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Abstract
BACKGROUND: Epigenetic age (EA) is an age estimate, developed using DNA methylation (DNAm) states of selected CpG sites across the genome. Although EA and chronological age are highly correlated, EA may not increase uniformly with time. Departures, known as epigenetic age acceleration (EAA), are common and have been linked to various traits and future disease risk. Limited by available data, most studies investigating these relationships have been cross-sectional, using a single EA measurement. However, the recent growth in longitudinal DNAm studies has led to analyses of associations with EA over time. These studies differ in (1) their choice of model; (2) the primary outcome (EA vs. EAA); and (3) in their use of chronological age or age-independent time variables to account for the temporal dynamic. We evaluated the robustness of each approach using simulations and tested our results in two real-world examples, using biological sex and birthweight as predictors of longitudinal EA.
RESULTS: Our simulations showed most accurate effect sizes in a linear mixed model or generalized estimating equation, using chronological age as the time variable. The use of EA versus EAA as an outcome did not strongly impact estimates. Applying the optimal model in real-world data uncovered advanced GrimAge in individuals assigned male at birth that decelerates over time.
CONCLUSION: Our results can serve as a guide for forthcoming longitudinal EA studies, aiding in methodological decisions that may determine whether an association is accurately estimated, overestimated, or potentially overlooked.
Original language | English |
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Article number | 187 |
Pages (from-to) | 187 |
Journal | CLINICAL EPIGENETICS |
Volume | 16 |
Issue number | 1 |
DOIs | |
Publication status | Published - 20 Dec 2024 |
Data Availability Statement
ALSPAC data are available on request at http://www.bristol.ac.uk/alspac/researchers/access/. Details of all the data are available through a fully searchable data dictionary and variable search tool on the ALSPAC study website: http://www.bristol.ac.uk/alspac/researchers/our-data/.Acknowledgements
We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.Funding
The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, who will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website: http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf . This research was funded by Science Foundation Ireland through the SFI Centre for Research Training in Genomics Data Science under Grant number 18/CRT/6214. It was also supported in part by the EU\u2019s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant H2020-MSCA-COFUND-2019-945385. This work was supported by the National Institute of Mental Health of the National Institutes of Health (Grant Number R01MH113930 awarded to ECD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. EW is funded by the European Union\u2019s Horizon 2020/Europe Research and Innovation Programme (EarlyCause Grant Agreement No 848158) and by UK Research and Innovation (UKRI) under the UK government\u2019s Horizon Europe/ERC Frontier Research Guarantee (BrainHealth, Grant Number EP/Y015037/1). AAL is supported by a fellowship from the Canadian Institute of Health Research.
Funders | Funder number |
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ERC Frontier Research Guarantee | EP/Y015037/1 |
European Union’s Horizon 2020/Europe Research and Innovation Programme | 848158 |
The Wellcome Trust | 217065/Z/19/Z |
H2020 Marie Skłodowska-Curie Actions | H2020-MSCA-COFUND-2019-945385 |
National Institutes of Health | R01MH113930 |
Science Foundation Ireland | 18/CRT/6214 |
Keywords
- ALSPAC
- Accelerated aging
- DNA methylation
- Epigenetic age
- Longitudinal studies
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Developmental Biology
- Genetics(clinical)
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BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee
Walton, E. (PI) & Ward, A. (CoI)
1/10/23 → 30/09/28
Project: EU Commission
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