Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

Cross-biobank analysis reveals that polygenic risk scores (PRS) for hypertension and obesity are associated with shorter lifespan, serving as a proof-of-principle that PRS could pinpoint causal risk factors that affect long-term health outcomes. While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks(1), a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted(2). To this end, we investigated the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (n(total) = 675,898; BioBank Japan (n = 179,066), UK Biobank (n = 361,194) and FinnGen (n = 135,638)). In contrast to observational studies, in which discerning the cause-and-effect can be difficult, PRSs could help to identify the driver biomarkers affecting human lifespan. A high systolic blood pressure PRS was trans-ethnically associated with a shorter lifespan (hazard ratio = 1.03[1.02-1.04], P-meta = 3.9 x 10(-13)) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 x 10(-86)). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (P-heterogeneity = 9.5 x 10(-8) for BMI). The causal effect of blood pressure and obesity on lifespan was further supported by Mendelian randomization studies. Beyond genotype-phenotype associations, our trans-biobank study offers a new value of PRSs in prioritization of risk factors that could be potential targets of medical treatment to improve population health.