The association of a polygenic lifespan score with the risk of common age-related diseases and mortality

BACKGROUND: Aging increases the risk of major noncommunicable diseases. Research into the genetics of health-related traits could reveal genetic pathways for robustness against these diseases. We studied how a genetic predisposition for a long lifespan is associated with the risk of all-cause mortality and major age-related noncommunicable diseases. METHODS: We analyzed data from 376 753 participants (mean age = 58.5 years; standard deviation = 13.9 years; 46.3% men) to examine how a polygenic lifespan score (PLS) is associated with the risk of all-cause mortality and major noncommunicable diseases. The associations between all-cause mortality, cancers, femur fracture, dementia, Alzheimer's disease, Parkinson's disease, type 2 diabetes, obesity, cardiovascular diseases, hypertension, ischemic heart diseases, coronary heart disease, stroke, and myocardial infarction were investigated using conventional and time-dependent Cox regression. RESULTS: The PLS was associated with all the above-mentioned outcomes except for Parkinson's disease. Most of the associations were time-dependent, and the hazard ratio (HR) varied over time from protective to risk-increasing. However, the current PLS predicted noncommunicable disease risks with small effect sizes (lowest HR ≈ 0.70, highest HR ≈ 1.20, Cox-Snell pseudo-R2 > 0.01). CONCLUSIONS: Genetic predisposition for a longer lifespan was associated with a smaller risk of common age-related noncommunicable diseases, suggesting greater robustness against these conditions. The lowest risks were found during periods when the incidences of diseases were greatest. The observed small effects highlight the need to better understand how accumulated environmental factors modify individual lifespans.