A Genetic Network Associated With Stress Resistance, Longevity, and Cancer in Humans.
Human longevity and diseases are likely influenced by multiple interacting genes within a few biologically conserved pathways. Using long-lived smokers as a phenotype (n = 90)-a group whose survival may signify innate resilience-we conducted a genome-wide association study comparing them to smokers at ages 52-69 (n = 730). These results were used to conduct a functional interaction network and pathway analysis, to identify single nucleotide polymorphisms that collectively related to smokers' longevity. We identified a set of 215 single nucleotide polymorphisms (all of which had p <5×10(-3) in the genome-wide association study) that were located within genes making-up a functional interaction network. These single nucleotide polymorphisms were then used to create a weighted polygenic risk score that, using an independent validation sample of nonsmokers (N = 6,447), was found to be significantly associated with a 22% increase in the likelihood of being aged 90-99 (n = 253) and an over threefold increase in the likelihood of being a centenarian (n = 4), compared with being at ages 52-79 (n = 4,900). Additionally, the polygenic risk score was also associated with an 11% reduction in cancer prevalence over up to 18 years (odds ratio: 0.89, p = .011). Overall, using a unique phenotype and incorporating prior knowledge of biological networks, this study identified a set of single nucleotide polymorphisms that together appear to be important for human aging, stress resistance, cancer, and longevity.
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles. melevine@mednet.ucla.edu.
Morgan E
ME
Levine
Davis School of Gerontology, University of Southern California, Los Angeles.
Eileen M
EM
Crimmins
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012907:Smoking; D013312:Stress, Physiological / Q000235:genetics*; D014481:United States
Cancer; Genetic network; HRS; Longevity; Polygenic risk score; Resilience