Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

Background: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. Methods: We conducted a genome wide association study ( Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models ( Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs ( 70, 987 autosomal SNPs with genotypic call rate >= 80%, minor allele frequency >= 10%, Hardy-Weinberg test p >= 0.001). Results: In family-based association test ( FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 ( physical positions 73,091,610 and 73, 527,652) were associated with age at death ( p-value < 10(-5)). The two sets of SNPs were in high linkage disequilibrium ( minimum r(2) = 0.58). The top 30 SNPs for generalized estimating equation ( GEE) tests of association with age at death included rs10507486 ( p = 0.0001) and rs4943794 ( p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations ( FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 ( p = 0.00003) near FOXO3a and rs3751591 ( p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Conclusion: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.