Rare Protein Truncating Genetic Variants Can Reduce Human Lifespan

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Research led by Biogen in Cambridge, Massachusetts, shows four rare protein truncating gene variants can negatively impact human lifespan.

“Human lifespan is a heritable quantitative trait that reflects a mix of health-related outcomes, environmental exposures and chance,” write Heiko Runz, Head of Human Genetics at Biogen, and colleagues in the journal Nature Aging.

“Twin and pedigree studies suggest that narrow-sense heritability of human lifespan ranges from 15% to 30%,” they add.

Earlier genome wide association studies (GWAS) have linked over 20 points on the genome to changes in human lifespan. But the impact of loss-of-function mutations on this trait was unclear.

Runz and colleagues analyzed whole-exome sequencing results from 352,338 UK Biobank participants (European ancestry) to assess whether protein-truncating variants play a role in lifespan using survival as a measure, as while at least 15,000 deaths have been recorded since the biobank started, most UK Biobank participants are still alive.

They looked at the impact of the variants they found on six outcomes linked with survival, namely, individual lifespan, individual lifespan in men, individual lifespan in women, mother’s lifespan, father’s lifespan and combined parental lifespan.

The team found four gene variants –in the genes BRCA1, BRCA2, ATM and TET2– were significantly linked with survival for at least two of the six survival outcomes. The strongest signal was seen for the cancer gene BRCA2, which strongly influenced survival in both men and women (hazard ratio: 2.6-3.0). The other well-known cancer gene BRCA1 was also strongly associated with survival, particularly in women.

TET2, another gene linked with cancer, in this case myeloid malignancies, was also significantly linked to survival, as was ATM, which helps respond to DNA damage and also has cancer links.

In an additional analysis, cancer was the main cause of lower survival with these gene variants, as might be expected.

“After exclusion of BRCA2, BRCA1, TET2 and ATM, 38 pathways remained nominally significant (P<0.05), suggesting that further genes therein will reach gene-level significant association with lifespan when sample sizes for protein-truncating variant-burden analyses increase further,” write the authors.

Notably, none of the four genes linked with survival in this study had previously been linked to lifespan in earlier GWAS evaluations.

While these results provide interesting insights into the genetics of aging and lifespan, the researchers caution that “due to lower participation and a lack of mortality data from other ethnicities, our results are based on white European individuals and thus may not translate to all ancestries.

“Moreover, UK Biobank participants are healthier than the general U.K. population, with participants being less likely to smoke, be obese or drink, which potentially dilutes our ability to capture the effects of these factors on mortality.”

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