Polygenic risk score of longevity predicts longer survival across an age-continuum

Niccolo' Tesi, Sven J van der Lee, Marc Hulsman, Iris E Jansen, Najada Stringa, Natasja M van Schoor, Philip Scheltens, Wiesje M van der Flier, Martijn Huisman, Marcel J T Reinders, Henne Holstege

Research output: Contribution to JournalArticleAcademicpeer-review


Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N=343), a population-matched cohort of older-adults from five cohorts (N=2905), and summary statistics data from a GWAS on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older-adults. This PRS was also associated with longer survival in an independent sample of younger individuals, (p=0.02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human lifespan is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

Original languageEnglish
Pages (from-to)750-759
JournalThe Journals of Gerontology. Series A : Biological Sciences and Medical Sciences
Issue number5
Early online date20 Nov 2020
Publication statusPublished - May 2021

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.


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