Author:
Seeboth Anne,McCartney Daniel L.,Wang Yunzhang,Hillary Robert F.,Stevenson Anna J.,Walker Rosie M.,Campbell Archie,Evans Kathryn L.,McIntosh Andrew M.,Hägg Sara,Deary Ian J.,Marioni Riccardo E.
Abstract
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, β = 0.0091, p < 2 × 10−16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10−4) and 1936 (N = 898, β = 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.
Funder
Medical Research Council
College of Medicine and Veterinary Medicine, University of Edinburgh
Alzheimer’s Research UK
Loo och Hans Ostermans Stiftelse för Medicinsk Forskning
Magnus Bergvalls Stiftelse
Stiftelsen för Gamla Tjänarinnor
Wellcome Trust
Chief Scientist Office, Scottish Government Health and Social Care Directorate
Scottish Funding Council
Biotechnology and Biological Sciences Research Council
Age UK
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Developmental Biology,Genetics,Molecular Biology