GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy

Linda Broer, Aron S. Buchman, Joris Deelen, Daniel S. Evans, Jessica D. Faul, Kathryn L. Lunetta, Paola Sebastiani, Jennifer A. Smith, Albert V. Smith, Toshiko Tanaka, Lei Yu, Alice M. Arnold, Thor Aspelund, Emelia J. Benjamin, Philip L. De Jager, Gudny Eirkisdottir, Denis A. Evans, Melissa E. Garcia, Albert Hofman, Robert C. KaplanSharon L.R. Kardia, Douglas P. Kiel, Ben A. Oostra, Eric S. Orwoll, Neeta Parimi, Bruce M. Psaty, Fernando Rivadeneira, Jerome I. Rotter, Sudha Seshadri, Andrew Singleton, Henning Tiemeier, André G. Uitterlinden, Wei Zhao, Stefania Bandinelli, David A. Bennett, Luigi Ferrucci, Vilmundur Gudnason, Tamara B. Harris, David Karasik, Lenore J. Launer, Thomas T. Perls, P. Eline Slagboom, Gregory J. Tranah, David R. Weir, Anne B. Newman, Cornelia M. Van Duijn, Joanne M. Murabito

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

Background. The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies. Methods. We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity. Results. In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10-7) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10-8) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10-10). Conclusions. We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume70
Issue number1
DOIs
StatePublished - Jan 1 2015

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Keywords

  • APOE
  • FOXO3
  • GWAS
  • Longevity

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

Broer, L., Buchman, A. S., Deelen, J., Evans, D. S., Faul, J. D., Lunetta, K. L., Sebastiani, P., Smith, J. A., Smith, A. V., Tanaka, T., Yu, L., Arnold, A. M., Aspelund, T., Benjamin, E. J., De Jager, P. L., Eirkisdottir, G., Evans, D. A., Garcia, M. E., Hofman, A., ... Murabito, J. M. (2015). GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 70(1), 110-118. https://doi.org/10.1093/gerona/glu166