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.
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18 June 2021
A Correction to this paper has been published: https://doi.org/10.1007/s11357-021-00400-7
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Funding
This work was supported by the National Institute on Aging (NIA cooperative agreements U19-AG023122 and UH2AG064704, and grant R01 AG061844), the Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072) (N. B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N. B.), NIH/NIA 1 R01AG044829 (PIs-Veghese/Barzilai), NIH/NIA1 NIH-1 R01AG 046949-R01 AG057909-01 (PIs Barzilai & Zhang), U19 AG056278 (Vjig), K23AG051148 (SM), R01AG061155 (SM), the National Institute of General Medical Sciences (grant R24 GM134210), and the NIH Office of the Director (grant S10 OD021728).
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L.L.J. is an employee and stock-holder of Novartis. D.J.G is an employee and stock-holder of Regeneron Pharmaceuticals.
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Gurinovich, A., Song, Z., Zhang, W. et al. Effect of longevity genetic variants on the molecular aging rate. GeroScience 43, 1237–1251 (2021). https://doi.org/10.1007/s11357-021-00376-4
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DOI: https://doi.org/10.1007/s11357-021-00376-4