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 language | English (US) |
---|---|
Pages (from-to) | 1237-1251 |
Number of pages | 15 |
Journal | GeroScience |
Volume | 43 |
Issue number | 3 |
DOIs | |
State | Published - 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