Abstract Body (Do not enter title and authors here): Background: Healthcare systems are increasingly collecting genotype data on patients. Polygenic risk scores (PRS), which quantify inherited risk of a given disease, have the potential to leverage this data to identify high risk individuals. While PRS for single traits have often been evaluated, the same data can be used to calculate PRSs across traits and evaluate the overall burden of high cardiometabolic polygenic risk using a single test.

Methods: We examined the association of cardiometabolic PRS from the Polygenic Score Catalog among 236,393 All of Us (AoU) participants for 6 target traits of interest, using all available PRS for coronary artery disease (CAD; 57 PRS), atrial fibrillation (AF; 30 PRS), heart failure (HF; 9 PRS), type 2 diabetes mellitus (T2DM; 133 PRS), venous thromboembolism (VTE; 9 PRS), and thoracic aortic aneurysm (TAA; 2 PRS). PRSMix is a tool that incorporates information across several PRS for a given trait to improve prediction accuracy for a target population. We generated a PRSMix for each trait and externally benchmarked its performance against individual PRS in the Mass General Brigham Biobank (MGBB). Phenotypes were ascertained using hospital diagnosis and procedural codes. Logistic regression was performed, adjusting for age, sex, and the first 10 principal components of inferred genetic similarity.

Results: Of the 53,306 genotyped MGBB participants, 55.6% are female, mean enrollment age is 53 ± 17 years. Each trait-specific PRSMix demonstrated generally stronger associations with the target trait compared to any individual contributing score. This included trait-specific PRSMix associations (OR/SD, [95%CI]) of 2.07 [1.99-2.15] for CAD, 1.88 [1.82-1.95] for AF, 1.47 [1.43-1.51] for HF, 2.07 [2.00-2.14] for T2DM, 1.43 [1.39-1.47] for VTE, and 1.40 [1.34-1.46] for TAA. Findings were consistent across inferred genetically similar ancestry groups, with stronger PRSMix associations for CAD detected in the EUR group (2.14 [2.05-2.22]) compared to the AFR group (1.43 [1.21-1.70]). Approximately 37% of people in MGBB have 3-fold greater risk of at least one cardiometabolic disease, with 22% at risk for CAD, 14% for T2DM, 13% for Afib, 3% for VTE, 2% for HF and <1% for TAA.

Conclusion: We developed PRSMix scores for cardiometabolic traits in AoU and validated them in MGBB. We identified 37% of biobank participants with at least 3-fold greater disease risk associated with high polygenic scores for at least one cardiometabolic outcome.