Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been hypothesized to underlie the pathophysiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Mice lacking the NR2A subunit of the NMDA receptor complex are known to display abnormal behaviour, similar to schizophrenic symptoms. The expression of NR2A starts at puberty, a period corresponding to the clinical onset of schizophrenia. This evidence suggests that the NR2A (GRIN2A) gene may play a role in the development of schizophrenia and disease phenotypes. In this study, we performed a genetic analysis of this gene in schizophrenia. Analysis of the GRIN2A gene detected four single nucleotide polymorphisms, and a variable (GT)(n) repeat in the promoter region of the gene. A case-control study (375 schizophrenics and 378 controls) demonstrated evidence of an association between the repeat polymorphism and the disease (P = 0.05, Mann-Whitney test), with longer alleles overly represented in patients. An in-vitro promoter assay revealed a length dependent inhibition of transcriptional activity by the (GT)(n) repeat, which was consistent with a receptor binding assay in postmortem brains. Significantly, the score of symptom severity in chronic patients correlated with repeat size (P = 0.01, Spearman's Rank test). These results illustrate a genotype-phenotype correlation in schizophrenia and suggest that the longer (GT)(n) stretch may act as a risk-conferring factor that worsens chronic outcome by reducing GRIN2A levels in the brain.
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PMID:A microsatellite repeat in the promoter of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene suppresses transcriptional activity and correlates with chronic outcome in schizophrenia. 1272 19

Hypofunction of glutamatergic neurotransmission has been hypothesized to underlie the pathophysiology of bipolar affective disorder, as well as schizophrenia. We examined the role of the N-methyl-D-aspartate receptor 2A subunit (GRIN2A) gene on 16p13.3, a region thought to be linked to bipolar disorder, (1) because in a prior study we identified a functional and polymorphic (GT)n repeat in the 5' regulatory region of the gene, with longer alleles showing lower transcriptional activity and an over representation in schizophrenia, and (2) because of the suggestion of a genetic overlap between affective disorder and schizophrenia. Family-based association tests detected a nominally significant preferential transmission of longer alleles in a panel of 96 multiplex bipolar pedigrees. These results support the hypothesis that a hypoglutamatergic state is involved in the pathogenesis of bipolar affective disorder.
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PMID:Genetic analysis of a functional GRIN2A promoter (GT)n repeat in bipolar disorder pedigrees in humans. 1280 87

Several pieces of evidence showed that N-methyl D-aspartate (NMDA)-receptor-mediated decreases in function may be a causative factor for schizophrenia. The NMDA receptors are composed of a common glutamate receptor, an ionotropic NMDA 1 (GRIN1) subunit and one of four GRIN2 subunits (GRIN2A-GRIN2D), combined in an undetermined ratio to make up the receptor complex. In this study, we tested the hypothesis of whether the GRIN2B 366C/G and 2664C/T genetic polymorphisms are related to Chinese treatment-refractory schizophrenic patients. 193 treatment-refractory schizophrenic patients and 176 normal subjects were recruited for this study. The results demonstrated that the genotype distribution was similar between schizophrenic patients and control subjects in 366C/G (p = 0.88) and 2664C/T (p = 0.336), but we found a higher mean clozapine dosage in 2664C/C genotype patients. These results show that GRIN2B genetic variations were not a major risk factor for treatment-refractory schizophrenic patients, but may influence the effect of clozapine during treatment.
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PMID:Association analysis of the genetic variants of the N-methyl D-aspartate receptor subunit 2b (NR2b) and treatment-refractory schizophrenia in the Chinese. 1282 39

Dysfunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. In this study, we extended our analyses, by increasing the number of case-control samples to a total of 672 schizophrenics and 686 controls, and excluded potential sample stratification effects. We confirmed the significant allelic association between the repeat polymorphism and disease (P = 0.011), and as in the previous study, we observed an over-representation of longer alleles in schizophrenia. These results suggest a probable genetic effect for the GRIN2A promoter (GT)n variation on the predisposition to schizophrenia in Japanese cohorts.
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PMID:Extended analyses support the association of a functional (GT)n polymorphism in the GRIN2A promoter with Japanese schizophrenia. 1577 66

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.
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PMID:Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. 1595 69

D-Serine is an endogenous coagonist that increases the opening of N-methyl-D-aspartate (NMDA)-type glutamate receptor channels. We previously reported a reduction of D-serine serum levels in schizophrenia, supporting the disease hypothesis of NMDA receptor-mediated hypo-neurotransmission. The serum levels of D-serine are thought to reflect brain d-serine content. It is important to understand whether there is a direct link between the altered D-serine levels and NMDA receptor expression in vivo or whether these are independent processes. Two polymorphisms are known to regulate the expression of NMDA receptor subunit genes: (GT)(n) (rs3219790) in the promoter region of the NR2A subunit gene (GRIN2A) and -200T > G (rs1019385) in the NR2B gene (GRIN2B). These polymorphisms are also reported to be associated with schizophrenia. Therefore, we examined the correlation between these two polymorphisms and d-serine serum levels in mentally healthy controls, schizophrenics and the combined group. We observed no significant genotype-phenotype correlations in any of the sample groups. However, analyses of larger sample numbers and the detection of additional polymorphisms that affect gene expression are needed before we can conclude that NMDA receptor expression and serum levels of d-serine, if involved in schizophrenia pathophysiology, are independent and additive events.
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PMID:Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes. 1626 83

Dysfunction of the N-methyl-d-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia, based on the observation that non-competitive antagonists of the NMDA receptor, such as phencyclidine, induce schizophrenia-like symptoms. Previous study identified a variable (GT)n polymorphism in the promoter region of the N-methyl-d-aspartate (NMDA) subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. Our present study was aimed at confirming the association of the (GT)n polymorphism of GRIN2A promoter with schizophrenia using 122 Han Chinese sib-pair families. Non-parametric linkage analysis and transmission/disequilibrium test (TDT) were undertaken using the GENEHUNTER, v2.1. In non-parametric linkage analysis, suggestive linkage was found for the (GT)n polymorphism (NPL=2.77, P=0.002902). The TDT was significant for (GT)n polymorphism and that the (GT)23 was preferentially transmitted to schizophrenia-affected children (T/NT: 123:72, chi(2)=13.34, P=0.000260). Our results indicate that the (GT)n polymorphism in the promoter of GRIN2A gene may play a significant role in the etiology of schizophrenia among our samples.
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PMID:Significant linkage and association between a functional (GT)n polymorphism in promoter of the N-methyl-D-aspartate receptor subunit gene (GRIN2A) and schizophrenia. 1701 3

Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity.
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PMID:eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? 1732 32

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.
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PMID:Molecular mechanisms of schizophrenia. 1798 52

Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time.
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PMID:Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. 2006 Apr 16


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