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

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...

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Main Authors:	Deelen, Joris, Uh, Hae-Won, Monajemi, Ramin, van Heemst, Diana, Thijssen, Peter E., Böhringer, Stefan, van den Akker, Erik B., de Craen, Anton J. M., Rivadeneira, Fernando, Uitterlinden, André G., Westendorp, Rudi G. J., Goeman, Jelle J., Slagboom, P. Eline, Houwing-Duistermaat, Jeanine J., Beekman, Marian
Format:	Online
Language:	English
Published:	Springer Netherlands 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543749/

id	pubmed-3543749
recordtype	oai_dc
spelling	pubmed-35437492013-01-14 Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways Deelen, Joris Uh, Hae-Won Monajemi, Ramin van Heemst, Diana Thijssen, Peter E. Böhringer, Stefan van den Akker, Erik B. de Craen, Anton J. M. Rivadeneira, Fernando Uitterlinden, André G. Westendorp, Rudi G. J. Goeman, Jelle J. Slagboom, P. Eline Houwing-Duistermaat, Jeanine J. Beekman, Marian Article 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. Springer Netherlands 2011-11-24 2013-02 /pmc/articles/PMC3543749/ /pubmed/22113349 http://dx.doi.org/10.1007/s11357-011-9340-3 Text en © The Author(s) 2011
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Deelen, Joris Uh, Hae-Won Monajemi, Ramin van Heemst, Diana Thijssen, Peter E. Böhringer, Stefan van den Akker, Erik B. de Craen, Anton J. M. Rivadeneira, Fernando Uitterlinden, André G. Westendorp, Rudi G. J. Goeman, Jelle J. Slagboom, P. Eline Houwing-Duistermaat, Jeanine J. Beekman, Marian
spellingShingle	Deelen, Joris Uh, Hae-Won Monajemi, Ramin van Heemst, Diana Thijssen, Peter E. Böhringer, Stefan van den Akker, Erik B. de Craen, Anton J. M. Rivadeneira, Fernando Uitterlinden, André G. Westendorp, Rudi G. J. Goeman, Jelle J. Slagboom, P. Eline Houwing-Duistermaat, Jeanine J. Beekman, Marian Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
author_facet	Deelen, Joris Uh, Hae-Won Monajemi, Ramin van Heemst, Diana Thijssen, Peter E. Böhringer, Stefan van den Akker, Erik B. de Craen, Anton J. M. Rivadeneira, Fernando Uitterlinden, André G. Westendorp, Rudi G. J. Goeman, Jelle J. Slagboom, P. Eline Houwing-Duistermaat, Jeanine J. Beekman, Marian
author_sort	Deelen, Joris
title	Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
title_short	Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
title_full	Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
title_fullStr	Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
title_full_unstemmed	Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
title_sort	gene set analysis of gwas data for human longevity highlights the relevance of the insulin/igf-1 signaling and telomere maintenance pathways
description	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.
publisher	Springer Netherlands
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3543749/
_version_	1611946575300395008

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

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