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 [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 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. 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.

Angels: In Network Support for Minimum Distribution Time in P2P Overlays

This paper proposes the use of in-network caches (which we call Angels) to reduce the Minimum Distribution Time (MDT) of a file from a seeder – a node that possesses the file – to a set of leechers – nodes who are interested in downloading the file. An Angel is not a leecher in the sense that it is not interested in receiving the entire file, but rather it is interested in minimizing the MDT to all leechers, and as such uses its storage and up/down-link capacity to cache and forward parts of the file to other peers. We extend the analytical results by Kumar and Ross [1] to account for the presence of angels by deriving a new lower bound for the MDT. We show that this newly derived lower bound is tight by proposing a distribution strategy under assumptions of a fluid model. We present a GroupTree heuristic that addresses the impracticalities of the fluid model. We evaluate our designs through simulations that show that our Group-Tree heuristic outperforms other heuristics, that it scales well with the increase of the number of leechers, and that it closely approaches the optimal theoretical bounds.

Angels: In-Network Support for Minimum Distribution Time in P2P Overlays

This thesis proposes the use of in-network caches (which we call Angels) to reduce the Minimum Distribution Time (MDT) of a file from a seeder – a node that possesses the file – to a set of leechers – nodes who are interested in downloading the file. An Angel is not a leecher in the sense that it is not interested in receiving the entire file, but rather it is interested in minimizing the MDT to all leechers, and as such uses its storage and up/down-link capacity to cache and forward parts of the file to other peers. We extend the analytical results by Kumar and Ross (Kumar and Ross, 2006) to account for the presence of angels by deriving a new lower bound for the MDT. We show that this newly derived lower bound is tight by proposing a distribution strategy under assumptions of a fluid model. We present a GroupTree heuristic that addresses the impracticalities of the fluid model. We evaluate our designs through simulations that show that our GroupTree heuristic outperforms other heuristics, that it scales well with the increase of the number of leechers, and that it closely approaches the optimal theoretical bounds.