Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes

Junyoung Park (), Andrés Peña-Tauber, Lia Talozzi, Michael D. Greicius and Yann Guen
Additional contact information
Junyoung Park: Stanford University
Andrés Peña-Tauber: Stanford University
Lia Talozzi: Stanford University
Michael D. Greicius: Stanford University
Yann Guen: Stanford University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one’s susceptibility to cancer and/or early death.

Date: 2025
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DOI: 10.1038/s41467-025-57315-6

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