title: Genomics of human health and aging.
abstract: Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR=2.9, p=5.0 × 10(-66)), onset of CVD (e.g., RR=1.6, p=4.6 × 10(-17)), and onset of cancer (e.g., RR=1.6, p=1.5 × 10(-6)). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p=3.6 × 10(-10)) enrichment of non-synonymous SNPs (N=27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.
authors.affiliation: Center for Population Health and Aging, Duke University, Box 90408, Trent Hall, Room 002, Durham, NC 27708, USA. Alexander.Kulminski@duke.edu
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kulminski
authors.forename: Irina
authors.initials: I
authors.lastname: Culminskaya
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000375:Aging / Q000235:genetics*; D000483:Alleles; D017209:Apoptosis / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000401:mortality; D009422:Nervous System Diseases / Q000235:genetics / Q000401:mortality; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models