Abstract

While polygenic risk scores (PRSs) are poised to be translated into clinical practice through prediction of inborn health risks, a strategy to utilize genetics to prioritize modifiable risk factors driving heath outcome is warranted. 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.

Paper

Title: Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan.
Publication: Nature Medicine
Author: Saori Sakaue, Masahiro Kanai1, Juha Karjalainen, Masato Akiyama, Mitja Kurki, Nana Matoba, Atsushi Takahashi, Makoto Hirata, Michiaki Kubo, Koichi Matsuda, Yoshinori Murakami, FinnGen, Mark J. Daly, Yoichiro Kamatani, Yukinori Okada
DOI: 10.1038/s41591-020-0785-8
Date: 23 March 2020