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

Abstract 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.