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. Kaplan & 27 others Sharon 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

114 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Odds Ratio
Single Nucleotide Polymorphism
Genome
Genes
Survival

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., ... 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

GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. / Broer, Linda; Buchman, Aron S.; Deelen, Joris; Evans, Daniel S.; Faul, Jessica D.; Lunetta, Kathryn L.; Sebastiani, Paola; Smith, Jennifer A.; Smith, Albert V.; Tanaka, Toshiko; Yu, Lei; Arnold, Alice M.; Aspelund, Thor; Benjamin, Emelia J.; De Jager, Philip L.; Eirkisdottir, Gudny; Evans, Denis A.; Garcia, Melissa E.; Hofman, Albert; Kaplan, Robert C.; Kardia, Sharon L.R.; Kiel, Douglas P.; Oostra, Ben A.; Orwoll, Eric S.; Parimi, Neeta; Psaty, Bruce M.; Rivadeneira, Fernando; Rotter, Jerome I.; Seshadri, Sudha; Singleton, Andrew; Tiemeier, Henning; Uitterlinden, André G.; Zhao, Wei; Bandinelli, Stefania; Bennett, David A.; Ferrucci, Luigi; Gudnason, Vilmundur; Harris, Tamara B.; Karasik, David; Launer, Lenore J.; Perls, Thomas T.; Eline Slagboom, P.; Tranah, Gregory J.; Weir, David R.; Newman, Anne B.; Van Duijn, Cornelia M.; Murabito, Joanne M.

In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 70, No. 1, 01.01.2015, p. 110-118.

Research output: Contribution to journalArticle

Broer, L, Buchman, AS, Deelen, J, Evans, DS, Faul, JD, Lunetta, KL, Sebastiani, P, Smith, JA, Smith, AV, Tanaka, T, Yu, L, Arnold, AM, Aspelund, T, Benjamin, EJ, De Jager, PL, Eirkisdottir, G, Evans, DA, Garcia, ME, Hofman, A, Kaplan, RC, Kardia, SLR, Kiel, DP, Oostra, BA, Orwoll, ES, Parimi, N, Psaty, BM, Rivadeneira, F, Rotter, JI, Seshadri, S, Singleton, A, Tiemeier, H, Uitterlinden, AG, Zhao, W, Bandinelli, S, Bennett, DA, Ferrucci, L, Gudnason, V, Harris, TB, Karasik, D, Launer, LJ, Perls, TT, Eline Slagboom, P, Tranah, GJ, Weir, DR, Newman, AB, Van Duijn, CM & Murabito, JM 2015, 'GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 70, no. 1, pp. 110-118. https://doi.org/10.1093/gerona/glu166
Broer, Linda ; Buchman, Aron S. ; Deelen, Joris ; Evans, Daniel S. ; Faul, Jessica D. ; Lunetta, Kathryn L. ; Sebastiani, Paola ; Smith, Jennifer A. ; Smith, Albert V. ; Tanaka, Toshiko ; Yu, Lei ; Arnold, Alice M. ; Aspelund, Thor ; Benjamin, Emelia J. ; De Jager, Philip L. ; Eirkisdottir, Gudny ; Evans, Denis A. ; Garcia, Melissa E. ; Hofman, Albert ; Kaplan, Robert C. ; Kardia, Sharon L.R. ; Kiel, Douglas P. ; Oostra, Ben A. ; Orwoll, Eric S. ; Parimi, Neeta ; Psaty, Bruce M. ; Rivadeneira, Fernando ; Rotter, Jerome I. ; Seshadri, Sudha ; Singleton, Andrew ; Tiemeier, Henning ; Uitterlinden, André G. ; Zhao, Wei ; Bandinelli, Stefania ; Bennett, David A. ; Ferrucci, Luigi ; Gudnason, Vilmundur ; Harris, Tamara B. ; Karasik, David ; Launer, Lenore J. ; Perls, Thomas T. ; Eline Slagboom, P. ; Tranah, Gregory J. ; Weir, David R. ; Newman, Anne B. ; Van Duijn, Cornelia M. ; Murabito, Joanne M. / GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2015 ; Vol. 70, No. 1. pp. 110-118.
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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.",
keywords = "APOE, FOXO3, GWAS, Longevity",
author = "Linda Broer and Buchman, {Aron S.} and Joris Deelen and Evans, {Daniel S.} and Faul, {Jessica D.} and Lunetta, {Kathryn L.} and Paola Sebastiani and Smith, {Jennifer A.} and Smith, {Albert V.} and Toshiko Tanaka and Lei Yu and Arnold, {Alice M.} and Thor Aspelund and Benjamin, {Emelia J.} and {De Jager}, {Philip L.} and Gudny Eirkisdottir and Evans, {Denis A.} and Garcia, {Melissa E.} and Albert Hofman and Kaplan, {Robert C.} and Kardia, {Sharon L.R.} and Kiel, {Douglas P.} and Oostra, {Ben A.} and Orwoll, {Eric S.} and Neeta Parimi and Psaty, {Bruce M.} and Fernando Rivadeneira and Rotter, {Jerome I.} and Sudha Seshadri and Andrew Singleton and Henning Tiemeier and Uitterlinden, {Andr{\'e} G.} and Wei Zhao and Stefania Bandinelli and Bennett, {David A.} and Luigi Ferrucci and Vilmundur Gudnason and Harris, {Tamara B.} and David Karasik and Launer, {Lenore J.} and Perls, {Thomas T.} and {Eline Slagboom}, P. and Tranah, {Gregory J.} and Weir, {David R.} and Newman, {Anne B.} and {Van Duijn}, {Cornelia M.} and Murabito, {Joanne M.}",
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T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy

AU - Broer, Linda

AU - Buchman, Aron S.

AU - Deelen, Joris

AU - Evans, Daniel S.

AU - Faul, Jessica D.

AU - Lunetta, Kathryn L.

AU - Sebastiani, Paola

AU - Smith, Jennifer A.

AU - Smith, Albert V.

AU - Tanaka, Toshiko

AU - Yu, Lei

AU - Arnold, Alice M.

AU - Aspelund, Thor

AU - Benjamin, Emelia J.

AU - De Jager, Philip L.

AU - Eirkisdottir, Gudny

AU - Evans, Denis A.

AU - Garcia, Melissa E.

AU - Hofman, Albert

AU - Kaplan, Robert C.

AU - Kardia, Sharon L.R.

AU - Kiel, Douglas P.

AU - Oostra, Ben A.

AU - Orwoll, Eric S.

AU - Parimi, Neeta

AU - Psaty, Bruce M.

AU - Rivadeneira, Fernando

AU - Rotter, Jerome I.

AU - Seshadri, Sudha

AU - Singleton, Andrew

AU - Tiemeier, Henning

AU - Uitterlinden, André G.

AU - Zhao, Wei

AU - Bandinelli, Stefania

AU - Bennett, David A.

AU - Ferrucci, Luigi

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Karasik, David

AU - Launer, Lenore J.

AU - Perls, Thomas T.

AU - Eline Slagboom, P.

AU - Tranah, Gregory J.

AU - Weir, David R.

AU - Newman, Anne B.

AU - Van Duijn, Cornelia M.

AU - Murabito, Joanne M.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - APOE

KW - FOXO3

KW - GWAS

KW - Longevity

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DO - 10.1093/gerona/glu166

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EP - 118

JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences

SN - 1079-5006

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