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

Abstract

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.

Keywords: FinnGen; genetic predisposition; noncommunicable diseases; time-dependent Cox regression.

Figure 1.

Time-dependent and time-invariant associations of the standardized polygenic lifespan score with the risk of the selected outcomes. All models were adjusted for sex, blood sample extraction age, birth year, and the first 10 genetic principal components of ancestry. Model-based time-dependent hazard ratios (HRs) for all-cause mortality, femur fracture, and major noncommunicable diseases during the follow-up age (years). The time-varying HRs (solid black lines) with their respective 95% confidence intervals (gray-filled areas) of the PLS and HRs for strictly equal hazards (horizontal dotted lines) are depicted in each plot for each of the used FinnGen outcomes. PLS, polygenic lifespan score.

Figure 2.

Cumulative survival over the follow-up time for the 15 selected outcomes. Unadjusted cumulative survival curves of all-cause mortality, femur fracture, and the 13 noncommunicable disease outcomes in this study are depicted as different colors. The y-axis signifies the proportion of surviving participants, and the x-axis signifies age in years.

Figure 3.

Participants at risk over the follow-up time for the 15 selected outcomes. Unadjusted cumulative survival curves of all-cause mortality, femur fracture, and the 13 noncommunicable disease outcomes in this study are depicted as different colors. The y-axis signifies the proportion of participants at risk, and the x-axis signifies age in years.