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Cited by 464Genetic Associations and EpidemiologyGenetics, Aging, and Longevity in Model OrganismsGenetics and Physical Performance

Genetic signatures of exceptional longevity in humans

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Sebastiani, Paola, Solovieff, Nadia, DeWan, Andrew T., Walsh, Kyle M., Puca, Annibale, Hartley, Stephen W., Melista, Efthymia, Andersen, Stacy +8 more·2012·PLoS ONE
DOI 10.1371/journal.pone.0029848PMC PMC3261167
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Abstract

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

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  • The APOE ε4 allele is a strong genetic risk factor for Alzheimer disease and is the strongest hit in genome-wide association studies of longevity.

    “the ɛ4 allele is a strong genetic risk factor for Alzheimer disease,20 and by far the strongest hit in genome-wide association studies of longevity.21,22”

    From Plasma levels of apolipoprotein E, <i>APOE</i> genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort (2019) · cites this paper as [21]

    The Results (Single SNP Analysis; page unavailable) identify rs2075650 in the TOMM40/APOE region as the genome-wide-significant longevity hit, and the Discussion calls it the most significantly associated SNP. The paper describes rs2075650 as a proxy for SNPs defining APOE alleles, but does not establish that the ε4 allele itself was the strongest GWAS hit. The Alzheimer disease clause is attached to a different citation. (LLM, conf=0.83)

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Authors
Sebastiani, P., Solovieff, N., DeWan, A. T., Walsh, K. M., Puca, A., Hartley, S. W., Melista, E., Andersen, S., Dworkis, D. A., Wilk, J. B., Myers, R. H., Steinberg, M. H., Montano, M., Baldwin, C. T., Hoh, J., & Perls, T. T.
Affiliations
  • Boston University (US)
  • Yale University (US)
  • MultiMedica (IT)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-01-18
Volume
7
Issue
1
Pages
e29848
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0029848
PMC
PMC3261167
OpenAlex
W2053900484
Cited by
464
References
17
Citations by year
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FWCI
30.07
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health
  • National Institute on Aging (K24AG025727, R01AG027216, U19AG023122)
  • National Heart, Lung, and Blood Institute (R01HL087681)
  • National Institute of Neurological Disorders and Stroke (R01NS036711, R01 NS36711-09)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR055115)
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 › Genetics and Physical Performance
Keywords
exceptional longevity, centenarians, nonagenarians, genetic signatures, genome-wide association study, single nucleotide polymorphisms, genetic risk models, lifespan
MeSH terms
Aged, Aged, 80 and over, Aging, Alleles, Bayes Theorem, Female, Gene Frequency, Genotype, Humans, Longevity, Male, Models, Genetic, Models, Statistical, Cohort Studies, Genome, Human, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide

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