Abstract
Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55–90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate (), of which 24 had an association p-value below . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.
Highlights
Epigenetics have become very important in our understanding of aging processes
(73–90 years) and had longer follow-up times compared to those of the Middle Aged Danish Twins Study (MADT) and birth weight-discordant twins (BWD); the most deaths occurred in the LSADT
For 2074 of the 2806 top sites (73.9%), hypomethylation was associated with increased mortality corresponding to a hazard ratio (HR)
Summary
Epigenetics have become very important in our understanding of aging processes. DNA methylation is an epigenetic mechanism that affects gene expression, and changes in the methylation pattern have been linked to various diseases [1,2,3,4]. The degree of DNA methylation at certain CpG sites has been shown to change consistently with age in various organs and in the blood. This has led to the establishment of epigenetic “clocks”. Genes 2018, 9, 78 that predict chronological age from methylation patterns [5,6]. The functioning of these sites is largely unknown, it is found that they can be associated with all-cause mortality, i.e., age at death. Previous studies have found that the deviation between methylation age as defined in [5,6] and chronological age is associated with all-cause mortality [7,8]
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