DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022) and rs2228611 (genotype P = 0.004, allele P = 0.022) were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023) and allele (P = 0.0063) increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033) was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009). DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026) confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.

In schizophrenia, genetic background may provide a substrate for intrinsic maldevelopment of the brain through environmental influences, by recruiting neurotrophic factors and cytokines, to trigger the changes that lead to impaired neuronal functions. Cytokines being the key regulators of immune/inflammatory reactions are also known to influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. Therefore, functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production. We screened polymorphisms in pro- and anti-inflammatory cytokine genes using a case-control association study in a South Indian population. The role of allele, genotype, haplotype, and diplotypes of these cytokine genes and their epistatic interactions were assessed in contributing to the risk of developing schizophrenia. Meta-analysis for the reported associations was also monitored for global significance. The pro-inflammatory cytokine gene polymorphisms in IL1Ars1800587, IL6rs1800796, TNFArs361525, and IFNGrs2069718 were associated with schizophrenia. The study also provides significant evidence for strong epistatic interactions among pro-inflammatory cytokine genes IL6 and IFNG in the development of schizophrenia. In silico analysis suggested that associated risk variants were indicative of altered transcriptional activity with higher production of IL1α, IL-6, TNF-α, and IFN-ɤ cytokines. Meta-analysis indicated heterogeneity among study population while IL1Ars1800587 was found to be globally significant. It is important to identify the nature of inflammatory response that can be amplified by the environment, to influence either Th1 response or Th2 response. The associated functional variants in the study are involved with increased expression resulting in higher production of the pro-inflammatory cytokines IL-1α, IL-6, TNF-α, and IFN-γ. The interaction of immunological stressors with these high producer alleles of pro-inflammatory cytokines may suggest that even a lower threshold may be sufficient to induce a resultant chronic effect on the psycho-social and environmental stressors that may result in the development and pathogenesis of schizophrenia. Understanding environmental factors that influence the expression of these pro-inflammatory cytokine genes or their interaction can possibly help in dissecting the phenotypic variation and therapeutic response to antipsychotics in schizophrenia.

Aim: The present study intends to evaluate whether antipsychotic drugs can modulate the host epigenome and if so whether drug-induced epigenetic modulation can explain the heterogeneity in drug response. Methods: Present study was conducted in in vitro cells and significance of these in vitro observations was further evaluated in a clinical setting, between drug responsive and nonresponsive schizophrenia patients. A number of DNA modifications were assessed at global level using 5-methylcytosine, 5-hydroxymethylcytosine and 5-formylcytosine followed by evaluating the expression of epigenetic modifier genes and their crosstalk with miRNAs. Results: In vitro data demonstrated that antipsychotic drugs induce epigenetic response by downregulating miRNA that target DNA methyltransferases, resulting in global hypermethylation. Similar trend was observed in clinical setting too and alterations were markedly associated with drug response rather than disease pathogenesis. Conclusion: Study demonstrates that antips...

The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.

BACKGROUND AND PURPOSE: Very few data are available with regard to high-resolution intracranial vessel wall imaging characteristics of Moyamoya disease and their relation to ischemic stroke risk. We investigated the high resolution imaging characteristics of MMD and its correlation with recent ischemic events. MATERIALS AND METHODS: Patients with Moyamoya disease confirmed by DSA, including patients after revascularization, were enrolled. All the patients underwent high-resolution intracranial vessel wall imaging. Vessel wall thickening, enhancement, and the remodeling index of the bilateral distal ICA and proximal MCA were noted. The patients were followed up at 3 months and 6 months after high-resolution intracranial vessel wall imaging and the association of ischemic events with imaging characteristics was assessed. RESULTS: Twenty-nine patients with Moyamoya disease were enrolled. The median age at symptom onset was 12 years (range, 1–51 years). A total of 166 steno-occlusive lesions were detected by high-resolution intracranial vessel wall imaging. Eleven lesions with concentric wall thickening (6.6%) were noted in 9 patients. Ten concentric contrast-enhancing lesions were observed in 8 patients, of which 3 patients (4 lesions) showed grade II enhancement. The presence of contrast enhancement (P = .01) and wall thickening (P ≤ .001) showed a statistically significant association with ischemic events within 3 months before and after the vessel wall imaging. Grade II enhancement showed a statistically significant (P = .02) association with ischemic events within 4 weeks of high-resolution intracranial vessel wall imaging. The mean ± standard deviation outer diameter of the distal ICA (right, −3.3 ± 0.68 mm; left, 3.4 ± 0.60 mm) and the remodeling index (right, 0.71 ± 0.13; left, 0.69 ± 0.13) were lower in Moyamoya disease. CONCLUSIONS: High-resolution intracranial vessel wall imaging characteristics of concentric wall thickening and enhancement are relatively rare in our cohort of patients with Moyamoya disease. The presence of wall thickening and enhancement may predict future ischemic events in patients with Moyamoya disease.