Downregulation of oligodendrocyte-related genes, referred to as oligodendrocyte dysfunction, in schizophrenia has been revealed by DNA microarray studies. Because oligodendrocyte-specific transcription factors regulate the differentiation of oligodendrocytes, genes encoding them are prime candidates for oligodendrocyte dysfunction in schizophrenia. We found that the cytosine-guanine dinucleotide (CpG) island of sex-determining region Y-box containing gene 10 (SOX10), an oligodendrocyte-specific transcription factor, tended to be highly methylated in brains of patients with schizophrenia, correlated with reduced expression of SOX10. We also found that DNA methylation status of SOX10 also was associated with other oligodendrocyte gene expressions in schizophrenia. This may be specific to SOX10, because the CpG island of OLIG2, which encodes another oligodendrocyte-specific transcription factor, was rarely methylated in brains, and the methylation status of myelin-associated oligodendrocytic basic protein, which encodes structural protein in oligodendrocytes, did not account for their expressions or other oligodendrocyte gene expressions. Therefore, DNA methylation status of the SOX10 CpG island could be an epigenetic sign of oligodendrocyte dysfunction in schizophrenia.
"Epigenetic alterations can reflect the interaction between genetic factors and environmental ones in the development of SCZ [Abdolmaleky and Thiagalingam, 2011]. As the major component of epigenetic regulation, DNA methylation of GAD, RELN, COMT, SOX10, BDNF, and CTLA4 genes have been reported to be correlated with the risk of SCZ [Abdolmaleky et al., 2005, 2006; Abdolmaleky and Thiagalingam, 2011; Grayson et al., 2005; Ikegame et al., 2013; Iwamoto et al., 2005; Kordi-Tamandani et al., 2013; Nohesara et al., 2011; Pun et al., 2011; Sharma et al., 2008; Tolosa et al., 2010]. SCZ is a complex mixed disorder with two major subtypes, paranoid and undifferentiated SCZ. "
"Microarray-based studies, measuring the methylation profiles of thousands of CpG sites across the genome in diverse tissues, have identified various additional candidate genes whose methylation may be associated with schizophrenia [Kinoshita et al., 2013; Wockner et al., 2014]. Other studies using varying methodologies, and targeting a variety of tissues, have found partly consistent evidence for epigenetic alterations associated with schizophrenia at genes including RELN [Abdolmaleky et al., 2005; Grayson et al., 2005], COMT [Abdolmaleky et al., 2006], SOX10 [Iwamoto et al., 2005], HTR2A [Abdolmaleky et al., 2011], BDNF, and ST6GALNAC1 [Nishioka et al., 2012]. Among the genes previously implicated in schizophrenia by genetic linkage or association, LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) is of particular interest from an epigenetic perspective [Francks et al., 2007; Francks et al., 2003]. "
"In addition, an increased mRNA expression of DNA methyl-transferases (DNMT1 and DNMT3a) has been observed in schizophrenia (Veldic et al., 2004, 2005; Ruzicka et al., 2007; Zhubi et al., 2009). Furthermore, aberrant DNA methylation in brains of patients with schizophrenia (Abdolmaleky et al., 2005, 2006, 2011; Grayson et al., 2005; Iwamoto et al., 2005; Tamura et al., 2007; Mill et al., 2008; Tolosa et al., 2010; Wockner et al., 2014) and the associations of different DNA methylation patterns with phenotypic discordance of schizophrenia between twins (Petronis et al., 2003; Dempster et al., 2011; Kinoshita et al., 2013) have been reported. However, the sample sizes in these previous epigenetic studies of schizophrenia were relatively small and the number of CpG sites interrogated was limited. "
[Show abstract][Hide abstract] ABSTRACT: Background: Schizophrenia is a complex psychiatric disorder with a lifetime morbidity rate of 0.5–1.0%. The pathophysiology of schizophrenia still remains obscure. Accumulating evidence indicates that DNA methylation, which is the addition of a methyl group to the cytosine in a CpG dinucleotide, might play an important role in the pathogenesis of schizophrenia.
Methods: To gain further insight into the molecular mechanisms underlying schizophrenia, a genome-wide DNA methylation profiling (27,578 CpG dinucleotides spanning 14,495 genes) of the human dorsolateral prefrontal cortex (DLPFC) was conducted in a large cohort (n = 216) of well characterized specimens from individuals with schizophrenia and non-psychiatric controls, combined with an analysis of genetic variance at ~880,000 SNPs.
Results: Aberrant DNA methylation in schizophrenia was identified at 107 CpG sites at 5% Bonferroni correction (p < 1.99 × 10−6). Of these significantly altered sites, hyper-DNA methylation was observed at 79 sites (73.8%), mostly in the CpG islands (CGIs) and in the regions flanking CGIs (CGI: 31 sites; CGI shore: 35 sites; CGI shelf: 3 sites). Furthermore, a large number of cis-methylation quantitative trait loci (mQTL) were identified, including associations with risk SNPs implicated in schizophrenia.
Conclusions: These results suggest that altered DNA methylation might be involved in the pathophysiology and/or treatment of schizophrenia, and that a combination of epigenetic and genetic approaches will be useful to understanding the molecular mechanism of this complex disorder.
Frontiers in Genetics 08/2014; 5:280. DOI:10.3389/fgene.2014.00280
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