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. 2017 Oct 12;72(11):1453-1464.
doi: 10.1093/gerona/glx027.

Four Genome-Wide Association Studies Identify New Extreme Longevity Variants

Paola Sebastiani  1 , Anastasia Gurinovich  2 , Harold Bae  3 , Stacy Andersen  4 , Alberto Malovini  5 , Gil Atzmon  6   7   8 , Francesco Villa  9   10 , Aldi T Kraja  11 , Danny Ben-Avraham  7   8 , Nir Barzilai  7   8 , Annibale Puca  9   10 , Thomas T Perls  4
Affiliations

Four Genome-Wide Association Studies Identify New Extreme Longevity Variants

Paola Sebastiani et al. J Gerontol A Biol Sci Med Sci. .

Abstract

The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators. To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years). The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease. The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.

Keywords: Genetic profiles; Genetic variants; Healthy aging; Human longevity.

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Figures

Figure 1.
Figure 1.
Schematic of the analyses conducted to discover longevity-associated variants (LAV), LAV with significant joint effect on extreme longevity (jLAV), and LAV with effects on extreme survival age (eSAV). Extreme longevity is defined as survival to at least the oldest one percentile of the 1900 birth year cohort life table, regardless of the attained age at death. Extreme survival age considers specifically age at death, conditioning on survival beyond the oldest one percentile of the 1900 birth year cohort. The top panels include description of the four studies and additional controls from the Illumina repository.
Figure 2.
Figure 2.
(A) Manhattan plot displaying the −log10(p-value) of SNP associations from the meta-analysis of the four GWAS of extreme longevity (y-axis). The x-axis displays the SNP positions by chromosomes that are in alternated colors. In addition to three loci that reached genome wide significance (horizontal bar in black, 5 × 10−8), 5 loci reached a 5 × 10−7 level of significance (horizontal bar in blue). (B–D) Regional plots of the locus on chromosome 7, 12, and 19. Data from the 1000 genomes were used to estimate linkage disequilibrium. Allele frequencies are summarized in Supplementary Figure 3C. (E–G) Functional annotation with expression data from GTEX. Rank-normalized expression by genotype. Plots were generated from the GTEX portal. Numbers on the x-axis are the genotype counts from GTEX.
Figure 3.
Figure 3.
Regional plots of the four SNPs in chromosomes 2, 4, 6, and 16, with p-values between 5E-7 and 5E-8. Data from the 1000 genomes were used to estimate linkage disequilibrium. Allele frequencies are summarized in Supplementary Figure 3C.
Figure 4.
Figure 4.
Forest plot summarizing the association of each individual SNP. Panel A: analysis restricted to case only; Panel B: analysis extended to all study participants. HR: hazard for mortality for carrier of the longevity variant (LA). All models were stratified by sex, adjusted for four principal components and family relatedness. The associations of rs7976168 and rs7185374 were not significant in the case-only analysis, as shown by the 95% confidence intervals including 1. Full details are in Supplement Figure 4. All associations reached statistical significance in the analysis extended to all participants (see Supplementary Figure 4 for details).
Figure 5.
Figure 5.
Kaplan–Meier curves of survival to extreme old ages stratified by genotype. Panel A: Analysis restricted to case only; Panel B: Analysis extended to all study participants. In each plot, the least common genotype is colored in green/light grey, and the most common genotype in black. The longevity allele is the most common allele of rs6857, rs769449, rs7976168, and rs7185374, and the least common allele of rs3764814 and rs28391193. Similar plots for rs72834698 and rs2008465 are in Supplementary Figure 5.
Figure 6.
Figure 6.
Result of the joint survival analysis in case only (N = 1922). Panel A: forest plot displaying the three SNPs that remained significantly associated with the hazard for mortality when analyzed jointly. HR: hazard for mortality for carrier of the longevity variant (LA). The model was stratified by sex, and adjusted for four principal components and family relatedness. Full details are in Supplementary Figure 4. Panel B: Kaplan–Meier curves of survival to extreme old ages stratified by genetic profiles described in the legend. Longevity alleles: rs6857: C; rs769449: G; rs3764814: C; rs28391193: A; rs7185374: A. Line thickness represents the prevalence of the associated genetic profile.
Figure 7.
Figure 7.
Result of the joint survival analysis in all subjects in the dataset (N = 10,194). Panel A: forest plot displaying the five SNPs that remained significantly associated with the hazard for mortality when analyzed jointly. HR: hazard for mortality for carrier of the longevity variant (LA). As in (A), the model was stratified by sex, and adjusted for four principal components and family relatedness. Full details are in Supplementary Figure 4. Panel B: Kaplan–Meier curves of survival to extreme old ages stratified by genetic profiles described in the legend. Longevity alleles: rs6857: C; rs769449: G; rs3764814: C; rs28391193: A; rs7185374: A. Line thickness represents the prevalence of the associated genetic profile.
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