A meta-analysis of genome-wide association studies identifies multiple longevity genes
Open accessAbstract
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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Several studies of large populations of individuals from European ancestry have raised the possibility that APOE is a longevity gene, with the APOEε2 variant associated with longer survival and the APOEε4 with shorter survival in a dose-dependent manner.
“Several studies of large populations of individuals from European ancestry have raised the possibility that APOE is a longevity gene, with the APOEε2 variant associated with longer survival and the APOEε4 with shorter survival in a dose-dependent manner90–94.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [92]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAPOE2 carriers trended towards better survival in patients with low risk of melanoma-associated death.
“In contrast, APOE2 carriers trended towards better survival in patients with low risk of melanoma-associated death (Extended Data Fig. 9c–g), consistent with the known association of APOE2 with enhanced lifespan in the general population24.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [24]
Genes that regulate lifespan in animal models and human studies, and multiple experimental paradigms, have demonstrated that it is possible to manipulate ageing biology to rejuvenate physiological functioning in complex model organisms.
“Genes that regulate lifespan in animal models6–9 and human studies10–14 as well as multiple experimental paradigms, such as caloric restriction, heterochronic parabiosis and partial epigenetic reprogramming, have demonstrated that it is possible to manipulate ageing biology to ‘rejuvenate’ physiological functioning in complex model organisms15–28.”
From Measuring biological age using omics data (2022) · cites this paper as [12]
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Song, Z., Li, W., Jin, X., Ying, J., Zhang, X., Song, Y., Li, H., & Fan, Q. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114271119 · Cited by 22 · see citing works
- 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
- Deelen, Joris
- Evans, Daniel S.
- Arking, Dan E.
- Tesi, Niccolò
- Nygaard, Marianne
- Liu, Xiaomin
- Wojczynski, Mary K.
- 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
- Beekman, Marian
- Blanché, Hélène
- Christensen, Kaare
- Christiansen, Lene
- 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
- Kingston, Andrew
- Kirkwood, Thomas B. L.
- Launer, Lenore J.
- Lehtimäki, Terho
- Lieb, Wolfgang
- Lyytikäinen, Leo-Pekka
- Martin-Ruiz, Carmen
- Min, Junxia
- 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.
- Smith, Jennifer
- Sørensen, Thorkild I. A.
- Taylor, Kent D.
- Uitterlinden, André G.
- van der Lee, Sven J.
- Vaupel, James W.
- Weir, David
- Ye, Kenny
- Zheng, Wanlin
- Holstege, Henne
- Kiel, Douglas P.
- Lunetta, Kathryn L.
- Slagboom, P. Eline
- Murabito, Joanne M.
- Venue
- Nature Communications
- Published
- 2019-08-14
- Volume
- 10
- Issue
- 1
- Pages
- 3669-3669
- ISSN
- 2041-1723 (ISSN-L)
- 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 · 2018: 1
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-23)
- Open access
- gold
- doi.org
- Locations
- 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)
- HAL (submittedVersion, cc-by)
- Opin vísindi (Opin vísindi) (submittedVersion, cc-by-nc-sa)
- UTUPub (University of Turku) (submittedVersion)
- UTUPub (University of Turku) (submittedVersion, cc-by)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- 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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