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 WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, 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.

Objective: To test whether the association between childhood abuse, cannabis use and psychotic experiences (PEs) was moderated by theCOMT(catechol‐O‐methyltransferase) gene.Method: Psychotic experiences (PEs), childhood abuse, cannabis use andCOMTVal158Met genotypes were assessed in 533 individuals from the general population. Data were analysed hierarchically by means of multiple linear regression models.Results: Childhood abuse showed a significant main effect on both positive (β = 0.09; SE = 0.04;P = 0.047) and negativePEs (β = 0.11; SE = 0.05;P = 0.038). A significant three‐way interaction effect was found among childhood abuse, cannabis use and theCOMTgene on positivePEs (β = −0.30; SE = 0.11;P = 0.006). This result suggests thatCOMTgenotypes and cannabis use only influencedPEscores among individuals exposed to childhood abuse. Furthermore, exposure to childhood abuse and cannabis use increasedPEscores in Val carriers. However, in individuals exposed to childhood abuse but who did not use cannabis,PEs increased as a function of the Met allele copies of theCOMTgene.Conclusion: Cannabis use after exposure to childhood abuse may have opposite effects on the risk ofPEs, depending on theCOMTgenotypes providing evidence for a qualitative interaction. Val carriers exposed to childhood abuse are vulnerable to the psychosis‐inducing effects of cannabis.

Scaffolding proteins represent an evolutionary solution to controlling the specificity of information transfer in intracellular networks. They are highly concentrated in complexes located in specific subcellular locations. One of these complexes is the postsynaptic density of the excitatory synapses. There, scaffolding proteins regulate various processes related to synaptic plasticity, such as glutamate receptor trafficking and signalling, and dendritic structure and function. Most scaffolding proteins can be grouped into 4 main families: discs large (DLG), discs-large-associated protein (DLGAP), Shank and Homer. Owing to the importance of scaffolding proteins in postsynaptic density architecture, it is not surprising that variants in the genes that code for these proteins have been associated with neuropsychiatric diagnoses, including schizophrenia and autism-spectrum disorders. Such evidence, together with the clinical, neurobiological and genetic overlap described between schizophrenia and autism-spectrum disorders, suggest that alteration of scaffolding protein dynamics could be part of the pathophysiology of both. However, despite the potential importance of scaffolding proteins in these psychiatric conditions, no systematic review has integrated the genetic and molecular data from studies conducted in the last decade. This review has the following goals: to systematically analyze the literature in which common and/or rare genetic variants (single nucleotide polymorphisms, single nucleotide variants and copy number variants) in the scaffolding family genes are associated with the risk for either schizophrenia or autism-spectrum disorders; to explore the implications of the reported genetic variants for gene expression and/or protein function; and to discuss the relationship of these genetic variants to the shared genetic, clinical and cognitive traits of schizophrenia and autism-spectrum disorders.