The contribution of genetic and environmental influences on DNA methylation at autosomal sites differs as a function of average DNA methylation level at that location.

<p>Shown are estimates of additive genetic effects (A), shared environmental effects (C) and non-shared (or unique) environmental effects (E) against mean DNA methylation level. The most heritable sites are characterized by intermediate levels of DNA methylation.</p

DNA methylation at sites associated with tobacco smoking is strongly influenced by additive genetic factors.

<p>Shown is a series of density plots for estimates of (<b>a</b>) additive genetic effects (A), (<b>b</b>) shared environmental effects (C) and (<b>c</b>) non-shared environmental effects (E) at 97 differentially methylated positions (DMPs) associated with smoking (green). Also shown are density plots for A, C and E at ‘background’ sites not associated with smoking (red). Shown below is a series of scatterplots showing the correlation in DNA methylation between MZ twins (x-axis) against DZ twins (y-axis) for sites associated with smoking in (<b>d</b>) all twins, (<b>e</b>) concordant non-smokers (n = 503 twin-pairs), (<b>f</b>) twins discordant for smoking status (n = 123 twin-pairs) and (<b>g</b>) concordant smokers (n = 106 twin-pairs). The shaded area on each plot indicates the heritability estimate (using Falconer’s formula) for each site.</p

The contribution of additive genetic and environmental factors to levels of DNA methylation.

<p>Shown are the results from structural equation models to estimate the mean proportion of variance in DNA methylation explained by additive genetic effects (A), shared environmental effects (C) and unshared (or unique) environmental effects (E) across Illumina 450K probes. Results are presented separately for DNA methylation sites located on the autosomes and X-chromosome, and stratified by whether they have intermediate levels of DNAm and/or are “variable”.</p

DNA methylation sites at which inter-individual variation is correlated across tissues are characterized by higher levels of heritability.

<p>(<b>a</b>) A density plot of heritability estimates for DNA methylation at sites split by the extent to which DNA methylation co-varies between whole blood and the prefrontal cortex using data from Hannon et al (2015). Heritability is significantly higher in probes where the cross-tissue covariation in DNA methylation is high (r² > 0.5, red). (<b>b-h</b>) An example of a probe (cg08449049) at which DNA methylation is strongly influenced by additive genetic effects and also co-varies between blood and multiple regions of the human brain. Shown are scatterplots of DNA methylation values at cg08449049 for (<b>b</b>) MZ (corr = 0.851) and <b>c)</b> DZ (corr = 0.364) twin pairs. Each point represents an individual twin-pair. (<b>d</b>) A boxplot of the distribution of DNA methylation levels at cg08449049 in blood and four brain regions (PFC = prefrontal cortex, EC = entorhinal cortex, STG = superior temporal gyrus, CER = cerebellum) from the same individual donors using data generated by Hannon et al (2015). (<b>e-h</b>) Scatterplots of the DNA methylation values in blood against the DNA methylation values in each of the four brain regions showing that there is significant covariation across tissues.</p