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Introduction: Bipolar disorder (BD) is a chronic, disabling disease characterised by alternate mood episodes, switching through depressive and manic/hypomanic phases. Mood stabilizers, in particular lithium salts, constitute the cornerstone of the treatment in the acute phase as well as for the prevention of recurrences. The pathophysiology of BD and the mechanisms of action of mood stabilizers remain largely unknown but several pieces of evidence point to gene x environment interactions. Epigenetics, defined as the regulation of gene expression without genetic changes, could be the molecular substrate of these interactions. In this literature review, we summarize the main epigenetic findings associated with BD and response to mood stabilizers., Methods: We searched PubMed, and Embase databases and classified the articles depending on the epigenetic mechanisms (DNA methylation, histone modifications and non-coding RNAs)., Results: We present the different epigenetic modifications associated with BD or with mood-stabilizers. The major reported mechanisms were DNA methylation, histone methylation and acetylation, and non-coding RNAs. Overall, the assessments are poorly harmonized and the results are more limited than in other psychiatric disorders (e.g. schizophrenia). However, the nature of BD and its treatment offer excellent opportunities for epigenetic research: clear impact of environmental factors, clinical variation between manic or depressive episodes resulting in possible identification of state and traits biomarkers, documented impact of mood-stabilizers on the epigenome., Conclusion: Epigenetic is a growing and promising field in BD that may shed light on its pathophysiology or be useful as biomarkers of response to mood-stabilizer., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Conversion to psychosis is a longitudinal process during which several epigenetic changes have been described. We tested the hypothesis that epigenetic variability in the methylomes of ultra-high risk (UHR) individuals may contribute to the risk of conversion. We studied a longitudinal cohort of UHR individuals (n = 39) and compared two groups (converters, n = 14 vs. non-converters, n = 25). A longitudinal methylomic study was conducted using Infinium HumanMethylation450 BeadChip covering half a million cytosine-phosphate-guanine (CpG) sites across the human genome from whole-blood samples. We used two statistical methods to investigate the variability of methylation probes. (i) The search for longitudinal variable methylation probes (VMPs) based on median comparisons identified two VMPs in converters only. The first CpG was located in the MACROD2 gene and the second CpG was in an intergenic region at 8q24.21. (ii) The detection of outliers using variance analysis related to private epimutations identified a dozen CpGs in converters only and highlighted two genes (RAC1 and SPHK1) from the sphingolipid signaling pathway. Our study is the first to support increased methylome variability during conversion to psychosis. We speculate that stochastic factors could increase DNA methylation variability and have a role in the complex pathophysiology of conversion to psychosis as well as in other psychiatric diseases.

Background: In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis., Methods: From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30)., Results: There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57)., Conclusions: In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

Schizophrenia and other psychoses are categorical psychiatric diagnoses corresponding to frequent and heterogeneous disorders. Their physiopathology still remains largely unknown despite numerous recent advances. In particular, the last decade has identified different types of genetic variants, thanks to emergence of high-throughput methods. These methods allow both the identification of rare variants with a large effect such as punctual mutations or copy-number variants and the identification of frequent variants with a limited effect such as polymorphisms. Many impacted genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Only a small fraction of psychoses could be easily explained by genetics but this screening in clinical practice is important as it can lead to therapeutic challenge or genetic counselling. Nowadays, it is clear that the pathophysiology of the psychoses can only be understood by an integrative approach taking into account the interaction between genes and environment. This interaction could be mediated by the epigenome defined as the modification of gene expression without changes in DNA sequence. Epigenome is stable but could be modified by environmental factors. Several epigenetic mechanisms have been studied in psychosis, in particular the DNA methylation, the modification of histones and the microRNA. All of these mechanisms are under regulation by genetic factors and variants in these epigenetic-involved genes and cofactors have been also associated with schizophrenia. Thus, pathophysiology of psychosis is complex and morestudiesare needed before definitive conclusions. Altogether, the recent advances in the genetics and epigenetics of psychosis are promising and could open the way to a recategorization of these disorders as well as the identification of new therapeutic targets., (© Société de Biologie, 2017.)

Background: Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders., Object: The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter., Methods: We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post-translational histone modifications., Results: First, in terms of epidemiology and transmission, the theoretical model of epigenetics applies to schizophrenia. Then, most environmental factors that have proved a link with this disease, may generate epigenetic mechanisms. Next, mutations have been found in regions implied in epigenetic mechanism among populations with schizophrenia. Some epigenetic alterations in DNA regions have been previously linked with neurodevelopmental abnormalities. In psychosis, some authors have found methylation differences in COMT gene, in reelin gene and in some genes implicated in dopaminergic, serotoninergic, GABAergic and glutamatergic pathways. Histone modifications have been described, in particular the H3L4 histone methylation. Finally, we tried to underline the difficulties in epigenetic research, notably in psychiatry, and the limits in this matter., Conclusion: The epigenetic field may explain a lot of questions around the physiopathology of the complex psychiatric disease that is schizophrenia. It may be a substratum to the prevailing hypothesis of gene x environment interaction. The research in the matter is definitely expanding. It justifies easily the need to improve the effort in the domain to overpass some limits inherent to the matter., (Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)