRSs) for individuals belonging to diverse ancestries. Our focus will be on developing PRSs for coronary heart disease (CHD) and its major risk factors (hypertension, diabetes, obesity, hypercholesterolemia), collectively an enormous public health burden world-wide. We will develop methods to account for diverse genetic ancestry in models of polygenic risk and integrate PRSs into existing clinical risk prediction equations to estimate absolute risk of CHD for use in clinical decision making.