Effect of longevity genetic variants on the molecular aging rate

Anastasia Gurinovich, Zeyuan Song, William Zhang, Anthony Federico, Stefano Monti, Stacy L. Andersen, Lori L. Jennings, David J. Glass, Nir Barzilai, Sofiya Millman, Thomas T. Perls, Paola Sebastiani

Research output: Contribution to journalArticlepeer-review

Abstract

We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E−16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

Original languageEnglish (US)
Pages (from-to)1237-1251
Number of pages15
JournalGeroScience
Volume43
Issue number3
DOIs
StatePublished - Jun 2021

Keywords

  • Extreme human longevity
  • Genetic variants
  • Molecular aging rate
  • SOMAscan array

ASJC Scopus subject areas

  • Aging
  • veterinary (miscalleneous)
  • Complementary and alternative medicine
  • Geriatrics and Gerontology
  • Cardiology and Cardiovascular Medicine

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