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

Hillary, Robert F.; Stevenson, Anna J.; Cox, Simon R.; McCartney, Daniel L.; Harris, Sarah E.; Seeboth, Anne; Higham, Jonathan; Sproul, Duncan; Taylor, Adele M.; Redmond, Paul; Corley, Janie; Pattie, Alison; Hernández, María del C. Valdés; Muñoz‐Maniega, Susana; Wardlaw, Joanna M.; Horvath, Steve; Ritchie, Craig W.; Spires‐Jones, Tara L.; McIntosh, Andrew M.; Evans, Kathryn; Deary, Ian J.; Marioni, Riccardo E.

doi:10.1101/703504

Cited by 23 publications

(23 citation statements)

References 60 publications

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“…There are several DNA methylation-based biomarkers which are used to measure epigenetic age or epigenetic age acceleration, known as the ‘epigenetic clock’, one of which is ‘DNA methylation GrimAge’ 18. This is a novel epigenetic clock which combines age, sex, DNA methylation-based surrogates for smoking and the levels of seven serum proteins 26. As is the case with other epigenetic clocks, the difference between DNA methylation GrimAge and chronological age—accelerated DNA methylation GrimAge (AgeAccelGrim)—provides a measure of biological ageing.…”

Section: Methodsmentioning

confidence: 99%

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Attitudes to ageing, biomarkers of ageing and mortality: the Lothian Birth Cohort 1936

McLachlan

Cole

Harris

et al. 2020

J Epidemiol Community Health

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Objective To investigate whether people with more positive attitudes to ageing are biologically younger as defined by leucocyte telomere length, accelerated DNA methylation GrimAge (AgeAccelGrim) and brainpredicted age difference, and whether these biomarkers explain relationships between attitudes to ageing and mortality. Methods We used linear regression to examine cross-sectionally attitudes to ageing (measured using the Attitudes to Ageing Questionnaire) and the three biomarkers in 758 adults, mean age 72.5 years, from the Lothian Birth Cohort 1936. We used Cox proportional hazards models to examine longitudinally attitudes to ageing and mortality and the role of the biomarkers. results More positive attitude to physical change was associated with younger biological age, as measured by AgeAccelGrim and brain-predicted age difference in age-adjusted and sex-adjusted models: for an SD higher score, AgeAccelGrim was lower by -0.73 (95% CI -1.03 to -0.42) of a year, and brain-predicted age difference was lower by -0.87 (1.51 to 0.23) of a year. Both associations were attenuated by adjustment for covariates and not significant after simultaneous adjustment for all covariates and correction for multiple testing. More positive attitudes to physical change were associated with lower mortality: for an SD higher score the age-adjusted and sex-adjusted HR (95% CI) was 0.66 (0.56 to 0.78). Adjustment for AgeAccelGrim or brainpredicted age difference attenuated this association slightly. It remained significant after adjustment for all covariates. Conclusion We found partial evidence that attitudes to ageing are linked with ageing biomarkers but they accounted for only a little of the association between attitudes and mortality.

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Section: Methodsmentioning

confidence: 99%

“…This variable was derived by taking residuals from a linear regression model of DNA methylation GrimAge on chronological age. Details of how these data were collected and measured have been reported previously 26–28…”

Section: Methodsmentioning

confidence: 99%

Attitudes to ageing, biomarkers of ageing and mortality: the Lothian Birth Cohort 1936

McLachlan

Cole

Harris

et al. 2020

J Epidemiol Community Health

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“…Epigenetic clocks use weighted linear combinations of CpGs to predict an individual's chronological age and have common SNPbased heritability estimates ranging from 0.15 to 0.19 [8,9]. Individuals with epigenetic clock estimates greater than their chronological age display "age acceleration", and have been shown to be at a greater risk of all-cause mortality and multiple adverse health outcomes [10].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

McCartney¹,

Min²,

Richmond³

et al. 2020

Preprint

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AbstractBiological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

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“…DNAm GrimAge served as a powerful correlate of various phenotypes in our study, and has been previously shown to associate with incident heart disease, time-to-cancer and neurological health (14,20). DNAm GrimAge is derived from chronological age, sex and methylation-based surrogates of smoking pack years and seven plasma proteins (including DNAm-based estimators of plasminogen activator inhibitor 1, growth differentiation factor 15 and cystatin C).…”

Section: Discussionmentioning

confidence: 87%

“…Lower values of age-adjusted DNAm TL are hypothesised to correlate with poorer health as this reflects shorter telomere length. To date, a number of studies have demonstrated associations between epigenetic clocks and risk of mortality and disease states (19)(20)(21)(22), or have provided comparisons of clocks (e.g. HorvathAge vs.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden

Hillary

Stevenson

McCartney

et al. 2020

Preprint

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Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These include methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). In this study, we test the association between these epigenetic markers of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in highincome countries. Furthermore, we test the clocks' relationships with phenotypic measures associated with these conditions, including spirometric and biochemical traits. We carry out these analyses in 9,537 individuals from the Generation Scotland: Scottish Family Health Study. We find that DNAm GrimAge outperforms other epigenetic clocks in its associations with self-report disease prevalence and related clinical traits. DNAm GrimAge associates with chronic obstructive pulmonary disease (COPD) prevalence (Odds Ratio = 3.29, P = 3.0 x 10 -4 ) and pulmonary spirometry tests (β = [-0.10 to -0.15], P = [1.4 x 10 -4 to 1.4 x 10 -6 ]) at study baseline after adjusting for possibly confounding risk factors including alcohol, body mass index, deprivation, education and smoking. After adjusting for these confounding risk factors, DNAm GrimAge, DNAm PhenoAge and DNAm Telomere Length, measured at study baseline, predict incidence of ICD-10-coded disease states including COPD, type 2 diabetes and cardiovascular disease after thirteen years of follow-up (Hazard Ratios = [0.80 (telomere length)to 2.19 (GrimAge)], P = [9.9 x 10 -4 , 1.9 x 10 -14 ]). Our data show that despite accounting for several possible confounding variables, epigenetic markers of ageing predict incidence of common disease.This may have significant implications for their potential utility in clinical settings to complement goldstandard methods of clinical assessment and management.

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

Cited by 23 publications

References 60 publications

Attitudes to ageing, biomarkers of ageing and mortality: the Lothian Birth Cohort 1936

Attitudes to ageing, biomarkers of ageing and mortality: the Lothian Birth Cohort 1936

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden

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