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Cited by 373Genetic Associations and EpidemiologyGenetics, Aging, and Longevity in Model OrganismsGenetic and phenotypic traits in livestock

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A meta-analysis of genome-wide association studies identifies multiple longevity genes

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Deelen, Joris, Evans, Daniel S., Arking, Dan E., Tesi, Niccolò, Nygaard, Marianne, Liu, Xiaomin, Wojczynski, Mary K., Biggs, Mary L., van der Spek, Ashley, Atzmon, Gil, Ware, Erin B., Sarnowski, Chloé, Smith, Albert V., Seppälä, Ilkka, Cordell, Heather J., Dose, Janina, Amin, Najaf, Arnold, Alice M., Ayers, Kristin L., Barzilai, Nir, Becker, Elizabeth J., Beekman, Marian, Blanché, Hélène, Christensen, Kaare, Christiansen, Lene, Collerton, Joanna C., Cubaynes, Sarah, Cummings, Steven R., Davies, Karen, Debrabant, Birgit, Deleuze, Jean-François, Duncan, Rachel, Faul, Jessica D., Franceschi, Claudio, Galan, Pilar, Gudnason, Vilmundur, Harris, Tamara B., Huisman, Martijn, Hurme, Mikko A., Jagger, Carol, Jansen, Iris, Jylhä, Marja, Kähönen, Mika, Karasik, David, Kardia, Sharon L. R., Kingston, Andrew, Kirkwood, Thomas B. L., Launer, Lenore J., Lehtimäki, Terho, Lieb, Wolfgang, Lyytikäinen, Leo-Pekka, Martin-Ruiz, Carmen, Min, Junxia, Nebel, Almut, Newman, Anne B., Nie, Chao, Nohr, Ellen A., Orwoll, Eric S., Perls, Thomas T., Province, Michael A., Psaty, Bruce M., Raitakari, Olli T., Reinders, Marcel J. T., Robine, Jean-Marie, Rotter, Jerome I., Sebastiani, Paola, Smith, Jennifer, Sørensen, Thorkild I. A., Taylor, Kent D., Uitterlinden, André G., van der Flier, Wiesje, van der Lee, Sven J., van Duijn, Cornelia M., van Heemst, Diana, Vaupel, James W., Weir, David, Ye, Kenny, Zeng, Yi, Zheng, Wanlin, Holstege, Henne, Kiel, Douglas P., Lunetta, Kathryn L., Slagboom, P. Eline, Murabito, Joanne M.·2019·Nature Communications
DOI 10.1038/s41467-019-11558-2PMC PMC6694136
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Abstract

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78 , associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

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Fig. 1 Results of the European genome-wide association meta-analyses. Manhattan plot presenting the –log10 P-values from the European genome-wide association meta-analysis of the 90th percentile cases versus all controls (a) and 99th percentile cases versus all controls (b). The red line indicates the threshold for genome-wide significance (P ≤ 5 × 10−8), while the blue line indicates the threshold for genetic variants that showed a suggestive significant association (P ≤ 1 × 10−6). The variants that are reported in Table 2 are highlighted in green. For representation purposes, the maximum of the y-axis was set to 14. Regional association plot for the APOE (c) and GPR78 (d) loci based on the results from the 90th percentile cases versus all controls meta-analysis. The colour of the variants is based on the linkage disequilibrium with rs429358 (ApoE ε4) (c) or rs7676745 (d)
Fig. 1 Results of the European genome-wide association meta-analyses. Manhattan plot presenting the –log10 P-values from the European genome-wide association meta-analysis of the 90th percentile cases versus all controls (a) and 99th percentile cases versus all controls (b). The red line indicates the threshold for genome-wide significance (P ≤ 5 × 10−8), while the blue line indicates the threshold for genetic variants that showed a suggestive significant association (P ≤ 1 × 10−6). The variants that are reported in Table 2 are highlighted in green. For representation purposes, the maximum of the y-axis was set to 14. Regional association plot for the APOE (c) and GPR78 (d) loci based on the results from the 90th percentile cases versus all controls meta-analysis. The colour of the variants is based on the linkage disequilibrium with rs429358 (ApoE ε4) (c) or rs7676745 (d)CC BY · PubMed Central
Fig. 2 Study-specific results for the genetic variants in APOE and GPR78. Forest plots for the ApoE ε4 (a) and ε2 (b) variants and rs7676745 (c) based on the results from the 90th percentile versus all controls analysis. The size of the boxes represents the sample size of the cohort. We had no data available for ApoE ε4 in LLFS and for rs7676745 in DKLS, GEHA Italy, GEHA Danish, LLS (combined with GEHA Dutch), Longevity, and Newcastle 85 + . The data for ApoE ε2 in FHS was based on imputation using the Haplotype Reference Consortium reference panel due to the low-imputation quality of this variant when using the 1000 Genomes reference panel
Fig. 2 Study-specific results for the genetic variants in APOE and GPR78. Forest plots for the ApoE ε4 (a) and ε2 (b) variants and rs7676745 (c) based on the results from the 90th percentile versus all controls analysis. The size of the boxes represents the sample size of the cohort. We had no data available for ApoE ε4 in LLFS and for rs7676745 in DKLS, GEHA Italy, GEHA Danish, LLS (combined with GEHA Dutch), Longevity, and Newcastle 85 + . The data for ApoE ε2 in FHS was based on imputation using the Haplotype Reference Consortium reference panel due to the low-imputation quality of this variant when using the 1000 Genomes reference panelCC BY · PubMed Central
Fig. 3 Results of the trans-ethnic genome-wide association meta-analyses. Manhattan plot presenting the –log10 P-values from the trans-ethnic genome-wide association meta-analysis of the 90th percentile cases versus all controls (a) and 99th percentile cases versus all controls (b). The red line indicates the threshold for genome-wide significance (P ≤ 5 × 10−8), while the blue line indicates the threshold for genetic variants that showed a suggestive significant association (P ≤ 1 × 10−6)
Fig. 3 Results of the trans-ethnic genome-wide association meta-analyses. Manhattan plot presenting the –log10 P-values from the trans-ethnic genome-wide association meta-analysis of the 90th percentile cases versus all controls (a) and 99th percentile cases versus all controls (b). The red line indicates the threshold for genome-wide significance (P ≤ 5 × 10−8), while the blue line indicates the threshold for genetic variants that showed a suggestive significant association (P ≤ 1 × 10−6)CC BY · PubMed Central

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  1. Oeppen, J. & Vaupel, J. W. Demography. Broken limits life Expect. Sci. 296, 1029–1031 (2002).

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Authors
Deelen, J., Evans, D. S., Arking, D. E., Tesi, N., Nygaard, M., Liu, X., Wojczynski, M. K., Biggs, M. L., van der Spek, A., Atzmon, G., Ware, E. B., Sarnowski, C., Smith, A. V., Seppälä, I., Cordell, H. J., Dose, J., Amin, N., Arnold, A. M., Ayers, K. L., Barzilai, N., Becker, E. J., Beekman, M., Blanché, H., Christensen, K., Christiansen, L., Collerton, J. C., Cubaynes, S., Cummings, S. R., Davies, K., Debrabant, B., Deleuze, J.-F., Duncan, R., Faul, J. D., Franceschi, C., Galan, P., Gudnason, V., Harris, T. B., Huisman, M., Hurme, M. A., Jagger, C., Jansen, I., Jylhä, M., Kähönen, M., Karasik, D., Kardia, S. L. R., Kingston, A., Kirkwood, T. B. L., Launer, L. J., Lehtimäki, T., Lieb, W., Lyytikäinen, L.-P., Martin-Ruiz, C., Min, J., Nebel, A., Newman, A. B., Nie, C., Nohr, E. A., Orwoll, E. S., Perls, T. T., Province, M. A., Psaty, B. M., Raitakari, O. T., Reinders, M. J. T., Robine, J.-M., Rotter, J. I., Sebastiani, P., Smith, J., Sørensen, T. I. A., Taylor, K. D., Uitterlinden, A. G., van der Flier, W., van der Lee, S. J., van Duijn, C. M., van Heemst, D., Vaupel, J. W., Weir, D., Ye, K., Zeng, Y., Zheng, W., Holstege, H., Kiel, D. P., Lunetta, K. L., Slagboom, P. E., & Murabito, J. M.
Affiliations
  • Leiden University (NL)
  • California Pacific Medical Center (US)
  • Johns Hopkins University (US)
  • University of Southern Denmark (DK)
  • BGI Group (China) (CN)
  • Washington University in St. Louis (US)
  • University of Washington (US)
  • Albert Einstein College of Medicine (US)
  • University of Michigan (US)
  • Boston University (US)
  • Tampere University (FI)
  • Centre for Life (GB)
  • Christian-Albrechts-Universität zu Kiel (DE)
  • Erasmus MC (NL)
  • Sema4 (United States) (US)
  • Fondation Jean Dausset-CEPH (FR)
  • Royal Victoria Infirmary (GB)
  • Inserm (FR)
  • Newcastle University (GB)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
  • Istituto delle Scienze Neurologiche di Bologna (IT)
  • University of Iceland (IS)
  • National Institutes of Health (US)
  • Amsterdam Public Health (NL)
  • Amsterdam Neuroscience (NL)
  • Bar-Ilan University (IL)
  • Zhejiang University (CN)
  • University of Pittsburgh (US)
  • Oregon Health & Science University (US)
  • Kaiser Permanente Washington Health Research Institute (US)
  • University of Turku (FI)
  • Delft University of Technology (NL)
  • Centre National de la Recherche Scientifique (FR)
  • The Lundquist Institute (US)
  • University of Copenhagen (DK)
  • University of California, Los Angeles (US)
  • Max Planck Institute for Demographic Research (DE)
  • Duke University (US)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Broad Institute (US)
Corresponding author
  • Deelen, Joris
  • Evans, Daniel S.
  • Slagboom, P. Eline
  • Murabito, Joanne M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-08-14
Volume
10
Issue
1
Pages
3669-3669
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-11558-2
PMC
PMC6694136
OpenAlex
W2967338832
Cited by
370
References
61
Citations by year
2026: 38 · 2025: 64 · 2024: 56 · 2023: 60 · 2022: 51 · 2021: 53 · 2020: 44 · 2019: 3
FWCI
5.07
Type
journal article
Language
en
Update notices
correction (2021-04-23)
Open access
Licence
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  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • VU Research Portal (publishedVersion, other-oa)
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  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
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  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
  • Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
  • Research Repository (Delft University of Technology) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by)
Funders
Alexander von Humboldt-Stiftung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
human longevity, longevity genes, apolipoprotein E, APOE ε4, APOE ε2, tissue-specific gene expression, genetic correlation, heritability of longevity, genetic overlap
MeSH terms
Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, Humans, Longevity, Apolipoprotein E4, Apolipoprotein E2, Genome-Wide Association Study

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