Excitement about DNA methylation biomarkers has been tempered by a growing appreciation of the complex causal relations with cell fate. Intersample differences in DNA methylation can be partitioned into those that are independent of cellular heterogeneity and those that are caused by differential mixtures of cell types. Generally, the field has assumed that the former are more likely to be causative of disease. The latter has been considered a likely consequence of disease and a confounder to be removed. We argue that the conceptual separation of these signals is artificial and not necessarily informative about causation. DNA methylation is a very sensitive measure of cell fate mix and therefore reveals much about underlying disease etiology including aspects of causation.
DNA methylation marks integrate genetic & environmental influences & hence have potential as prognostic & stratification biomarkers & also as read-outs of intervention efficacyLoci-specific DNA 5-methylcytosine levels at CpG sites are easily measured at scale in biological samples. They vary across individuals and this variation has been robustly associated with a range of disease phenotypes and environmental exposures [1][2][3][4][5][6]. As interindividual DNA methylation is specified by the interaction of both genotypic and environmental influences [7,8], it may be a more powerful prognostic biomarker than either genotypic or lifestyle factors alone [9]. DNA methylation is dynamic throughout the lifecourse and is potentially modifiable by therapeutic interventions. This raises the possibility of sensitive real-time biomarkers of disease status to track intervention efficacy [10].Locus-specific observations were first to demonstrate the role of early life environmental influence on interindividual variation in methylation. For instance, postnatal maternal care in rats or childhood trauma in humans, affects DNA methylation levels at the NR3C1 gene in blood and the hippocampus; methylation levels at this locus then predict adult psychopathology [11][12][13]. Observations such as this have inspired many epigenome wide association studies (EWAS) to determine the epigenetic consequences of early life influences. Although epigenetic programming was originally envisioned to pertain to very early life factors (i.e., fetal programming, see for example [14]), it could be generalized to account for environmental influences throughout the lifecourse. Some of the best evidence for the later life effect of the environment on DNA methylation is from Fasanelli and colleagues, who showed (by EWAS) that smoking reversibly caused hypomethylation of the AHRR and FR2L3 genes in adults and that