Despite evidence of a substantial genetic component, the genetic factors that underlie longevity in humans remain to be identified. Previous genome-wide linkage and association studies have not found strong evidence for the contribution of common variants besides the APOE gene, suggesting the role of rare variants in human longevity. To discover rare variants that might contribute to longevity, we selected 988 candidate genes and performed a pilot study to identify novel non-synonymous variants in 6 Ashkenazi Jewish centenarians older than 105. Our candidate genes act in pathways implicated in aging and longevity, including neurodegeneration, cognitive function, lipid metabolism, DNA repair, and genome maintenance. By implementing custom-designed Agilent SureSelect target capture and next-generation sequencing, we discovered a total of 89 novel non-synonymous SNPs (nsSNPs) and validated 51 nsSNPs by iPLEX MassArray assays. Genotyping analysis of these novel SNPs in 410 Ashkenazi Jewish controls and 390 centenarians showed significant enrichment (5.3 fold, p= 0.02) of the p.Y318C variant in PMS2 and significant depletion (7.5 fold, p= 0.04) of the p.V465A variant in GABRR3 in centenarians compared to controls. Our study presents the potential of targeted next-generation sequencing for discovery of rare but functional genetic variation which may lead to exceptional longevity in humans.
Bibliographical noteFunding Information:
We would like to thank Genomics Shared Facility at Albert Einstein College of Medicine for their assistance with the iPLEX MassArray assay. This work was funded by NIH grant AG024391 , AG027734 , and AG17242 . YS is the recipient of a Glenn Award for Research in Biological Mechanisms of Aging.
- Candidate genes
- Functional variant
- Human longevity
- Target capture and next-generation sequencing
ASJC Scopus subject areas
- Developmental Biology