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

Springer Science and Business Media LLC - Tập 35 - Trang 235-249 - 2011
Joris Deelen1,2, Hae-Won Uh2,3, Ramin Monajemi3, Diana van Heemst4, Peter E. Thijssen1,5, Stefan Böhringer3, Erik B. van den Akker1,6, Anton J. M. de Craen4, Fernando Rivadeneira7,8, André G. Uitterlinden2,7,8, Rudi G. J. Westendorp2,4, Jelle J. Goeman3, P. Eline Slagboom1,2, Jeanine J. Houwing-Duistermaat3, Marian Beekman1,2
1Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
2Netherlands Consortium for Healthy Ageing, Leiden University Medical Center, Leiden, The Netherlands
3Section of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
4Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
5Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
6Department of Mediamatics, Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
7Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
8Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Tóm tắt

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.

Tài liệu tham khảo

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