Journal
BMC MEDICAL GENETICS
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1471-2350-8-S1-S13
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Funding
- DIVISION OF EPIDEMIOLOGY AND CLINICAL APPLICATIONS [N01HC025195] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR041398] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS017950] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG028321] Funding Source: NIH RePORTER
- NCRR NIH HHS [1S10RR163736-01A1] Funding Source: Medline
- NHLBI NIH HHS [N01HC25195, N01-HC-25195] Funding Source: Medline
- NIAMS NIH HHS [R01 AR041398] Funding Source: Medline
- NIA NIH HHS [R01 AR/AG 41398, AG028321, R01 AG028321] Funding Source: Medline
- NINDS NIH HHS [R01 NS017950] Funding Source: Medline
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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.
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