Impact of NRG1 HapICE gene variants on digit ratio and dermatoglyphic measures in schizophrenia.

Multiple lines of evidence have suggested a potential role of Neuregulin-1 (NRG1) in the neurodevelopmental pathogenesis of schizophrenia. Interaction between genetic risk variants present within NRG1 locus and non-specific gestational putative insults can significantly impair crucial processes of brain development. Such genetic effects can be analyzed through the assessment of digit ratio and dermatoglyphic patterns. We examined the role of two well-replicated polymorphisms of NRG1 (SNP8NRG221533 and SNP8NRG243177) on schizophrenia risk and its probable impact on the digit ratio and dermatoglyphic measures in patients (N = 221) and healthy controls (N = 200). In schizophrenia patients, but not in healthy controls, a significant association between NRG1 SNP8NRG221533 C/C genotype with lower left 2D:4D ratio, as well as with higher FA_TbcRC and DA_TbcRC. The substantial effect of SNP8NRG221533 on both digit ratio and dermatoglyphic measures suggest a potential role for NRG1 gene variants on neurodevelopmental pathogenesis of schizophrenia.

Leukocyte mitochondrial DNA copy number in schizophrenia.

OBJECTIVE: Schizophrenia is a complex neuropsychiatric disorder with significant genetic predisposition. In a subset of schizophrenia patients, mitochondrial dysfunction could be explained by the genomic defects like mitochondrial DNA Copy Number Variations, which are considered as a sensitive index of cellular oxidative stress. Given the high energy demands for neuronal functions, altered Mitochondrial DNA copy number (mtDNAcn) and consequent impaired mitochondrial physiology would significantly influence schizophrenia pathogenesis. In this context, we have made an attempt to study mitochondrial dysfunction in schizophrenia by assessing mtDNAcn in antipsychotic-naïve/free schizophrenia patients. METHOD: mtDNAcn was measured in 90 antipsychotic-naïve / free schizophrenia (SCZ) patients and 147 Healthy Controls (HC). The relative mtDNAcn was determined by quantitative real-time polymerase chain reaction (qPCR) using TaqMan® multiplex assay method. RESULT: A statistically significant difference between groups [t = 5.22, P < 0.001] was observed, with significantly lower mtDNAcn in SCZ compared to HC. The group differences persisted even after controlling for age and sex [F (4, 232) = 22.68, P < 0.001, η2 = 0.09]. CONCLUSION: Lower mtDNAcn in SCZ compared to HC suggests that mtDNAcn may hold potential to serve as an important proxy marker of mitochondrial function in antipsychotic-naïve/free SCZ patients.

Impact of antipsychotic medication on IL-6/STAT3 signaling axis in peripheral blood mononuclear cells of drug-naive schizophrenia patients.

AIM: Immunopathogenesis remains a widely appreciated etiopathological model of schizophrenia. Persistent efforts have aimed to identify schizophrenia biomarkers indexing immune system abnormalities and also immuno-dampening effects of antipsychotic medications. Although data arising from published reports are encouraging, such studies are limited to a few immune parameters and not focused on a specific pathway. Th17 cells-mediated immuno-inflammatory responses have emerged as a potential mechanism in various neuropsychiatric conditions, including schizophrenia. The Th17 pathway is distinctly regulated through a coordinated action of multiple cytokines and transcription factors. In this study, we explored whether antipsychotic medication has any effect on the cytokines and transcription factors of the Th17 pathway. METHODS: A total of 27 drug-naive schizophrenia patients were recruited and followed up for 3 months after initiation of antipsychotic medication. Lymphocyte gene expression levels of two transcription factors (STAT3 and RORC) and one of their upstream regulators, IL6, were quantified before and after treatment. Plasma levels of cytokines, such as interleukin (IL)-1ß, IL-6, IL-17A, IL-23, and IL-33, were also analyzed before and after treatment. RESULTS: Treatment with antipsychotic medication for 3 months resulted in significant downregulation of STAT3 gene expression as well as reduction in plasma levels of IL-1ß, IL-6, and IL-17A. Significant reduction in total scores for the Scale for Assessment of Positive Symptoms and the Scale for Assessment of Negative Symptoms was also observed in schizophrenia patients after 3 months of antipsychotic treatment. CONCLUSION: Our findings suggest possible immuno-modulatory effects of antipsychotic medication on the critical regulators, such as IL-6 and STAT3, of the Th17 pathway in schizophrenia patients. The IL-6/STAT3 signaling axis involved in the transcriptional regulation of Th17 cells might appear as an important target of antipsychotic treatment in schizophrenia patients. Alternatively, irrespective of the effect of antipsychotic drugs, the IL-6/STAT3 signaling axis might be crucially involved in ameliorating psychotic symptoms.

Role of IL-6/RORC/IL-22 axis in driving Th17 pathway mediated immunopathogenesis of schizophrenia.

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1ß and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients.

Impact of antipsychotic treatment on methylation status of Interleukin-6 [IL-6] gene in Schizophrenia.

Immunopathogenesis of schizophrenia has emerged as one of the predominant research paradigms in recent times. Based on the altered serum levels as well as gene expression, IL-6 has been considered as a peripheral biomarker of schizophrenia. However, the precise mechanism underlying the altered expression of IL6 in schizophrenia is inadequately known. Given the profound influence of environmental factors on schizophrenia risk, it is important to understand the effect of epigenetic changes on schizophrenia risk. Further, it is not known whether epigenetic changes modulate the expression of IL6 and its subsequent effects on the risk and progression of schizophrenia. In this study, we analysed and compared the methylation status of IL6 promoter sequence from -1200bp to +27bp in antipsychotic-naïve/free schizophrenia patients (N = 47) and matched healthy controls (N = 47) using bisulfite sequencing method. In addition, we also examined the methylation status in these patients at least after 3-months of treatment with antipsychotics (N = 40). At baseline, a state of hypomethylation was observed in the IL6 promoter of schizophrenia subjects in comparison to healthy controls. This state of hypomethylation was shown to be reversed by the administration of antipsychotics. In summary, our observations emphasize a significant role for IL-6 promoter methylation in schizophrenia pathogenesis as well as treatment with antipsychotic medications.

CHRFAM7A gene expression in schizophrenia: clinical correlates and the effect of antipsychotic treatment.

Earlier studies have implicated CHRNA7, coding α-7 nicotinic acetylcholine receptor (α7 nAChR), and its partially duplicated chimeric gene CHRFAM7A in schizophrenia. However, the relationship between the alterations in peripheral gene expression of CHRFAM7A and severity of clinical symptoms has not been examined. Furthermore, potential influence of the antipsychotic medication on CHRFAM7A expression in drug-naive or drug-free schizophrenia is an unexplored area. CHRFAM7A gene expression in lymphocytes was analyzed in 90 antipsychotic-naïve or free schizophrenia patients using TaqMan-based quantitative RT-PCR. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms (SANS). The relationship between psychopathology and CHRFAM7A expression was examined. In addition, measurement of CHRFAM7A gene expression was repeated during follow-up after short-term antipsychotic treatment in 38 patients. There was significant inverse correlation between CHRFAM7A expression and total negative psychopathology score-SANS, and this relationship persisted after accounting for possible confounders such as age, sex and smoking. On exploration of the factor structure of psychopathology using principal component analysis, all the negative symptoms-affective flattening, alogia, apathy, anhedonia and inattention were found to be inversely associated with CHRFAM7A expression. Furthermore, analysis of repeated measures revealed a significant increase in CHRFAM7A expression in patients after short-term administration of antipsychotic medication. Our study observations support the role for CHRFAM7A gene in schizophrenia pathogenesis and suggest a potential novel link between deficient CHRFAM7A expression and negative psychopathology. Furthermore, up-regulation of CHRFAM7A gene expression by antipsychotics suggests that it could be a potential state marker for clinical severity.

Influence of correlation between HLA-G polymorphism and Interleukin-6 (IL6) gene expression on the risk of schizophrenia.

Converging evidence suggests important implications of immuno-inflammatory pathway in the risk and progression of schizophrenia. Prenatal infection resulting in maternal immune activation and developmental neuroinflammation reportedly increases the risk of schizophrenia in the offspring by generating pro-inflammatory cytokines including IL-6. However, it is not known how prenatal infection can induce immuno-inflammatory responses despite the presence of immuno-inhibitory Human Leukocyte Antigen-G (HLA-G) molecules. To address this, the present study was aimed at examining the correlation between 14 bp Insertion/Deletion (INDEL) polymorphism of HLA-G and IL-6 gene expression in schizophrenia patients. The 14 bp INDEL polymorphism was studied by PCR amplification/direct sequencing and IL-6 gene expression was quantified by using real-time RT-PCR in 56 schizophrenia patients and 99 healthy controls. We observed significantly low IL6 gene expression in the peripheral mononuclear cells (PBMCs) of schizophrenia patients (t = 3.8, p = .004) compared to the controls. In addition, schizophrenia patients carrying Del/Del genotype of HLA-G 14 bp INDEL exhibited significantly lower IL6 gene expression (t = 3.1; p = .004) than the Del/Ins as well as Ins/Ins carriers. Our findings suggest that presence of "high-expressor" HLA-G 14 bp Del/Del genotype in schizophrenia patients could attenuate IL-6 mediated inflammation in schizophrenia. Based on these findings it can be assumed that HLA-G and cytokine interactions might play an important role in the immunological underpinnings of schizophrenia.

The impact of IL10 polymorphisms and sHLA-G levels on the risk of schizophrenia.

Early life immune aberrations have strongly been associated with the risk of schizophrenia. Amongst them, inflammation induced neurodevelopmental origin has emerged as one of the widely recognized underlying mechanisms. Interleukin-10 (IL-10) is an important anti-inflammatory and immunoregulatory cytokine. It modulates the expression of another immuno-inhibitory molecule, Human Leukocyte Antigen-G (HLA-G), predominantly expressed at the feto-maternal interface. Under physiological conditions, IL-10 and HLA-G molecules regulate the feto-maternal immune homeostasis by limiting the inflammatory states and influence the outcome of pregnancy. The aberrant expression of these molecules can cause pregnancy complications, which are known to confer strong risk to schizophrenia in the offspring. However, there is a considerable lack of information on the effect of the functional interactions between IL-10 and HLA-G on the risk of schizophrenia. We therefore examined the impact of possible correlation between IL-10 genetic variations and the plasma levels of soluble HLA-G (sHLA-G) on schizophrenia risk. Genotyping of IL10 (-592 C>A, -1082 A>G) single nucleotide polymorphisms (SNPs) was performed by PCR-RFLP method in 219 schizophrenia patients and 197 healthy subjects and levels of sHLA-G were estimated by ELISA in 46 patients and 44 healthy subjects. There was no significant difference in the genotype and allele frequencies between the groups for both the IL10 SNPs analyzed. However, we observed a correlation between IL10 genetic variation and plasma levels of sHLA-G in schizophrenia patients. Patients carrying CC genotype of IL10 -592C>A polymorphism had significantly lower sHLA-G levels compared to CA and AA genotypes. Our findings suggest the impact of possible correlation between IL-10 and HLA-G on schizophrenia risk.

The impact of HLA-G 3' UTR variants and sHLA-G on risk and clinical correlates of schizophrenia.

The Major Histocompatibility Complex (MHC)/Human Leukocyte Antigen (HLA) is known to influence the pathogenesis of several complex human diseases resulting from gene-environmental interactions. Recently, it has emerged as one of the risk determinants of schizophrenia. The HLA-G protein (a non-classical MHC class I molecule), encoded by the HLA-G gene, is shown to play important role in embryonic development. Importantly, its genetic variations and aberrant expression have been implicated in pregnancy complications like preeclampsia, inflammation, and autoimmunity. Converging evidence implicates these phenomena as risk mechanisms of schizophrenia. However, the functional implications of HLA-G in schizophrenia are yet to be empirically examined. The impact of two functional polymorphisms [14bp Insertion/Deletion (INDEL) and +3187 A>G] and soluble HLA-G (sHLA-G) levels on schizophrenia risk was evaluated. In this exploratory study, the Ins/Ins genotype of 14bp INDEL was found to confer a strong risk for schizophrenia. Further, low levels of sHLA-G were shown to have a significant impact on Clinical Global Impression (CGI) severity in people with schizophrenia.

Transcranial direct current stimulation and neuroplasticity genes: implications for psychiatric disorders.

BACKGROUND AND AIM: Transcranial direct current stimulation (tDCS) is a non-invasive and well-tolerated brain stimulation technique with promising efficacy as an add-on treatment for schizophrenia and for several other psychiatric disorders. tDCS modulates neuroplasticity; psychiatric disorders are established to be associated with neuroplasticity abnormalities. This review presents the summary of research on potential genetic basis of neuroplasticity-modulation mechanism underlying tDCS and its implications for treating various psychiatric disorders. METHOD: A systematic review highlighting the genes involved in neuroplasticity and their role in psychiatric disorders was carried out. The focus was on the established genetic findings of tDCS response relationship with BDNF and COMT gene polymorphisms. RESULT: Synthesis of these preliminary observations suggests the potential influence of neuroplastic genes on tDCS treatment response. These include several animal models, pharmacological studies, mentally ill and healthy human subject trials. CONCLUSION: Taking into account the rapidly unfolding understanding of tDCS and the role of synaptic plasticity disturbances in neuropsychiatric disorders, in-depth evaluation of the mechanism of action pertinent to neuroplasticity modulation with tDCS needs further systematic research. Genes such as NRG1, DISC1, as well as those linked with the glutamatergic receptor in the context of their direct role in the modulation of neuronal signalling related to neuroplasticity aberrations, are leading candidates for future research in this area. Such research studies might potentially unravel observations that might have potential translational implications in psychiatry.