Genetic associations with human longevity are enriched for oncogenic genes

Area of Science:

• Genetics and Genomics
• Longevity Research
• Precision Health

Background:

• Human lifespan is a complex trait influenced by genetic and environmental factors.
• Understanding genetic contributions to survival and mortality is crucial for advancing precision health.
• Previous research has linked specific genetic variants to lifespan, but comprehensive analyses are ongoing.

Purpose of the Study:

• To investigate the association of common and rare genetic variants with human lifespan.
• To identify genetic loci associated with longevity and genes linked to reduced lifespan.
• To explore the role of genetic variants in cancer predisposition and early mortality.

Main Methods:

• Survival analysis was performed on UK Biobank participants of European ancestry (N=35,551 for age-at-death, N=358,282 for last-known-age).
• Common genetic variants and the burden of rare non-synonymous variants (loss-of-function and pathogenic missense) were analyzed.
• A direction-agnostic SKAT-O approach was used to identify additional significant associations.

Main Results:

• Three longevity-associated loci identified: APOE, ZSCAN23, and MUC5B.
• Six genes (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1) showed association between loss-of-function variant burden and reduced lifespan.
• Eight genes (DNMT3A, SF3B1, CHL1, TET2, PTEN, SOX21, TP53, SRSF2) showed association between pathogenic missense variant burden and reduced lifespan.
• SKAT-O identified associations with C1orf52, TERT, IDH2, and RLIM, linking telomere function and oncogenesis to longevity.
• Identified variants are predominantly linked to cancer pathways and clonal hematopoiesis.

Conclusions:

• Genetic factors significantly influence human lifespan, with specific variants impacting longevity and mortality risk.
• The findings highlight the importance of genetic variants in prevalent causes of mortality, particularly cancer.
• Early genetic testing may identify individuals susceptible to cancer and/or premature death, enabling personalized health strategies.