Dataset Information

DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.

ABSTRACT: BACKGROUND:DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples. RESULTS:Here, we showed an association between age and log10-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, ? = 0.0091, p < 2 × 10-16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, ? = 0.033, p = 7.9 × 10-4) and 1936 (N = 898, ? = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log10-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HRmeta = 1.12; 95% CImeta = [1.02; 1.21]; pmeta = 0.021). CONCLUSIONS:These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.

SUBMITTER: Seeboth A

PROVIDER: S-EPMC7098133 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.

Seeboth Anne A McCartney Daniel L DL Wang Yunzhang Y Hillary Robert F RF Stevenson Anna J AJ Walker Rosie M RM Campbell Archie A Evans Kathryn L KL McIntosh Andrew M AM Hägg Sara S Deary Ian J IJ Marioni Riccardo E RE

Clinical epigenetics 20200326 1

<h4>Background</h4>DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples.<h4>Result ...[more]

PMID: 32216821

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Project description:[Correction Notice: An Erratum for this article was reported online in Psychology and Aging on Mar 5 2020 (see record 2020-16850-001). This article should have been published under the terms of the Creative Commons Attribution License (CC BY 3.0). Therefore, the article was amended to list the authors as copyright holders, and information about the terms of the CC BY 3.0 was added to the author note. In addition, the article is now open access. All versions of this article have been corrected.] It is unclear how scores on self-report resilience scales relate to key ageing-related domains in older age and if they truly measure resilience. We examined antecedents and outcomes of age-76 Brief Resilience Scale (BRS) scores in participants of the Lothian Birth Cohort 1936 (n = 655). We found bivariate associations between age-76 BRS scores and ageing-relevant antecedent variables measured at least 3 years earlier, from domains of cognitive ability, physical fitness, and wellbeing and, additionally, sociodemographics and personality (absolute r's from .082 to .49). Biological health variables were not associated with BRS scores. Age-73 cognitive ability (largest β = 0.14), physical fitness (largest β = 0.084), and wellbeing variables (largest β = 0.26) made positive independent contributions to age-76 BRS scores in multivariate models. In a conservative model including all variables as covariates, corrected for multiple comparisons, only emotional stability (neuroticism) significantly independently contributed to BRS score (β = 0.33). An exploratory backward elimination model indicated more wellbeing and personality associates of BRS scores (βs from .087 to .32). We used latent difference score modeling to assess outcomes of BRS scores; we examined associations between age-76 BRS and change in latent factors of age-related domains between age 76 and 79. Whereas BRS scores were related cross-sectionally to levels of latent cognitive ability (r = .19), physical fitness (r = .20), and wellbeing (r = .60) factors, they were not related to declines in these domains. The independence of the BRS construct from established wellbeing and personality factors is unclear. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Project description:BACKGROUND:Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia. METHODS:Study subjects (n =?488) were members of the Lothian Birth Cohort 1921. Dementia case ascertainment used data from death certificates, electronic hospital records, and clinical reviews. Venous blood samples were taken at baseline, at age 79?years. DNA methylation and measures of epigenetic age were calculated in accordance with Horvath's epigenetic clock tutorial, using the online calculator (https://dnamage.genetics.ucla.edu/). From these values, four measures of accelerated ageing were calculated: extrinsic epigenetic age acceleration (EEAA), intrinsic epigenetic age acceleration (IEAA), AgeAccelPheno and AgeAccelGrim. Competing risk regression models - with death as a competing risk - were performed to examine the association between each measure of accelerated ageing and incident dementia. APOE ?4 status, sex, age, smoking status, history of cardiovascular disease, cerebrovascular disease, hypertension, and diabetes were included as covariates. RESULTS:None of the multivariate models revealed a positive association between increased epigenetic age acceleration and dementia risk. Across all included models, never-smoking increased risk for dementia (HR 1.69 [1.06, 2.71], p =?0.03), and having no APOE ?4 alleles reduced risk for dementia (HR 0.44 [0.29, 0.67], p <?0.001). CONCLUSIONS:The present study did not demonstrate any consistent association between DNA methylation-based measures of accelerated ageing and dementia in subjects aged over 79?years. Further, larger studies - including separate analyses of dementia subtypes - are required to further investigate the potential association between DNA methylation-based measures of accelerated ageing and dementia.

Dataset Information

DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.

Publications

DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936.

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