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

Summary In 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 SNP s, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNP s 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 SNP s 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 SNP syn. Synergies were further tested by the multidimensional reduction ( MDR ) approach, both intra‐ and interpathways. The best combinations ( FDR <0.0001) resulted those encompassing IGF 1R‐ rs12437963 and PTPN 1‐ rs6067484, TP 53‐ rs2078486 and ERCC 2‐ rs50871, TXNRD 1‐ rs17202060 and TP 53‐ rs2078486, the latter two supporting a central role of TP 53 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 , PTPN 1 , PARK 7, MRE 11A ). The combination GHSR ‐ MREA 11 , 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.