title: Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study.
abstract: 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 > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 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 r2 = 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 webcite.
  
  
  CONCLUSIONS
  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.
authors: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA. klunetta@bu.edu
authors: Kathryn L
authors: KL
authors: Lunetta
authors: Ralph B
authors: RB
authors: D'Agostino
authors: David
authors: D
authors: Karasik
authors: Emelia J
authors: EJ
authors: Benjamin
authors: Chao-Yu
authors: CY
authors: Guo
authors: Raju
authors: R
authors: Govindaraju
authors: Douglas P
authors: DP
authors: Kiel
authors: Margaret
authors: M
authors: Kelly-Hayes
authors: Joseph M
authors: JM
authors: Massaro
authors: Michael J
authors: MJ
authors: Pencina
authors: Sudha
authors: S
authors: Seshadri
authors: Joanne M
authors: JM
authors: Murabito
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D005819:Genetic Markers