Abstract 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. Purpose We quantified the potential clinical benefits arising from a knowledge of PRS across seven diseases with existing screening programs globally focused on cardiometabolic conditions (coronary artery disease, hypertension, abdominal aortic aneurysm, type 2 diabetes) and cancer (breast cancer, prostate cancer, and colorectal cancer). Methods Using UK Biobank (n = 444,949), we quantified the potential clinical benefits arising from a knowledge of PRS across these seven cardiometabolic diseases and cancer. We identified individuals at high genetic risk (PRS OR2) and very high genetic risk (PRS OR3) 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. Results For the four cardiometabolic diseases, very high risk individuals reach the risk level associated with usual starting screening age on average 12.8 years earlier, high risk individuals 10.3 years earlier and reduced risk individuals (OR0.5) 19 years later. Appropriate interventions following PRS-guided screening would reduce premature deaths in high risk individuals by 24.2%. Across all seven diseases (cardiometabolic and cancer), 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 (OR0.5) 16.8 years later. 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.Study Design Optimal screening ages for 7 diseases
O'sullivan et al. (Sat,) studied this question.