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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 manner90–94.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [92]
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“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]
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“This is aligned with previous findings and reinforces the hypothesis that disease risk reduces lifespan via shared biological pathways45–47.”
From Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans (2026) · cites this paper as [46]
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“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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“Although GWASs for longevity yielded a considerable sparsity of novel locus conferring survival (11), there is one exception.”
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Heritability of human lifespan is about 50% when confounding factors are addressedPreprint
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“As with many polygenic traits studied through genome-wide association studies (GWAS), only a limited number of loci have been definitively linked to exceptional longevity, explaining only a fraction of the heritability indicated by twin studies 1,3 .”
Self-citationGenetic links between multimorbidity and human aging
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German longevity study reveals novel rare pro-longevity alleles clustering in mTOR signaling pathway
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“Surprisingly, the number of associations that have been confirmed across multiple studies and populations has been limited to only a few variants, such as those in APOE and FOXO3 , that explain only a small fraction of the total heritability of longevity [6, 7].”
Self-citationSUDEP risk is influenced by longevity genomics: a polygenic risk score study
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“16 The GWAS for longevity has shown genome-wide significant single SNP associations for rs429358 variant (apolipoprotein E (ApoE) ε 4, associated with decreased odds of surviving to the 90th and 99th percentile age), and rs7412 (ApoE ε 2, associated with the opposite effect).”
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“The study of very long-lived individuals aims to improve the knowledge of the genetic [5], environmental [6] and lifestyle factors associated with increased survival and quality of life [7, 8], which should guide actions addressing the health and social problems affecting this population.”
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Self-citationDynamics of genetic and somatic trade-offs in ageing and mortality
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“According to a genome-wide association (GWA) study, the APOE rs429358 polymorphism (APOE ε4 allele) is significantly associated with a reduced risk of longevity (29).”
BackgroundThe Human Genome, Physical Activity, Fitness, and Health
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“To identify genetic variation associated with human lifespan, research has focused on specific candidate genes and more recently common variant genome-wide association studies (GWAS) (Broer et al., 2015; Deelen et al., 2014; Deelen et al., 2019; Joshi et al., 2017; Pilling et al., 2017; Sebastiani et al., 2017; Zeng e…”
BackgroundSelf-citationGenetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageingPreprint
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“In contrast, most complex diseases were negatively correlated with longevity, consistent with earlier findings (Timmers et al. 2019; Deelen et al. 2019; Hu et al. 2022) and supporting the idea that disease risk undermines lifespan through shared biological pathways.”
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Statistical Inference for High Dimensional Regression with Proxy Data
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“It is crucial in PRS prediction to provide confidence intervals for Besides, summary data provide the opportunity to combine multiple studies (e.g., cohorts) into one large study to increase the sample size (Albi ˜ nana et al., 2021), which is the goal of meta-analysis (Deelen et al., 2019).”
MethodGuan, C., Otchere, A., Laskovs, M., Papatheodorou, I., & Slack, C. (2025) · Aging Cell · doi:10.1111/acel.14500 · Cited by 1
“…nucleotide polymorphisms (SNPs) that modify the activity or expression of GPCRs, including the dopamine 2 receptor and AT1a receptor, appear more frequently in people with extreme longevity such as centenarians or supercentenarians (Benigni et al. 2013; Crocco et al. 2016; Deelen et al. 2019).”
A life course approach to multimorbidity and healthy ageing
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“Controls comprised individuals who either died at or before reaching the age corresponding to the 60 th survival percentile in these life tables or whose last recorded follow-up occurred on or before reaching this age [23].”
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“For example, research has found moderate genetic correlations among longevity, (lack of) drug use, and medication adherence (Cordioli et al. 2024, Deelen et al. 2019).”
Cai, Z., Yang, Y., Qu, P., Fu, S., & Li, X. (2025) · Journal of Global Health · doi:10.7189/jogh.15.04279 · Cited by 1
“…European, East Asian, and African American populations, with cases defined as individuals exceeding the 90th survival percentiles (n = 11 262) – criteria derived from standardised life table analyses – while 25 483 participants below the 60th percentile were designated as controls [ 38 ].”
The APOE ε4 allele affects the survival of patients with Parkinson's disease independent of dementia
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“…for PD susceptibility and progression have been identified [21, 35–37, 42– 47 ], the only few genetic However, it is well-known that GWAS focusing on longevity and survival in the general population have consistently identified rs429358 ( APOE ε4) as the strongest risk genetic factor [49, 50].”
Genetic determinants of gene expression noise and its role in complex trait variation
Long, Y., Ni, X., Chen, T.-W., Huang, X., Hong, Q., Wang, J., Wang, C., Huang, Z., Xu, H., Sun, M., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116612 · Cited by 1
Lee, E.-G., Leong, L., Chen, S., Tulloch, J., & Yu, C. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010302 · Cited by 1
“These alleles are associated with diverse conditions, including aging/longevity [1,2], Alzheimer’s disease (AD) [3], coronary artery disease [4], diabetes [5], fragile X-associated ataxia [6], glomerulopathy [7], Lewy body dementia [8], metabolic syndrome [9], retinal-related disorders [10],…”
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“We also applied a PRS associated with longevity [27] with 4 matched variants, as we did previously for coronary artery event prediction in PWH (S1 Table) [14].”
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ProtPhenoAge: Integrating plasma proteomics to predict Aging-Related disease Risks
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“org) and the Human Genotyping Unit at the Spanish National Cancer Research Center (GU-CNIO) in Madrid, (1) to describe the health of the regional population aged ≥95, (2) to identify the environment and life-style factors associated with their health status and quality of life, (3) to confirm/rule out already describe…”
BackgroundGlotov, O., Chernov, A., Fedyakov, M., Larionova, V., Zaretsky, A., Donnikov, M., & Glotov, A. (2022) · Biological Communications · doi:10.21638/spbu03.2022.403 · Cited by 2
Genetics of rearing success in four pure laying hen lines during the first 17 weeks of age
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CNS resilience in the progression of MS
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Brain Structural Covariances in the Ageing Brain in the UK Biobank
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“Longevity GWAS (Deelen et al., 2019) summary statistics were downloaded from the GWAS Catalog (https://www.”
MethodBierhoff, H. (2024) · Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz · doi:10.1007/s00103-024-03873-x · Cited by 1
Genetics of healthy aging and longevity
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Long-term effects of APOEε4 on mortality
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SNP rs6543176 is associated with extreme human longevity but increased risk for cancer
Gurinovich, A., Song, Z., Bae, H. T., Leshchyk, A., Li, M., Lords, H. J., Andersen, S. L., Nygaard, M., Christensen, K., Daw, E. W., et al. (2025) · GeroScience · doi:10.1007/s11357-024-01478-5 · Cited by 1
“While genome-wide association studies have identified several longevity-associated variants [10, 11], these studies are limited to relatively common variants.”
Self-citationIntegrative genetic analysis to decode the causal effect of air pollution on accelerated aging
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Toward a Systematic Understanding of Epigenetic Contribution to Normal Aging and Alzheimer’s Disease
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Separating the Effects of Adiposity Across Different Life Stages on Human Longevity and Aging
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“Summary statistics for longevity were obtained from a longevity genomics consortium, where longevity was defined as an age > 90th survival percentile (Deelen et al. 2019).”
Who is Responsible for Aging: Life Style or Genetics or Both?
Gupta, P. (2021) · Journal of Aging Science · doi:10.35248/2329-8847.21.9.247 · Cited by 1
“, the heritability is responsible for increase in human lifespan is only about 25%, [14].”
BackgroundCancer Diagnosis, Polygenic Risk, and Longevity-Associated VariantsPreprint
Goetz, L. H., Don, J., Schork, A. J., Duggan, D. J., Price, N. D., Evans, D. S., Cummings, S., Perls, T. T., Sebastiani, P., & Schork, N. J. (2020) · medRxiv · doi:10.1101/2020.09.18.20197475 · Cited by 1
“Since many published studies provide evidence that genetic variants exist that predispose to a long life,(30,31,34) a good question concerns the degree to which such variants are absent from cancer PRS, or whether the possession of longevity-enhancing variants protects individuals against the deleterious effects of ha…”
BackgroundInfluentialSelf-citationVesicle-bound regulatory RNAs are associated with tissue agingPreprint
Kern, F., Kuhn, T., Ludwig, N., Simon, M. C., Gröger, L., Fabis, N., Salhab, A., Fehlmann, T., Hahn, O., Engel, A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.07.443093 · Cited by 1
Sobczyk, M. K., & Gaunt, T. R. (2023) · medRxiv · doi:10.1101/2023.10.02.23296427 · Cited by 1
Xiao, S., Kaushik, P., Du, G., Liu, B., Hosawi, S. B. I., Hastoy, B., Argentieri, M. A., Winchester, L. M., Nevado‐Holgado, A. J., Kaddurah‐Daouk, R., et al. (2025) · medRxiv · doi:10.1101/2025.10.30.25339071 · Cited by 1
Self-citationResilience to dominant genetic disease in the healthy elderlyPreprint
Lacaze, P. A., Sebra, R., Riaz, M., Tiller, J. M., Revote, J., Phung, J., Parker, E. J., Orchard, S. G., Lockery, J. E., Wolfe, R. S., et al. (2019) · medRxiv · doi:10.1101/19006932
A joint analysis of longevity and age-related disease variants for gene expression associationPreprint
Zeng, L., Peng, S., Kim, S., Zhu, J., Zhang, B., Suh, Y., & Tu, Z. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.25.428082 · Cited by 1
Metadata
- 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
- 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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