Effect of longevity genetic variants on the molecular aging rate

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.

Keywords: Extreme human longevity; Genetic variants; Molecular aging rate; SOMAscan array.

Fig. 1

Manhattan plot of the genome-wide association with extreme human longevity in the New England Centenarian Study. The x-axis reports chromosomes and coordinates within chromosomes. The y-axis reports the −log10 (p-value). The 4 heatmaps report the log-transformed standardized protein expression data (rows) for the 224 individuals (columns) included in the serum protein SOMAscan experiment. The heatmap for the APOE locus includes only the top significant proteins

Fig. 2

Summary of concordant and discordant protein effects. The figure summarizes 4 possible relations between longevity genetic variants and serum proteins of aging. Serum proteins of aging can increase (green) or decrease (blue) with older age, and carriers of the longevity variants can have lower or higher values of these proteins. When the age and longevity change patterns are disconcordant (a and d), we hypothesize that the longevity variants delay age-related accumulation of damage. When the age and longevity patterns are concordant (b and c), then we hypothesize that changes of those proteins with age may actually be protective

Fig. 3

Examples of pQTLs in CDKN2B. Example of 6 proteins that correlate with genotypes of the SNP rs7857345 in the CDKN2B that was associated with extreme human longevity in the genome-wide association studies in the New England Centenarian Study and LonGenity Gene Project. For each protein: the boxplots on the left show the distribution of the log-transformed protein data by genotype group (black = homozygote genotype for the longevity allele; red = genotypes on carriers of 1 or 2 non-longevity alleles); the scatter plot on the right shows the distribution of the log-transformed protein data (y-axis) versus the age of study participants (x-axis). The 3 plots on the left show 3 proteins that increase with age and are on average lower in carriers of the longevity-associated variant (black). The 3 plots on the right show 3 proteins that decrease with age and are on average higher in carriers of the longevity-associated variant