The genetic component of human longevity: New insights from the analysis of pathway‐based SNP‐SNP interactions

Abstract

SummaryIn human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA,PTPN1,PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

“…In particular the evaluation of heritability is based on an additive model for complex traits that does not consider other inheritance patterns, such as epistasis among others 10 . In literature example of epistatic interactions in longevity exists [11][12][13] . Tan and colleagues 14 analyzing centenarians identified a significant association between the interaction REN gene allele/mitochondrial haplotype H and longevity while the two gene analysed separately showed no significant association.…”

Impact of Growth Hormone-Related Mutations on Mammalian Aging

“…Moreover, mortality is increased in individuals with pathologic excess of GH ( Baumann, 1987 ). Studies of the genetic polymorphism of candidate genes, genome-wide association studies (GWAs), and analysis of signaling pathways, genetic networks, and copy number variations, provided evidence that human aging is influenced by genes related to the somatotropic axis ( van Heemst et al, 2005 ; Suh et al, 2008 ; Bonafe and Olivieri, 2009 ; Dato et al, 2018 ) and its downstream targets including FOXO3A ( Blankenburg et al, 2018 ; Revelas et al, 2018 ; Zhao et al, 2018 ).…”

Untitled

“…These mutations have been shown to extend life by about 50% in mammals and more in nematodes. In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with metabolic effects [11]. About a hundred of these metabolic manipulations enhance longevity by retarding aging comparable to CR, are not as effective as repair strategies which can reverse aging process.…”