Background: Polygenic risk scores (PRS) have demonstrated predictive validity across a range of cohorts and diseases, but quantifying their clinical utility remains a challenge. As PRS can be derived from a single biological sample and remain stable throughout life, we explore the potential of PRS to optimize existing screening programs. Methods: Using UK Biobank (n = 444,949), we quantified the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs globally (breast cancer, prostate cancer, colorectal cancer, abdominal aortic aneurysm, type 2 diabetes, hypertension, and coronary artery disease). We identified individuals at high genetic risk (PRS OR>2) and very high genetic risk (PRS OR>3) and estimated the optimal screening ages for these genetically high risk individuals, based on the equivalent risk to population-level risk at recommended screening ages. We then leveraged published mortality estimates, with and without screening-based interventions, to assess the potential benefits of tailoring screening age based on genetic risk. We also estimated the case enrichment ratio, which is a ratio of the percentage of cases in the high PRS risk group and in the total population. Findings: Very high risk individuals reach the risk level associated with usual starting screening age on average 10.8 years earlier, high risk individuals 8.9 years earlier and reduced risk individuals (OR<0.5) 16.8 years later. During this time, case enrichment in the high risk group is between 1.7 and 3.0 depending on disease. Across all seven diseases, appropriate interventions following PRS-guided screening would reduce premature deaths in high risk individuals by 19.0%. Conclusion: Knowledge of genetic risk, measured using PRS, has the potential to deliver substantial public health benefits when aggregated across conditions, and could reduce premature mortality by tailoring existing screening programs.

MC, DT, MW, FRM, DW, VP, GM, PD, SH are all current or immediately prior Genomics employees and may own stock as part of a standard compensation. PD and GM are partners in Peptide Groove LLP. PD and GM are Founders and Directors of Genomics, and PD is the CEO of Genomics. EA reports advisory board fees from Apple and Foresite Labs. EA has ownership interest in SVEXA, Nuevocor, DeepCell, and Personalis, outside the submitted work. EA is a board member of AstraZeneca. JOS has received funding from the Wu-Tsai Human Performance Alliance, The American Heart Association (25POST1363977), Google, and The American College of Cardiology (102024-126).

This study was funded by Genomics

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This research was conducted using the UK Biobank Resource under application number 9659.

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