Genetic Correlates of Longevity and Selected Age-Related Phenotypes: A Genome-Wide Association Study in the Framingham

Kathryn L Lunetta, Ralph B D'Agostino Sr, David Karasik, Emelia J Benjamin, Chao-Yu Guo, Raju Govindaraju, Douglas P Kiel, Margaret Kelly-Hayes, Joseph M Massaro, Michael J Pencina, Sudha Seshadri and Joanne M Murabito*

* Corresponding author

Published: 19 September 2007

This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Family studies and heritability estimates provide evidence for a genetic contribution to variation in lifespan. We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on five 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, eight 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 seven SNPs, and GEE models identified nine 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 more genes and biological pathways proposed as contributing to longevity and healthy aging previously reported to be associated with longevity in model organisms or humans.

Background

Genetic factors associated with human longevity and healthy aging remain largely unknown. Heritability estimates of longevity derived from twin registries and large population-based samples suggest a significant but modest genetic contribution to the human lifespan (heritability ~15 to 30%) [1-4]. However, genetic influences on lifespan may be greater once an individual achieves age 60 years [5]. Moreover, the reported magnitude of the genetic contribution to other important aspects of aging such as healthy physical aging (wellness) [6], physical performance [7,8], cognitive function [9], and bone aging [10] are much larger. Both exceptional longevity and a healthy aging phenotype have been linked to the same region on chromosome 4 [11,12], suggesting that although longevity per se and healthy aging are different phenotypes, they may share some common genetic pathways.

Methods

Study sample