Schizophrenia (SCZ) is a chronic, life-long, and debilitating disorder characterized by the presence of psychosis, social withdrawal, unusual and uncharacteristic behavior, and cognitive impairment, which could have a genetic and neurobiological background. The worldwide prevalence of this disease is about 1%. SCZ strikes men and women equally, and can affect different aspects of life, including self-care, family and social relationships, education, employment, and housing. SCZ has three main symptoms: positive symptoms (i.e., auditory hallucinations and delusion), negative symptoms (i.e., impaired motivation, social withdrawal, and reduction in spontaneous speech), and cognitive impairment.
There is evidence suggesting that severe alterations in the glia may contribute to the pathophysiology of SCZ. Some variations include reduced number of oligodendrocytes and low expression of myelin/oligodendrocyte-related genes, which can be linked to white matter abnormalities leading to abnormalities in the hemispheric connectivity previously reported in SCZ, as well as changes in astrocyte/oligodendrocyte populations in the white matter that may affect the structural or metabolic support of axons. In addition, astrocyte and oligodendrocyte gene sets have been associated with an increased risk of SCZ. It has been proposed that neuroinflammatory factors may be relevant to the pathophysiology of psychosis. The microglia (immune cells resident in the brain) are mainly associated with neuroinflammatory processes in the several brain regions of SCZ patients, and there is evidence of increased density and activation of microglia in this illness.
It has been suggested that SCZ has a substantial genetic component, such that the concordance of this pathology is higher in monozygotic twins than dizygotic twins. Several candidate genes are associated with this pathology, such as DISC1, DTNBP1, NRG1, and catechol-O-methyltransferase (COMT). However, studies of gene variants do not necessarily indicate causal pathways of the disease and the associations found are not specific to it.
In addition to the genetic factors, epigenetic mechanisms are relevant because they can regulate the expression pattern of genes involved in various pathologies. It has been seen that gene-environment interaction can be mediated by epigenetic tags and environmental risk factors can play a crucial role in developing severe psychiatric disorders. Epigenetic marks linked to environmental risk factors have been suggested to explain the increased risk of SCZ. Epigenetic changes are external modifications to DNA, the most common being DNA methylation, histone posttranslational modification, and transcriptional regulation by miRNAs. Interestingly, epigenetic marks are dynamic and often reversible, making them attractive therapeutic targets for treating complex diseases.
MATERIALS AND METHODS
Search strategy and study selection
This study is in concordance with the five-stage scoping review framework described previously by Arksey and O’Malley. This review was guided by the research question, “What genetic and epigenetic changes have been previously reported in glial cells or glial-associated genes in SCZ?” We searched articles from PubMed, PubMed Central, Medline, Medscape, and Embase databases up to December 2020. We considered relevant peer-reviewed articles in English for this review. The keywords employed for the search strategy consisted of terms associated with SCZ (psychotic or positive symptoms, negative symptoms, cognitive symptoms, first-episode SCZ, major psychosis, and paranoid SCZ), and epigenetic alterations such as DNA methylation, DNA hydroxymethylation, histone modification, and interference RNA. All articles were imported to the EndNote software (Clarivate Analytics), and duplicate reports were removed. All studies included in the analysis were case − control studies: (a) involved in a human cohort (b) medicated and drug-naïve patients with SCZ (c) monozygotic twins and concordance for SCZ (d) major psychosis and, (e) first-episode SCZ. The titles and abstracts were screened to eliminate irrelevant citations for the research question of this review. The search on review resulted in 24 records. The data were ordered in four thematic vias: (1) oligodendrocytes, (2) microglia, (3) astrocytes, and (4) perspectives.
Approved gene symbols and nomenclature were obtained from the HUGO Gene Nomenclature Committee.
A description of the studies of genetic variants associated with glia-related genes is provided in Table 1. Table 2 summarizes the main findings on epigenetic modifications. The glial-genes differential methylated sites described in epigenome-wide association studies (EWAS) are summarized in Table 3.
There is evidence of reported oligodendrocyte and myelin dysfunction and impaired myelination in SCZ. Microarray and qPCR experiments allowed to observe a reduction of crucial oligodendrocyte-related and myelin-related genes in SCZ, such as the oligodendrocyte transcription factors OLIG1, OLIG2, and SOX10, the platelet-derived growth factor receptor alpha, myelin basic protein, myelin-associated glycoprotein, proteolipid protein 1, claudin 11, myelin oligodendrocyte glycoprotein, Erb-B2 receptor tyrosine kinase 3 and transferrin. There is evidence of a significant association of psychotic symptoms in Alzheimer’s patients and two SNPs of the OLIG2 gene (rs762237 and rs2834072) in the Caucasian population. Table 1 summarizes the main findings of genetic variants associated with glia-related genes. A direct correlation between the DNA methylation status of the SOX10 CpG Islands in the Y-box and their lower gene expression levels in postmortem prefrontal cortices (BA10) in SCZ participants has been reported in comparison with controls. However, these were not observed for OLIG2 or MOBP (oligodendrocytic basic protein) genes. It has been proposed that Olig2 may activate the Sox10 distal enhancer in mice models. Also, relative hypermethylation of the SOX10 promoter in the peripheral blood of monozygotic discordant twins for SCZ has been shown. A genome-wide DNA methylation analysis performed on the frontal cortex of postmortem human brain tissue from individuals with SCZ found that cg23109891 and cg06614002 sites on SOX10 were differentially methylated in SCZ patients. However, this study did not screen for the use of antipsychotic medications in study subjects. This limitation is notable because haloperidol can be associated with higher global DNA methylation in SCZ. The SNP rs139887, located at Intron 3 of SOX10, was found to have a significant association with SCZ in the Japanese population, especially in male patients. However, the effect of DNA methylation status and polymorphism on the expression of SOX10 in SCZ remains unclear.
The GNA13 gene that encodes the G protein subunit alpha 13 may be considered a potential biomarker of SCZ, according to genome-wide association studies studies. It has been described that GNA13 may play an essential role for g-protein signaling in the development and maintenance of white matter microstructure. Transcript levels of GNA13 from untransformed lymphocytes were significantly correlated with global fractional anisotropy which reflects a combination of myelin thickness, fiber coherence, and axon integrity. In addition, a DNA methylation profile study from the prefrontal cortex from schizophrenic patients and healthy controls described GNA13 as one of the ten SCZ candidate genes differentially methylated genes.
Another notable feature in SCZ is the decreased density in cortical layer III oligodendrocytes and a decrease in the white matter in schizophrenic human brains; this progressive reduction of white matter has been associated with greater negative SCZ symptom severity. The Zinc Finger Protein 804A (ZNF804A) has been associated with brain white matter microstructure. In gestational brains, ZNF804A is highly expressed in radial glial cells and is critical for embryonic neurodevelopment. It has been suggested that ZNF804A plays a role in DNA binding and transcription, and their expression regulates transcription levels of the SCZ-associated genes COMT, dopamine receptor D2, phosphodiesterase 4B, and serine protease 16 (PRSS16). Variations in the ZNF804A intronic single-nucleotide polymorphism rs1344706 lead to white matter microstructural abnormalities in SCZ. It has been reported that truncated ZNF804A transcript (ZNF804AE3E4) expression was decreased in the dlPFC (dorsolateral prefrontal cortex) from patients with SCZ. Furthermore, a significant effect of rs1344706 on the ZNF804AE3E4 splice variant was found. A genome-wide association study of SCZ provided strong evidence for the association of ZNF804A as an SCZ susceptibility gene. Besides, a positive association of rs1344706 with SCZ was observed in the Northern Chinese population. Notably, the position ch. 2.3731798R of the ZNF804A gene was found to be differentially methylated when postmortem brains of SCZ patients and controls were compared. On the other hand, a study performed in peripheral blood of patients with first-onset SCZ showed a significantly reversed expression profile of ZNF804A and miR-148b-3p. This work reveals that miR-148b-3p can regulate COMT and PRSS16 genes by targeting sites in the 3’- UTR region of ZNF804A messenger RNA (mRNA).
2’,3’-Cyclic Nucleotide 3’ Phosphodiesterase (CNP) is an oligodendroglial transmembrane protein that may play a role in the oligodendrocyte function and myelination. Previous studies have shown significantly-reduced CNP mRNA levels in post-mortem tissue from the PFC (prefrontal cortex) of SCZ patients. On the other hand, it has been shown that the loss of MeCP2 in the MeCP2 null mice model displayed reduced expression of CNP and other myelin-related proteins. The lower-expressing A allele of the rs2070106 was significantly associated with SCZ in Caucasian populations. However, in the Chinese Han population studies, the exonic SNP rs2070106 showed no significant association. The observation may be due to the differences in the allele frequency between ethnic groups.
Microglia are the primary innate immune cells of the brain and may play a role in the cortical circuitry disturbances reported in SCZ, such as decreased dendritic spine density on PFC pyramidal neurons in SCZ. There are reports about microglial dysfunction in SCZ, suggesting a relation with the pathology of grey and white matter. It has been suggested that neuroinflammation processes may be associated with white matter pathology in people with SCZ, contributing to structural and functional abnormalities observed in psychosis. Furthermore, the pro-inflammatory cytokine interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and interferon-gamma (IFN-g) are produced by microglial cells, which play roles in cytotoxicity and have significant effects on dopaminergic and glutamatergic pathways and cognitive processes that are implicated in SCZ. Interestingly, the rs1800629 (-G308A) TNF-a gene polymorphism has been associated with SCZ. There is evidence that the TNF receptor 1 (TNF-R1) is increased in the brain (anterior cingulate and frontal cortex) and serum of patients with SCZ. Similarly, rs4149577 and rs1860545 of TNFR1 have been associated with the intensity of the excitement symptoms of paranoid SCZ in Caucasian Polish men.
Increases of IL-6 mRNA are found in peripheral blood in people with SCZ compared to healthy controls and in dlPFC (BA46); these findings support the pro-inflammatory pathophysiological role of cytokine IL-6 in patients with SCZ. Besides, the association of IL6 rs1800795 (-174G/C) polymorphism and higher serum IL-6 with SCZ was found in the Armenian population, which might be an SCZ risk factor. A study carried out in patients diagnosed with SCZ analyzed the methylation status of the IL6 promoter in antipsychotic-naïve/free patients compared with matched healthy controls from peripheral blood by bisulfite sequencing method, and a hypomethylation pattern in the IL6 promoter in SCZ was shown. Interestingly, this methylation pattern was reversed by antipsychotic administration. Contrastingly, associations between several human leukocyte antigen (HLA) polymorphisms and SCZ risk were observed. Another study examined differential methylation levels and genome-wide genotype data from peripheral blood of SCZ patients versus healthy controls; this research showed CpG sites of HLA-C gene differentially methylated and expressed in patients. HLA-C is located within the MHC region on chromosome 6 and belongs to the HLA class 1 molecules.
As previously mentioned, there is evidence of glutamate abnormalities in SCZ, the dynamic control of the glutamate uptake achieved by astrocytes regulating the activity of glutamatergic synapses. An increase in the expression profiles of cortical astrocytes and decreased expression profiles of fast-spiking parvalbumin interneurons was reported in subjects with SCZ. Furthermore, there is evidence of over-activation of astrocytes in SCZ. Parvalbumin interneurons coordinate the optimal balance of excitation and inhibition in the PFC, maintaining the efficiency of cortical information processing. Glutathione S-transferases (GSTs) are a superfamily of enzymes that quench reactive molecules with the addition of glutathione and protect the cell from oxidative damage. It has been suggested that GSTs, particularly GSTM1, may mediate the astrocyte and microglia inflammation. There is evidence that GSTM1 levels are significantly decreased in the post-mortem prefrontal cortex of patients with SCZ and major depressive disorder. It has also been suggested that the GSTM1 null genotype (GSTM1*0) might be associated with increased susceptibility to SCZ and early-onset severe psychiatric illness. Additionally, another study indicates that the double-null genotype of GSTM1 and GSTT1, which encodes GST theta 1, confers an increased risk of developing treatment-resistant schizophrenia (TRS) in Brazilian patients. There is the decreased level of antioxidants in TRS, together with an increased generation of reactive oxygen species in the brain that may damage particular areas in the brain. A significant association between SCZ and the GSTT1 active genotype was observed in a Tunisian population. The aim of the study was to investigate the association of the promoter methylation status of GSTT1 and GSTP1 by Methylation-specific PCR analysis of peripheral blood of patients with SCZ and healthy controls. In another study, promoter methylation frequency of GSTT and GSTP in the patients was higher, suggesting that GSTs hypermethylation may modify the risk of SCZ.
Findings suggest that the HSP70 (Heat shock protein 70) mediates neuroinflammation in astrocytes. The single nucleotide polymorphisms rs2075799 and rs1043618 in HSPA1A (heat shock protein family A “HSP70” member 1A), have been associated with SCZ. At the moment, no epigenetic mechanisms have been described that may regulate the HSP70 expression in SCZ. Nonetheless, it has been reported that valproic acid (VPA) and other HDAC inhibitors (molecules that selectively alter gene transcription by chromatin remodeling), such as sodium butyrate, trichostatin A, MS-275, and apicidin, which are Class I HDAC inhibitors, may increase levels of H3K4Me2 and H3K4Me3 at the HSP70 promoter in astrocytes. H3K4me2 and H3K4 me3 are associated with transcriptionally active chromatin areas. Interestingly, VPA induced activation of the HSP70 promoter in astrocytes by recruiting histone acetyltransferase p300 in rat cortical astrocytes. Besides, there is evidence of increased HSPA1A expression and other genes related to immune function, such as the pro-inflammatory mediators IFITM1, IFITM2, and IFITM3 in postmortem dlPFC cortex samples from SCZ. The HSPA8 variant (rs1136141) was significantly associated with first-episode psychosis in Greek schizophrenic patients.
Regulator of G-protein–signaling 4 (RGS4) is a GTPase-activating protein that plays a key role in the regulation of G-protein–coupled receptor signaling, modulating receptor-mediated neuronal signaling at the synapse. A variation in the RGS4 polymorphism (rs951436) results in specific reductions in white matter structural volume. There are reports regarding the downregulation of RGS4 transcripts in the dlPFC of SCZ patients compared with healthy controls, which may support this gene as a candidate gene for SCZ. Another work showed that RSG4 expression levels of the longest variant RGS4-1 were decreased in the dlPFC of schizophrenic patients. A study tested the methylation status of CpG islands of the RGS4 regulatory region in the postmortem dlPFC samples obtained from subjects with SCZ and healthy controls. The findings suggested that the lower RGS4-1 mRNA expression levels were not associated with hypermethylation status of its CpG islands in the 5’ region. Interestingly, the lower RGS4-1 expression was associated with SNPs rs10917670, rs2661347, rs951436, and rs2661319 in the 5’ regulatory region. A study carried out by Vrajová et al. evaluated the possible epigenetic mechanism of RGS4 expression through silenced RGS4 gene using siRNA against human RGS4 and studied the effects of differential expression in neuroblastoma cell lines. They observed that downregulated RGS4 mRNA changes the expression of 67 genes, including critical transcription factors such as brain derived neurotrophic factor and DISC1 which are associated with SCZ pathology.
EWAS explore new potential molecular targets. For example, a study carried out by Kinoshita et al. showed altered DNA methylation in peripheral blood samples from patients with SCZ, such as CpG sites located in the CpG islands in the promoter regions of putative SCZ susceptibility genes such as PCM1 (pericentriolar material 1), GFRA2 (GDNF family receptor alpha 2) and HDAC4 (histone deacetylase 4). PCM1 has been reported in the centrosome in glia, and GFRA2 is localized in microglia and astrocytes. Genome-wide DNA methylation analysis is critical because it opens the possibility of finding and deepening new DNA methylation-based biomarkers in SCZ. In this sense, a study showed differentially methylated CpG sites in genes such as CD244 (CD244 molecule), MPG (Methylpurine-DNA glycosylase), and FAM173A (Mitochondrial protein-lysine N-methyltransferase), hypomethylated in SCZ patients compared to controls. The participation of CD244 in cortical microglia as part of the immune system, MPG in cell death in astrocyte cultures in the base excision-repair system, and FAM173A in mitochondrial respiration in astrocytes have all been reported. Besides, another case-control study of methylomic variation associated with SCZ performed in peripheral blood showed differentially methylated positions associated with SCZ in the body of some putative genes identified in glia such as SIK3 (SIK family kinase 3), DDO (D-aspartate oxidase), family with sequence similarity 126 member A, TNF-a induced protein 8, and IL15. Those genes participate in different cellular processes such as metabolic homeostasis, catabolic process, oligodendrocytes formation, apoptosis, and pro-inflammatory response, respectively. Genome-wide DNA methylation analysis is critical because it opens the possibility of finding and deepening new DNA methylation-based biomarkers in SCZ. It is necessary to investigate SNP and new rare variants, such as copy number variants, which may represent an important genetic component of complex diseases, such as SCZ. However, the contribution in glial interactions has not been explored yet.
It is also essential to investigate the presence of less common epigenetic marks in those SCZ-related genes whose expression was not previously associated with promoter DNA methylation, histone modifications, or miRNA expression. The presence of chemical modifications on DNA and 5-hydroxymethylcytosine (5hmC) or N (6)-methyladenine are novel modifications found in mammalian cells. There is evidence that 5hmC levels were elevated in the inferior parietal lobule of psychotic patients. Also, increased 5hmC levels were reported at GAD1 promoter in these patients, decreasing GAD67 mRNA expression.
CircRNA is a novel class of long noncoding RNA. A differential circRNA expression in postmortem dorsolateral prefrontal cortex (BA46) of SCZ patients has been suggested. Some target genes were significantly related to neurogenesis, differentiation, and synapse. Human glial cells reveal that oligodendrocytes express circRNAs more abundantly than the other glial cells. Furthermore, miRNAs dysregulation has the potential to be used as a novel SCZ diagnostic model. Recently, an elevation of miR-223 in peripheral blood samples of patients with first-episode SCZ has been observed. Some targets of miR-223 are cell migration-related genes such as INPP5B, and RHOB 78. It has even been described that some miRNAs can be released by extracellular vesicles of endocytic origin (exosomes), such as miR-497, described in the postmortem prefrontal cortex of SCZ patients. There is evidence of exosomal regulation in astrocytes and oligodendrocytes. In this sense, this class of RNAs should be explored more due to their potential importance in the pathophysiology of SCZ.
Till date, the cellular and molecular mechanisms behind SCZ remain poorly understood. However, evidence suggests glial role in SCZ, such as abnormal morphological and functional maturation of oligodendrocytes and astrocytes, contributing to hypomyelination and disrupted white matter integrity. Additionally, an increased density of microglial cells might display aberrant immune responses in psychosis. The above suggests an aberrant expression of glia-related genes in psychosis, which may be defined by genetic predisposition and the influence of epigenetic mechanisms.
The sample size is an essential aspect of population genetic studies, so much that small sample sizes will often result in the identification of few polymorphisms with large effects. An example of the above is the odds ratio (OR) observed by Bozidis et al., 2014, in the rs1136141 polymorphism (OR = 2.8, IC = 1. 08–9. 06) with a sample size of 50 first-episode psychosis patients and 50 healthy participants. In contrast, a large sample size may improve disease prediction with sufficient statistical power. In this sense, the study performed by Maeno et al., 2007, has a modest OR rs139887 (OR = 0.83, IC = 0.72–0.95) with a sample size of 915 schizophrenic patients and 927 controls. Notably, most genetic cohorts cited here have larger small sizes, except for small cohorts such as those of Pinheiro et al., 2017, and Ding et al., 2016, where the sample size was due to patients with specific treatment-resistant profiles and insufficient material in some samples, respectively. Nonetheless, future studies in larger sample sizes are necessary to confirm the findings.
Another critical factor to consider in genetic studies is the populations evaluated. The SNPs mentioned here were evaluated in populations with different ethnic origins, so the allelic frequency of each SNP can affect the OR for particular populations. For example, the allelic frequency observed for +190G/C polymorphism (rs1043618) in HSPA1A is different to the cohorts used by Kowalczyk et al., 2014, and Kim et al., 2008. Notably, the rs1043618 was significant in the Polish population (P = 0.0172), while in the Korean population (P = 0.88) it was not. Curiously, the rs1344706 was associated with lower expression of ZNF804A splice variant and SCZ, despite the different allelic frequency between the American cohort employed by Tao et al., 2014, and the British subjects recruited by O’Donovan et al., 2008. However, these observations may be influenced by the different sample sizes.
Notably, most of the gene variants described in this review are located in intronic regions. Intronic polymorphism can impact alternative splicing by interfering with splice site recognition. An example of the above is the truncated ZNF804A transcript (ZNF804AE3E4), which, when influenced by the psychosis risk polymorphism rs1344706 ZNF804AE3E4, is predicted to encode a protein lacking the zinc finger domain. Nevertheless, the effect of the exonic synonymous variant such as rs2075799 of HSPA1A gene, not to be underestimated due to the mechanism of exonic splicing enhancers in human genetic diseases, should be given more relevance.
Epigenetic changes react to environmental stimuli and are attractive targets due to their reversibility. Notwithstanding, there are still few studies described in human glial cells. Most studies cited here were performed in peripheral blood cells, except the cohorts employed by Ding et al., 2016, and Iwamoto et al., 2005, performed in the prefrontal cortex. It has been described that the DNA methylation profile in the white blood cells was significantly lower in SCZ patients in contrast with controls. However, the epigenetic changes in glial genes in peripheral tissue as possible blood biomarker signatures should be evaluated.
Antipsychotic drugs are known to influence DNA methylation and histone modification. This review includes studies with treatment-resistant SCZ, drug-naïve patients with SCZ, and medication-free subjects with SCZ. Therefore, the psychiatric treatment and the psychiatric adherence may be a source of heterogeneity. Despite the medication-free protocol being the best because it may avoid epigenetic influence, these studies are poorly explored.
Although there are many advantages to case-control studies included here, we detected several limitations. All studies cited here were performed in the frontal cortex and peripheral tissue, but none with a cell-type-specific resolution to tackle key biological questions, maybe due to cell sorting and single-cell techniques’ high costs and technical limitations. Also, the accuracy in different methods of genotyping and epigenetic essays may be causes for such heterogeneity.
SCZ is a complex biological disorder and remains poorly understood. There is evidence that suggests a strong connection between SCZ and abnormalities in the glia cells. As shown in this review, genetic and epigenetic factors that influence the expression of glia-related genes may contribute to abnormalities observed in SCZ. Understanding genetic causes and epigenetic changes that influence this mental disorder may provide valuable inputs for a reliable diagnostic system and clinical management of SCZ.
Financial support and sponsorship
This work was supported by the National Council of Science and Technology (CONACyT) under Grant CONACyT-SALUD-S0008-2015-02.
Conflicts of interest
There are no conflicts of interest.
1. Arciniegas DB Psychosis Continuum (Minneap Minn) 2015 21 715–36
2. Millan MJ, Fone K, Steckler T, Horan WP Negative symptoms of schizophrenia
:Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment Eur Neuropsychopharmacol 2014 24 645–92
3. Tripathi A, Kar SK, Shukla R Cognitive deficits in schizophrenia
:Understanding the biological correlates and remediation strategies Clin Psychopharmacol Neurosci 2018 16 7–17
4. Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, et al Schizophrenia
Nat Rev Dis Primers 2015 1 15067
5. Owen MJ, Sawa A, Mortensen PB Schizophrenia
Lancet 2016 388 86–97
6. Hercher C, Chopra V, Beasley CL Evidence for morphological alterations in prefrontal white matter glia in schizophrenia
and bipolar disorder J Psychiatry Neurosci 2014 39 376–85
7. Goudriaan A, de Leeuw C, Ripke S, Hultman CM, Sklar P, Sullivan PF, et al Specific glial functions contribute to schizophrenia
susceptibility Schizophr Bull 2014 40 925–35
8. Laskaris LE, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, et al Microglial activation and progressive brain changes in schizophrenia
Br J Pharmacol 2016 173 666–80
9. Narayan CL, Shikha D, Shekhar S Schizophrenia
in identical twins Indian J Psychiatry 2015 57 323–4
10. Henriksen MG, Nordgaard J, Jansson LB Genetics of schizophrenia
:Overview of methods, findings and limitations Front Hum Neurosci 2017 11 322
11. Maric NP, Svrakic DM Why schizophrenia
genetics needs epigenetics:A review Psychiatr Danub 2012 24 2–18
12. Schmitt A, Malchow B, Hasan A, Falkai P The impact of environmental factors in severe psychiatric disorders Front Neurosci 2014 8 19
13. Liu L, Li Y, Tollefsbol TO Gene-environment interactions and epigenetic basis of human diseases Curr Issues Mol Biol 2008 10 25–36
14. Arksey H, O'Malley L Scoping studies:Towards a methodological framework Int J Soc Res Methodol 2005 8 19–32
15. Sims R, Hollingworth P, Moskvina V, Dowzell K, O'Donovan MC, Powell J, et al Evidence that variation in the oligodendrocyte lineage transcription factor 2 (OLIG2) gene is associated with psychosis in Alzheimer's disease Neurosci Lett 2009 461 54–9
16. Maeno N, Takahashi N, Saito S, Ji X, Ishihara R, Aoyama N, et al Association of SOX10 with schizophrenia
in the Japanese population Psychiatr Genet 2007 17 227–31
17. Tao R, Cousijn H, Jaffe AE, Burnet PW, Edwards F, Eastwood SL, et al Expression of ZNF804A in human brain and alterations in schizophrenia
, bipolar disorder, and major depressive disorder:A novel transcript fetally regulated by the psychosis risk variant rs1344706 JAMA Psychiatry 2014 71 1112–20
18. O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V, et al Identification of loci associated with schizophrenia
by genome-wide association and follow-up Nat Genet 2008 40 1053–5
19. Kadasah S, Arfin M, Rizvi S, Al-Asmari M, Al-Asmari A Tumor necrosis factor-a and -b genetic polymorphisms as a risk factor in Saudi patients with schizophrenia
Neuropsychiatr Dis Treat 2017 13 1081–8
20. Suchanek-Raif R, Kucia K, Kowalczyk M, Raif P, Paul-Samojedny M, Fila-Daniłow A, et al Association study of Tumor Necrosis Factor Receptor 1 (TNFR1
) gene polymorphisms with schizophrenia
in the polish population Mediators Inflamm 2017 2017 6016023
21. Pinheiro DS, Santos RD, de Brito RB, Cruz AH, Ghedini PC, Reis AA GSTM1/GSTT1 double-null genotype increases risk of treatment-resistant schizophrenia
:A genetic association study in Brazilian patients PLoS One 2017 12 e0183812
22. Raffa M, Lakhdar R, Ghachem M, Barhoumi S, Safar MT, Bel Hadj Jrad B, et al Relationship between GSTM1 and GSTT1 polymorphisms and schizophrenia
:A case-control study in a Tunisian population Gene 2013 512 282–5
23. Kim JJ, Mandelli L, Lim S, Lim HK, Kwon OJ, Pae CU, et al Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia
Eur Arch Psychiatry Clin Neurosci 2008 258 239–44
24. Kowalczyk M, Owczarek A, Suchanek R, Paul-Samojedny M, Fila-Danilow A, Borkowska P, et al Heat shock protein 70 gene polymorphisms are associated with paranoid schizophrenia
in the Polish population Cell Stress Chaperones 2014 19 205–15
25. Bozidis P, Hyphantis T, Mantas C, Sotiropoulou M, Antypa N, Andreoulakis E, et al HSP70 polymorphisms in first psychotic episode drug-naïve schizophrenic patients Life Sci 2014 100 133–7
26. Ding L, Styblo M, Drobná Z, Hegde AN Expression of the longest RGS4 splice variant in the prefrontal cortex is associated with single nucleotide polymorphisms in schizophrenia
patients Front Psychiatry 2016 7 26
27. Kordi-Tamandani DM, Mojahed A, Sahranavard R, Najafi M Association of glutathione S-transferase gene methylation with risk of schizophrenia
in an Iranian population Pharmacology 2014 94 179–82
28. Venugopal D, Shivakumar V, Subbanna M, Kalmady SV, Amaresha AC, Agarwal SM, et al Impact of antipsychotic treatment on methylation status of interleukin-6 [IL-6] gene in Schizophrenia
J Psychiatr Res 2018 104 88–95
29. Iwamoto K, Bundo M, Yamada K, Takao H, Iwayama-Shigeno Y, Yoshikawa T, et al DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia
J Neurosci 2005 25 5376–81
30. Bönsch D, Wunschel M, Lenz B, Janssen G, Weisbrod M, Sauer H Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins Psychiatry Res 2012 198 533–7
31. Wu S, Wang P, Tao R, Yang P, Yu X, Li Y, et al Schizophrenia
-associated microRNA-148b-3p regulates COMT and PRSS16 expression by targeting the ZNF804A gene in human neuroblastoma cells Mol Med Rep 2020 22 1429–39
32. Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, et al Genome-wide DNA methylation analysis of human brain tissue from schizophrenia
patients Transl Psychiatry 2014 4 e339
33. Lee SA, Huang KC Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia
BMC Med Genomics 2016 9 68
34. van Eijk KR, de Jong S, Strengman E, Buizer-Voskamp JE, Kahn RS, Boks MP, et al Identification of schizophrenia
-associated loci by combining DNA methylation and gene expression data from whole blood Eur J Hum Genet 2015 23 1106–10
35. Kinoshita M, Numata S, Tajima A, Shimodera S, Ono S, Imamura A, et al DNA methylation signatures of peripheral leukocytes in schizophrenia
Neuromolecular Med 2013 15 95–101
36. Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R, et al An integrated genetic-epigenetic analysis of schizophrenia
:Evidence for co-localization of genetic associations and differential DNA methylation Genome Biol 2016 17 176
37. Vikhreva OV, Rakhmanova VI, Orlovskaya DD, Uranova NA Ultrastructural alterations of oligodendrocytes in prefrontal white matter in schizophrenia
:A post-mortem morphometric study Schizophr Res 2016 177 28–36
38. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, et al Oligodendrocyte dysfunction in schizophrenia
and bipolar disorder Lancet 2003 362 798–805
39. Küspert M, Hammer A, Bösl MR, Wegner M Olig2 regulates Sox10 expression in oligodendrocyte precursors through an evolutionary conserved distal enhancer Nucleic Acids Res 2011 39 1280–93
40. Melas PA, Rogdaki M, Ösby U, Schalling M, Lavebratt C, Ekström TJ Epigenetic aberrations in leukocytes of patients with schizophrenia
:Association of global DNA methylation with antipsychotic drug treatment and disease onset FASEB J 2012 26 2712–8
41. Jia P, Wang L, Fanous AH, Pato CN, Edwards TL, et alInternational Schizophrenia
Consortium Network-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia
PLoS Comput Biol 2012 8 e1002587
42. Sprooten E, Knowles EE, McKay DR, Göring HH, Curran JE, Kent JW Jr, et al Common genetic variants and gene expression associated with white matter microstructure in the human brain Neuroimage 2014 97 252–61
43. Höistad M, Segal D, Takahashi N, Sakurai T, Buxbaum JD, Hof PR Linking white and grey matter in schizophrenia
:Oligodendrocyte and neuron pathology in the prefrontal cortex Front Neuroanat 2009 3 9
44. Kubicki M, McCarley RW, Shenton ME Evidence for white matter abnormalities in schizophrenia
Curr Opin Psychiatry 2005 18 121–34
45. Bernstein HG, Steiner J, Dobrowolny H, Bogerts B ZNF804A protein is widely expressed in human brain neurons:Possible implications on normal brain structure and pathomorphologic changes in schizophrenia
Schizophr Bull 2014 40 499–500
46. Girgenti MJ, LoTurco JJ, Maher BJ ZNF804a regulates expression of the schizophrenia
-associated genes PRSS16, COMT, PDE4B, and DRD2 PLoS One 2012 7 e32404
47. Ikuta T, Peters BD, Guha S, John M, Karlsgodt KH, Lencz T, et al Aschizophrenia risk gene, ZNF804A, is associated with brain white matter microstructure Schizophr Res 2014 155 15–20
48. Rao S, Yao Y, Ryan J, Jin C, Xu Y, Huang X, et al Genetic association of rs1344706 in ZNF804A with bipolar disorder and schizophrenia
susceptibility in Chinese populations Sci Rep 2017 7 41140
49. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, et al White matter changes in schizophrenia
:Evidence for myelin-related dysfunction Arch Gen Psychiatry 2003 60 443–56
50. Vora P, Mina R, Namaka M, Frost EE A novel transcriptional regulator of myelin gene expression:Implications for neurodevelopmental disorders Neuroreport 2010 21 917–21
51. Peirce TR, Bray NJ, Williams NM, Norton N, Moskvina V, Preece A, et al Convergent evidence for 2',3'- cyclic nucleotide 3'- phosphodiesterase as a possible susceptibility gene for schizophrenia
Arch Gen Psychiatry 2006 63 18–24
52. Voineskos AN, de Luca V, Bulgin NL, van Adrichem Q, Shaikh S, Lang DJ, et al Afamily-based association study of the myelin-associated glycoprotein and 2',3'-cyclic nucleotide 3'- phosphodiesterase genes with schizophrenia
Psychiatr Genet 2008 18 143–6
53. Che R, Tang W, Zhang J, Wei Z, Zhang Z, Huang K, et al No relationship between 2',3'- cyclic nucleotide 3'-phosphodiesterase and schizophrenia
in the Chinese Han population:An expression study and meta-analysis BMC Med Genet 2009 10 31
54. Volk DW Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia
Neurobiol Dis 2017 99 58–65
55. Najjar S, Pearlman DM Neuroinflammation and white matter pathology in schizophrenia
:Systematic review Schizophr Res 2015 161 102–12
56. Girgis RR, Kumar SS, Brown AS The cytokine model of schizophrenia
:Emerging therapeutic strategies Biol Psychiatry 2014 75 292–9
57. Xiu M, Zhang G, Chen N, Chen S, Tan Y, Yin G, et al The TNF-alpha gene -1031T>C polymorphism is associated with onset age but not with risk of schizophrenia
in a Chinese population Neuropsychology 2019 33 482–9
58. Dean B, Gibbons AS, Tawadros N, Brooks L, Everall IP, Scarr E Different changes in cortical tumor necrosis factor-a-related pathways in schizophrenia
and mood disorders Mol Psychiatry 2013 18 767–73
59. Boerrigter D, Weickert TW, Lenroot R, O'Donnell M, Galletly C, Liu D, et al Using blood cytokine measures to define high inflammatory biotype of schizophrenia
and schizoaffective disorder J Neuroinflammation 2017 14 188
60. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, et al Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia
Mol Psychiatry 2013 18 206–14
61. Zakharyan R, Petrek M, Arakelyan A, Mrazek F, Atshemyan S, Boyajyan A Interleukin-6 promoter polymorphism and plasma levels in patients with schizophrenia
Tissue Antigens 2012 80 136–42
62. Kodavali CV, Watson AM, Prasad KM, Celik C, Mansour H, Yolken RH, et al HLA associations in schizophrenia
:Are we re-discovering the wheel? Am J Med Genet B Neuropsychiatr Genet 2014 165B 19–27
63. Anderson CM, Swanson RA Astrocyte glutamate transport:Review of properties, regulation, and physiological functions Glia 2000 32 1–14
64. Toker L, Mancarci BO, Tripathy S, Pavlidis P Transcriptomic evidence for alterations in astrocytes and parvalbumin interneurons in subjects with bipolar disorder and schizophrenia
Biol Psychiatry 2018 84 787–96
65. Müller N, Schwarz MJ Immune system and schizophrenia
Curr Immunol Rev 2010 6 213–20
66. Ferguson BR, Gao WJ PV interneurons:Critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders Front Neural Circuits 2018 12 37
67. Kumar S, Trivedi PK Glutathione S-transferases:Role in combating abiotic stresses including arsenic detoxification in plants Front Plant Sci 2018 9 751
68. Kano SI, Choi EY, Dohi E, Agarwal S, Chang DJ, Wilson AM, et al Glutathione S-transferases promote proinflammatory astrocyte-microglia communication during brain inflammation Sci Signal 2019 12 eaar2124
69. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Yatham LN, Young LT Prefrontal cortex glutathione S-transferase levels in patients with bipolar disorder, major depression and schizophrenia
Int J Neuropsychopharmacol 2011 14 1069–74
70. Pejovic-Milovancevic MM, Mandic-Maravic VD, Coric VM, Mitkovic-Voncina MM, Kostic MV, Savic-Radojevic AR, et al Glutathione S-transferase deletion polymorphisms in early-onset psychotic and bipolar disorders:A case-control study Lab Med 2016 47 195–204
71. Yu WW, Cao SN, Zang CX, Wang L, Yang HY, Bao XQ, et al Heat shock protein 70 suppresses neuroinflammation induced by a-synuclein in astrocytes Mol Cell Neurosci 2018 86 58–64
72. Marinova Z, Leng Y, Leeds P, Chuang DM Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons Neuropharmacology 2011 60 1109–15
73. Arion D, Unger T, Lewis DA, Levitt P, Mirnics K Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia
Biol Psychiatry 2007 62 711–21
74. Gerber KJ, Squires KE, Hepler JR Roles for regulator of G protein signaling proteins in synaptic signaling and plasticity Mol Pharmacol 2016 89 273–86
75. Buckholtz JW, Meyer-Lindenberg A, Honea RA, Straub RE, Pezawas L, Egan MF, et al Allelic variation in RGS4 impacts functional and structural connectivity in the human brain J Neurosci 2007 27 1584–93
76. Liu YL, Shen-Jang Fann C, Liu CM, Wu JY, Hung SI, Chan HY, et al Evaluation of RGS4 as a candidate gene for schizophrenia
Am J Med Genet B Neuropsychiatr Genet 2006 141B 418–20
77. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P Disease-specific changes in Regulator of G-Protein Signaling 4 (RGS4) expression in schizophrenia
Mol Psychiatry 2001 6 293–301
78. Vrajová M, Peková S, Horácek J, Höschl C The effects of siRNA-mediated RGS4 gene silencing on the whole genome transcription profile:Implications for schizophrenia
Neuro Endocrinol Lett 2011 32 246–52
79. Eastwood SL, Walker M, Hyde TM, Kleinman JE, Harrison PJ The DISC1 Ser704Cys substitution affects centrosomal localization of its binding partner PCM1 in glia in human brain Hum Mol Genet 2010 19 2487–96
80. Liu J, Chen J, Ehrlich S, Walton E, White T, Perrone-Bizzozero N, et al Methylation patterns in whole blood correlate with symptoms in schizophrenia
patients Schizophr Bull 2014 40 769–76
81. Zöller T, Attaai A, Potru PS, Ruß T, Spittau B Aged mouse cortical microglia display an activation profile suggesting immunotolerogenic functions Int J Mol Sci 2018 19 706
82. Harrison JF, Rinne ML, Kelley MR, Druzhyna NM, Wilson GL, Ledoux SP Altering DNA base excision repair:Use of nuclear and mitochondrial-targeted N-methylpurine DNA glycosylase to sensitize astroglia to chemotherapeutic agents Glia 2007 55 1416–25
83. Reddy AS, O'Brien D, Pisat N, Weichselbaum CT, Sakers K, Lisci M, et al Acomprehensive analysis of cell type-specific nuclear RNA from neurons and glia of the brain Biol Psychiatry 2017 81 252–64
84. Levy RJ, Xu B, Gogos JA, Karayiorgou M Copy number variation and psychiatric disease risk Methods Mol Biol 2012 838 97–113
85. Dong E, Gavin DP, Chen Y, Davis J Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients Transl Psychiatry 2012 2 e159
86. Mahmoudi E, Green MJ, Cairns MJ Dysregulation of circRNA expression in the peripheral blood of individuals with schizophrenia
and bipolar disorder J Mol Med (Berl) 2021 99 981–91
87. Curry-Hyde A, Gray LG, Chen BJ, Ueberham U, Arendt T, Janitz M Cell type-specific circular RNA expression in human glial cells Genomics 2020 112 5265–74
88. Saeedi S, Israel S, Nagy C, Turecki G The emerging role of exosomes in mental disorders Transl Psychiatry 2019 9 122
89. Venturini A, Passalacqua M, Pelassa S, Pastorino F, Tedesco M, Cortese K, et al Exosomes from astrocyte processes:Signaling to neurons Front Pharmacol 2019 10 1452
90. Frühbeis C, Kuo-Elsner WP, Müller C, Barth K, Peris L, Tenzer S, et al Oligodendrocytes support axonal transport and maintenance via exosome secretion PLoS Biol 2020 18 e3000621
91. Subramanian S The effects of sample size on population genomic analyses –Implications for the tests of neutrality BMC Genomics 2016 17 123
92. Tazi J, Bakkour N, Stamm S Alternative splicing and disease Biochim Biophys Acta 2009 1792 14–26
93. Blencowe BJ Exonic splicing enhancers:Mechanism of action, diversity and role in human genetic diseases Trends Biochem Sci 2000 25 106–10
94. Seo MK, Kim YH, McIntyre RS, Mansur RB, Lee Y, Carmona NE, et al Effects of antipsychotic drugs on the epigenetic modification of brain-derived neurotrophic factor gene expression in the hippocampi of chronic restraint stress rats Neural Plast 2018 2018 2682037