Integrated health-related phenotype by Polygenic Risk Scores stratifies risk population for all-cause mortality: A cohort study based on UK Biobank

Background: Genetic predisposition is a key factor that influences individuals’ risk of multiple health-related outcomes. Genome-wide association studies examine each susceptibility variant's association but usually neglect the combined effect. We aimed to establish a Polygenic Risk Score (PRS), which could quantify genetic contribution for various phenotypes. Subsequently, we assess the association between the genetic surrogate marker and the lifespan utilizing UK Biobank data. Results: Sex (HR: 1.73, 95% CI = 1.68-1.77), smoking status (HR: 1.78, 95% CI = 1.73-1.83) and BMI (HR per SD: 1.05, 95% CI = 1.04-1.06) were associated with all-cause mortality. iPRS achieved a dose-effect relationship and risk stratification, the highest iPRS with any BMI level could increase from 1.23-1.90 times mortality risk than normal weight population. The same goes for smokers, mortality risk increased from 38 % to 178% due to different genetic predispositions. Conclusion: We have evaluated the survival probability of all-cause mortality at the genetic level prediction ability of iPRS. It can be an auxiliary instrument for stratifying risk factors with demographic or behavior exposure.