Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by pleiotropic genes. The prevailing explanation points to the interplay between predisposing genes and environmental exposure. Accumulated evidence suggests that epigenetic regulation of the genome may mediate dynamic gene–environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors. This systematic review summarizes the current knowledge linking schizophrenia and other psychotic disorders to epigenetics, based on PubMed and Web of Science database searches conducted according to the PRISMA guidelines. Three groups of mechanisms in case–control studies  of human tissue (i.e., postmortem brain and bio-fluids) were considered: DNA methylation, histone modifications, and non-coding miRNAs. From the initial pool of 3,204 records, 152 studies met our inclusion criteria (11,815/11,528, 233/219, and 2,091/1,827 cases/controls for each group, respectively). Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). Overall, actual evidence moderately supports an association between epigenetics and schizophrenia and other psychotic disorders. However, heterogeneous results and cross-tissue extrapolations call for future work. Integrating epigenetics into systems biology may critically enhance research on psychosis and thus our understanding of the disorder. This may have implications for psychiatry in risk stratification, early recognition, diagnostics, precision medicine, and other interventional approaches targeting epigenetic fingerprints.

Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings

Social dysfunction is a core symptom of many psychiatric disorders and current medications have little or no remedial effects on this. Following on from extensive studies on animal models demonstrating that the neuropeptide oxytocin plays an important role in social recognition and bonding, human-based research has explored its therapeutic potential for social dysfunction in psychiatric disorders. Here we outline the historical background of this human-based research and some of the current methodological challenges it is facing. To date, research has primarily attempted to establish functional effects through measuring altered endogenous concentrations, observing effects of exogenous administration and by investigating the effects of polymorphisms and epigenetic modifications of the oxytocin receptor gene. We summarize some of the key findings on behavioral and neural effects that have been reported in healthy subjects in the context of social cognition which have provided encouragement that oxytocin could represent a promising therapeutic target. At the same time, we have identified a number of key areas where we urgently need further information about optimal dosing strategies and interactions with other peptide and transmitter systems. Finally, we have summarized current translational findings, particularly in the context of therapeutic outcomes of intranasal oxytocin administration in autism and schizophrenia. These clinical findings while somewhat varied in outcome do offer increasing cause for optimism that targeting the oxytocin system may provide a successful therapeutic approach for social dysfunction. However, future research needs to focus on the most effective treatment strategy and which types of individuals are likely to benefit most.

Overview of Human Oxytocin Research

The neuropeptide Oxytocin (OXT) plays a central role in birthing, mother-infant bonding and a broad range of related social behaviours in mammals. More recently, interest has extended to epigenetic programming of genes involved in oxytocinergic neurotransmission. This review brings together early findings in a rapidly developing field of research, examining relationships between DNA methylation (DNAm) of the Oxytocin Receptor Gene (OXTR) and social and emotional behaviour in human populations. A systematic search across Web of Knowledge/Science, Scopus, Medline and EMBASE captured all published studies prior to June 2017 examining the association between OXTR DNAm and human social and emotional outcomes. Search terms included ‘oxytocin gene’ or ‘oxytocin receptor gene’ and ‘epigenetics’ or ‘DNA methylation’. Any article with a focus on social and emotional functioning was then identified from this set by manual review. Nineteen studies met eligibility criteria. There was considerable heterogeneity of study populations, tissue samples, instrumentation, measurement, and OXTR site foci. Only three studies examined functional consequences of OXTR DNAm on gene expression and protein synthesis. Increases in OXTR DNAm were associated with callous-unemotional traits in youth, social cognitive deficits in Autistic Spectrum Disorder (ASD), rigid thinking in anorexia nervosa, affect regulation problems, and problems with facial and emotional recognition. In contrast, reductions in DNAm were associated with perinatal stress, postnatal depression, social anxiety and autism in children. Consistent with an emerging field of inquiry, there is not yet sufficient evidence to draw conclusions about the role of OXTR DNAm in human social and emotional behaviour. However, taken together, findings point to increased OXTR DNAm in general impairments in social, cognitive and emotional functioning, and decreased OXTR DNAm in specific patterns of impairment related to mood and anxiety disorders (but not in all). Future progress in this field would be enhanced by adequately powered designs, greater phenotypic precision, and methodological improvements including longitudinal studies with multiple time-points to facilitate causal inference.

/pdf/the-role-of-oxytocin-receptor-gene-oxtr-dna-methylation-dnam-52xn6uogz1.pdf

The role of oxytocin receptor gene (OXTR) DNA methylation (DNAm) in human social and emotional functioning: a systematic narrative review.

The neuropeptide oxytocin regulates mammalian social behavior Disruptions in oxytocin signaling are a feature of many psychopathologies One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (OXTR) Such studies focus on DNA methylation in two regions of OXTR, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1 However, the relative contribution of exon 3 and MT2 in regulating OXTR gene expression in the brain is currently unknown Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting Oxtr gene expression in a region of the brain that has been shown to drive Oxtr related behavior in the vole, the nucleus accumbens We show that the genetic structure of Oxtr in prairie voles resembles human OXTR We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the Oxtr promoter: MT2 and exon 3 We show that early nurture in the form of parental care results in DNA hypomethylation of Oxtr in both MT2 and exon 3, but only DNA methylation in MT2 is associated with Oxtr gene expression Network analyses indicate that CpG sites in the 3′ portion of MT2 are most highly associated with Oxtr gene expression We also identify two novel SNPs in exon 3 of Oxtr in prairie voles and a novel alternative transcript originating from the third intron of the gene Expression of the novel alternative transcript is associated with genotype at SNP KLW2 These results identify putative regulatory features of Oxtr in prairie voles which inform future studies examining OXTR in human social behaviors and disorders These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3′ portion, is more predictive of Oxtr gene expression than DNA methylation in exon 3 Similarly, in human temporal cortex, we find that DNA methylation in the 3′ portion of MT2 is associated with OXTR expression Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of OXTR gene expression We also identify novel features of prairie vole Oxtr, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of OXTR

/pdf/genetic-epigenetic-and-environmental-factors-controlling-3vmg0pzdsa.pdf

Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression.

Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability.

https://www.pnas.org/content/pnas/113/27/E3816.full.pdf

Epigenetic modification of OXT and human sociability.

Sex and Diagnosis-Specific Associations Between DNA Methylation of the Oxytocin Receptor Gene With Emotion Processing and Temporal-Limbic and Prefrontal Brain Volumes in Psychotic Disorders

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Sex and Diagnosis-Specific Associations Between DNA Methylation of the Oxytocin Receptor Gene With Emotion Processing and Temporal-Limbic and Prefrontal Brain Volumes in Psychotic Disorders