Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways

Abstract

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.

Fig. 1

Insulin/IGF-1 signaling pathway. The insulin/IGF-1 signaling pathway consists of the core components IGF1R/IR/IRR, IRS, PI3K, AKT/SGK, FOXO and SIRT, and proteins that have a direct activating or inhibiting effect on these proteins. The small closed circles (containing Ac, P, or Ub) indicate an activating effect of the posttranslational modification on the protein, while the small dashed circles indicate an inhibiting effect. The straight arrows pointing to these small circles indicate an activating effect on the posttranslational modification, while the dashed arrows indicate an inhibiting effect. Ac acetylation, P phosphorylation, Ub ubiquitylation

Fig. 2

Telomere maintenance pathway. The telomere maintenance pathway consists of proteins belonging to telomerase and its associated factors or to the shelterin complex. Telomere elongation is performed by telomerase after binding to the telomere (a). However, binding of the shelterin protein POT1 to the telomere blocks this process (b)