Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins

<jats:title>Abstract</jats:title><jats:p>Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the <jats:italic>WDR26</jats:italic> gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of <jats:italic>WDR26</jats:italic> has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as <jats:italic>CACNA1C</jats:italic>, <jats:italic>IGF2</jats:italic> and the p38 MAP kinase <jats:italic>MAPK11</jats:italic>, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.</jats:p>