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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 × 10 -13 ) and parental lifespan (hazard ratio = 1.06[1.06-1.07], P = 2.0 × 10 -86 ). The obesity PRS showed distinct effects on lifespan in Japanese and European individuals (P heterogeneity  = 9.5 × 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.