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Cited by 142Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchGenetics, Aging, and Longevity in Model Organisms

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An epigenetic predictor of death captures multi-modal measures of brain health

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Hillary, Robert F., Stevenson, Anna J., Cox, Simon R., McCartney, Daniel L., Harris, Sarah E., Seeboth, Anne, Higham, Jon, Sproul, Duncan, Taylor, Adele M., Redmond, Paul, Corley, Janie, Pattie, Alison, Hernández, Maria del. C. Valdés, Muñoz-Maniega, Susana, Bastin, Mark E., Wardlaw, Joanna M., Horvath, Steve, Ritchie, Craig W., Spires-Jones, Tara L., McIntosh, Andrew M., Evans, Kathryn L., Deary, Ian J., Marioni, Riccardo E.·2021·Molecular Psychiatry
DOI 10.1038/s41380-019-0616-9PMC PMC8550950

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Abstract

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed ‘DNAm GrimAge’ has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 ( n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10 −16 ). Higher DNAm GrimAge was associated with lower age 11 IQ ( β = −0.11), lower age 73 general cognitive ability ( β = −0.18), decreased brain volume ( β = −0.25) and increased brain white matter hyperintensities ( β = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.

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Crossref · 10.1038/s41380-019-0616-9

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Figures

Fig. 1 DNAm GrimAge and its component surrogate markers predict mortality in the LBC1936. a Forest plot showing hazard ratios and 95% confidence intervals (horizontal lines) from Cox proportional hazard models for DNAm GrimAge and its constituent DNAm surrogate markers in the LBC1936 (n = 906, no. of deaths = 226 following nine years of follow-up). All associations with the exceptions of DNAm Leptin were significant. b Kaplan–Meier survival curve exhibiting the survival probabilities for the top (highest DNAm GrimAge) and bottom quartiles (lowest DNAm GrimAge) for DNAm GrimAge in the LBC1936 following 9 years of follow-up
Fig. 1 DNAm GrimAge and its component surrogate markers predict mortality in the LBC1936. a Forest plot showing hazard ratios and 95% confidence intervals (horizontal lines) from Cox proportional hazard models for DNAm GrimAge and its constituent DNAm surrogate markers in the LBC1936 (n = 906, no. of deaths = 226 following nine years of follow-up). All associations with the exceptions of DNAm Leptin were significant. b Kaplan–Meier survival curve exhibiting the survival probabilities for the top (highest DNAm GrimAge) and bottom quartiles (lowest DNAm GrimAge) for DNAm GrimAge in the LBC1936 following 9 years of follow-upCC BY · PubMed Central
Fig. 2 Cross-sectional association between age-adjusted DNAm GrimAge and cognitive, neuroimaging and physical traits in the LBC1936. Cognitive: An accelerated DNAm GrimAge was negatively associated with the general factor of cognitive ability, digit symbol coding, symbol search and matrix reasoning tasks. DNAm GrimAge was also associated with an increased mean four choice reaction time. Neuroimaging: Age-adjusted DNAm GrimAge was negatively associated with the ratios of white matter volume, brain volume and grey matter volume to intracranial volume, and positively associated with the ratio of volume of white matter hyperintensities to intracranial volume. Physical: An accelerated DNAm GrimAge was negatively associated with four measures of lung function: forced expiratory volume in 1 s, forced vital capacity, forced expiratory ratio and peak expiratory flow, as well as levels of iron, low-density lipoprotein cholesterol and total cholesterol. Age-adjusted DNAm GrimAge was positively associated with weight, levels of creatinine, body mass index as well as levels of C-reactive protein and interleukin-6. Horizontal lines indiciate 95% confidence intervals. BMI body mass index, CRP C-reactive protein, FCRT four choice reaction time, FER forced expiratory ratio, FEV forced expiratory volume, FVC forced vital capacity, GM grey matter, ICV intracranial volume, IL6 interleukin-6, LDL low-density lipoprotein, PEF peak expiratory flow, WM white matter, WHM white matter hyperintensities
Fig. 2 Cross-sectional association between age-adjusted DNAm GrimAge and cognitive, neuroimaging and physical traits in the LBC1936. Cognitive: An accelerated DNAm GrimAge was negatively associated with the general factor of cognitive ability, digit symbol coding, symbol search and matrix reasoning tasks. DNAm GrimAge was also associated with an increased mean four choice reaction time. Neuroimaging: Age-adjusted DNAm GrimAge was negatively associated with the ratios of white matter volume, brain volume and grey matter volume to intracranial volume, and positively associated with the ratio of volume of white matter hyperintensities to intracranial volume. Physical: An accelerated DNAm GrimAge was negatively associated with four measures of lung function: forced expiratory volume in 1 s, forced vital capacity, forced expiratory ratio and peak expiratory flow, as well as levels of iron, low-density lipoprotein cholesterol and total cholesterol. Age-adjusted DNAm GrimAge was positively associated with weight, levels of creatinine, body mass index as well as levels of C-reactive protein and interleukin-6. Horizontal lines indiciate 95% confidence intervals. BMI body mass index, CRP C-reactive protein, FCRT four choice reaction time, FER forced expiratory ratio, FEV forced expiratory volume, FVC forced vital capacity, GM grey matter, ICV intracranial volume, IL6 interleukin-6, LDL low-density lipoprotein, PEF peak expiratory flow, WM white matter, WHM white matter hyperintensitiesCC BY · PubMed Central
Fig. 3 Cross-sectional association between age-adjusted DNAm GrimAge and regional cortical volume in the LBC1936. Left panel: t values indicate the magnitude of the negative association (values have been flipped for visualisation purposes). An accelerated DNAm GrimAge was negatively associated with cortical volume. Right panel: Corresponding FDR-corrected P values indicate the spatial distribution of significant associations. FDR false discovery rate
Fig. 3 Cross-sectional association between age-adjusted DNAm GrimAge and regional cortical volume in the LBC1936. Left panel: t values indicate the magnitude of the negative association (values have been flipped for visualisation purposes). An accelerated DNAm GrimAge was negatively associated with cortical volume. Right panel: Corresponding FDR-corrected P values indicate the spatial distribution of significant associations. FDR false discovery rateCC BY · PubMed Central

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Cites

Research works printed but not linked: 2

  1. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. · DOI · Paper page
  2. Deary IJ, Gow AJ, Taylor MD, Corley J, Brett C, Wilson V, et al. The Lothian Birth Cohort 1936: a study to examine influences on cognitive ageing from age 11 to age 70 and beyond. BMC Geriatr. 2007;7:28. · DOI

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Metadata

Authors
Hillary, R. F., Stevenson, A. J., Cox, S. R., McCartney, D. L., Harris, S. E., Seeboth, A., Higham, J., Sproul, D., Taylor, A. M., Redmond, P., Corley, J., Pattie, A., Hernández, M. D. C. V., Muñoz-Maniega, S., Bastin, M. E., Wardlaw, J. M., Horvath, S., Ritchie, C. W., Spires-Jones, T. L., McIntosh, A. M., Evans, K. L., Deary, I. J., & Marioni, R. E.
Affiliations
  • University of Edinburgh (GB)
  • Edinburgh Cancer Research (GB)
  • UK Dementia Research Institute (GB)
  • University of California, Los Angeles (US)
  • Institute of Genetics and Cancer (GB)
Corresponding author
Marioni, Riccardo E.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-12-03
Volume
26
Issue
8
Pages
3806-3816
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0616-9
PMC
PMC8550950
OpenAlex
W2993770134
Cited by
139
References
70
Citations by year
2026: 16 · 2025: 26 · 2024: 14 · 2023: 26 · 2022: 22 · 2021: 21 · 2020: 14
FWCI
4.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lancaster EPrints (Lancaster University) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Alzheimer's Research UK (ARUK-PG2017B-10.)
  • Wellcome Trust (108890/Z/15/Z)
  • Fondation Leducq
  • U.S. Department of Health & Human Services | National Institutes of Health (R01AG054628)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
DNA methylation, epigenetic clocks, biological aging, mortality prediction, all-cause mortality, cognitive ability, child intelligence, brain volume, white matter hyperintensities, cognitive decline, Lothian Birth Cohort 1936, brain health
MeSH terms
Birth Cohort, Aged, Aging, Brain, Child, Humans, DNA Methylation, Epigenesis, Genetic, Epigenomics

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