title: 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.
authors: Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. j.deelen@lumc.nl
authors: Joris
authors: J
authors: Deelen
authors: Hae-Won
authors: HW
authors: Uh
authors: Ramin
authors: R
authors: Monajemi
authors: Diana
authors: D
authors: van Heemst
authors: Peter E
authors: PE
authors: Thijssen
authors: Stefan
authors: S
authors: Böhringer
authors: Erik B
authors: EB
authors: van den Akker
authors: Anton J M
authors: AJ
authors: de Craen
authors: Fernando
authors: F
authors: Rivadeneira
authors: André G
authors: AG
authors: Uitterlinden
authors: Rudi G J
authors: RG
authors: Westendorp
authors: Jelle J
authors: JJ
authors: Goeman
authors: P Eline
authors: PE
authors: Slagboom
authors: Jeanine J
authors: JJ
authors: Houwing-Duistermaat
authors: Marian
authors: M
authors: Beekman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D016615:Telomere
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I