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. 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=7,010, {beta}=0.0091, p<2x10-16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N=430, {beta}=0.033, p=7.9x10-4) and 1936 (N=898, {beta}=7.9x10-3, p=0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, 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 but it was in a meta-analysis (HRmeta=1.12; 95%CImeta=[1.02; 1.21]; pmeta=0.021). 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.

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