Epigenetics of major psychosis: Progress, problems and perspectives

The Krembil Family Epigenetics Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, ONT, M5T 1R8, Canada.
Trends in Genetics (Impact Factor: 9.92). 05/2012; 28(9):427-35. DOI: 10.1016/j.tig.2012.04.002
Source: PubMed


Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals with schizophrenia (SCZ) and bipolar disorder (BPD). We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.

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Available from: Viviane Labrie, Jul 10, 2015
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    • "Psychosis is a severe mental disorder characterized by a loss of contact with reality. Several types of psychosis are classified based on psychopathological features, such as schizophrenia (SCH) which is applied to a syndrome with long duration, bizarre delusions , negative symptoms, and few affective symptoms (van Os and Kapur, 2009) and bipolar disorder (BPD) which is characterized by recurrent mania or hypomania and depressive episodes that impair overall function and quality of life (Labrie et al., 2012). "
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    ABSTRACT: Emerging evidence suggests an underlying immune and inflammatory response for a variety of psychiatric disorders. Herein, we employed an optimized native-polyacrylamide gel electrophoresis to isolate psychosis-related serum immunoinflammation-related protein complexes (IIRPCs) from 147 patients with schizophrenia (SCH), 158 patients with bipolar disorder (BPD), 132 patients with other psychosis, and 145 normal controls. All participants could be classified into four categories based on serum IIRPCs, which correspond to 290, 215, 70, and 7 serum samples, correspondingly. For each category, significantly enhanced levels of serum IIRPCs in patients with SCH, BPD, and other psychosis groups were observed compared with normal controls. Receiver operating characteristic analysis indicated that serum IIRPCs have excellent diagnostic performance to differentiate SCH, BPD, and other psychosis groups from normal controls, with high sensitivities and specificities of >85%. Total serum amounts of IgG, IgA, and IgM in all patients were significantly decreased compared with normal controls. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    08/2015; 230(1). DOI:10.1016/j.psychres.2015.08.029
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    • "Schizophrenia (SZ) and bipolar disorder (BP) are complex mental diseases. Similar to cancer or diabetes, these neuropsychiatric disorders aggregate in families but do not segregate in a strictly Mendelian manner [1] [2]. Over the past decades, numerous genetic association and linkage studies have shed light on molecular pathways involved in SZ and BP [3] [4] [5]. "
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    ABSTRACT: Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to controls both in an understudied population, Hispanics along the U.S.-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters, 3’-UTRs and 5’-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG-islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3’ shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.
    BioMed Research International 10/2014; 2015. DOI:10.1155/2015/201587 · 1.58 Impact Factor
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    • "Therefore, future studies of Gadd45 proteins in Sz will need to address potential alterations in 5hmC levels as well. Finally, the functional interactions between canonical epigenetic cascades suggest Gadd45 proteins may also mediate the contributions of histone modifi cations to psychosis pathology and treatment (Sharma et al. 2008 ; Guidotti et al. 2009 ; Kurita et al. 2012 ; Labrie et al. 2012 ). "
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    ABSTRACT: The growth arrest and DNA damage-inducible (Gadd)45 proteins have been associated with numerous cellular mechanisms including cell-cycle control, DNA damage sensation and repair, genotoxic stress, neoplasia, and molecular epigenetics. The genes were originally identified in in vitro screens of irradiation- and interleukin-induced transcription and have since been implicated in a host of normal and aberrant central nervous system processes. These include early and postnatal development, injury, cancer, memory, aging, and neurodegenerative and psychiatric disease states. The proteins act through a variety of molecular signaling cascades including the MAPK cascade, cell-cycle control mechanisms, histone regulation, and epigenetic DNA demethylation. In this review, we provide a comprehensive discussion of the literature implicating each of the three members of the Gadd45 family in these processes.
    Advances in Experimental Medicine and Biology 10/2013; 793:81-119. DOI:10.1007/978-1-4614-8289-5_6 · 1.96 Impact Factor
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