Abstract
Age-associated DNA methylation changes have been widely reported across many different tissue and cell types. Epigenetic ‘clocks’ that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. However, the relative amount of age-associated DNAm changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. Here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue DNA methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. We further show that ELOVL2 is not unique and that many other CpG sites, some mapping to genes in the Wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. We propose that while most age-associated DNAm changes are shared between cell-types that the putative functional effect is likely to be tissue-specific.
Highlights
Age-associated DNA methylation (DNAm) changes have been reported for a long time [1,2,3]
The authors perform additional analyses using an arbitrary threshold on the effect size, as an alternative to statistics and P-values to select associated differentially methylated positions (aDMPs), to argue that the “lack of overlap of aDMPs derived from different tissues” is not due to a lack of power
We have tried to address what appears to be an apparent paradox between a number of studies reporting pan-tissue epigenetic clocks that yield DNAm-based correlates of age independently of cell or tissue-type [9, 13, 14], and a recent study suggesting that only sites mapping to the ELOVL2 promoter constitute cell and
Summary
Age-associated DNA methylation (DNAm) changes have been reported for a long time [1,2,3]. One of the first studies to indicate that age-associated DNAm changes, termed epigenetic drift, could be largely tissue specific was a study by Christensen et al [4] This first study only sampled a small percentage of the DNA methylome, was largely underpowered and did not adjust for potentially confounding cell-type heterogeneity [5, 6]. While this controls for the FamilyWise-Error-Rate (FWER), the use of a Bonferroni threshold is known to suffer from a very large False Negative Rate (FNR), i.e. to a substantial reduction in power This is pertinent because their analyses generally compare age-associated differentially methylated positions (aDMPs) between studies and tissues, which according to our estimates were not adequately powered. As shown recently by us, tissues like buccal, kidney or liver are highly heterogeneous, containing a substantial amount of immune-cell infiltrates [15], which means that adjustment for variations in the amount of infiltrating leukocytes and other stromal cells is critically important [5, 15, 16]
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