1Psychiatr. Genet. 2001 Dec 11: 219-22
PMID11807413
TitleAssociation analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia.
AbstractIt is known that a syndrome resembling schizophrenia is produced by the N-methyl-d-aspartate receptor antagonists. It has also been demonstrated that the level of an ionotropic N-methyl-d-aspartate 2B subunit (GRIN2B) of the glutamate receptor tends to increase after subchronic administration of clozapine, suggesting that GRIN2B may play an active role in the pathogenesis of schizophrenia and the function of clozapine medication. We studied 100 schizophrenic patients, investigating the associations for the GRIN2B genetic variants, and psychiatric symptoms and clozapine response. No significant differences were demonstrated comparing these three groups in terms of the baseline Brief Psychiatric Rating Scale (BPRS) score (P = 0.441). The percentage of patients scoring within 20% of baseline BPRS after clozapine treatment was similar for the three genotype groups (P = 0.132). A marginally higher mean clozapine dosage was revealed, however, for patients bearing the 2664C/C genotype (P = 0.013). Although replication of this research is required to confirm the results, an association for the GRIN2B C2664T polymorphism and clozapine treatment is suggested from our findings, which may assist in the prediction of optimal dosage for schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2Psychiatr. Genet. 2001 Dec 11: 219-22
PMID11807413
TitleAssociation analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia.
AbstractIt is known that a syndrome resembling schizophrenia is produced by the N-methyl-d-aspartate receptor antagonists. It has also been demonstrated that the level of an ionotropic N-methyl-d-aspartate 2B subunit (GRIN2B) of the glutamate receptor tends to increase after subchronic administration of clozapine, suggesting that GRIN2B may play an active role in the pathogenesis of schizophrenia and the function of clozapine medication. We studied 100 schizophrenic patients, investigating the associations for the GRIN2B genetic variants, and psychiatric symptoms and clozapine response. No significant differences were demonstrated comparing these three groups in terms of the baseline Brief Psychiatric Rating Scale (BPRS) score (P = 0.441). The percentage of patients scoring within 20% of baseline BPRS after clozapine treatment was similar for the three genotype groups (P = 0.132). A marginally higher mean clozapine dosage was revealed, however, for patients bearing the 2664C/C genotype (P = 0.013). Although replication of this research is required to confirm the results, an association for the GRIN2B C2664T polymorphism and clozapine treatment is suggested from our findings, which may assist in the prediction of optimal dosage for schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3Mol. Psychiatry 2001 Mar 6: 211-6
PMID11317224
TitleMutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia.
AbstractNMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4Neuropsychobiology 2003 -1 47: 178-81
PMID12824739
TitleAssociation analysis of the genetic variants of the N-methyl D-aspartate receptor subunit 2b (NR2b) and treatment-refractory schizophrenia in the Chinese.
AbstractSeveral 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5Neuropsychobiology 2003 -1 47: 178-81
PMID12824739
TitleAssociation analysis of the genetic variants of the N-methyl D-aspartate receptor subunit 2b (NR2b) and treatment-refractory schizophrenia in the Chinese.
AbstractSeveral 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6Ann. N. Y. Acad. Sci. 2003 Nov 1003: 22-35
PMID14684433
TitleGenomics and variation of ionotropic glutamate receptors.
AbstractSequencing of the human, mouse, and rat genomes has enabled a comprehensive informatics approach to gene families. This approach is informative for identification of new members of gene families, for cross-species sequence conservation related to functional conservation, for within-species diversity related to functional variation, and for historical effects of selection. This genome informatics approach also focuses our attention on genes whose genomic locations coincide with linkages to phenotypes. We are identifying ionotropic glutamate receptor (IGR) sequence variation by resequencing technologies, including denaturing high-performance liquid chromoatography (dHPLC), for screening and direct sequencing, and by information mining of public (e.g., dbSNP and ENSEMBL) and private (i.e., Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map (for example, the Celera map) are established, and comparison to mouse and rat sequences has been performed, revealing substantial conservation of these genes, which are located on different chromosomes but found within syntenic groups of genes. A collection of 38 missense variants were identified by the informatics and resequencing approaches in several of these receptor genes, including GRIN2B, GRIN3B, GRIA2, GRIA3, and GRIK1. This represents only a fraction of the sequence variation across these genes, but, in fact, these may constitute a large fraction of the common polymorphisms at these genes, and these polymorphisms are a starting point for understanding the role of these receptors in neurogenetic variation. Genetically influenced human neurobehavioral phenotypes that are likely to be linked to IGR genetic variants include addictions, anxiety/dysphoria disorders, post-brain injury behavioral disorders, schizophrenia, epilepsy, pain perception, learning, and cognition. Thus, the effects of glutamate receptor variation may be protean, and the task of relating variation to behavior difficult. However, functional variants of (1) catechol-O-methyltransferase, (2) serotonin transporter, and (3) brain-derived neurotrophic factor have recently been linked both to behavioral differences and to intermediate phenotypes, suggesting a pathway by which functional variation at IGRs can be tied to an etiologically complex phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 27-9
PMID15211626
TitleVariations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study.
AbstractA well established model for the pathophysiology of schizophrenia postulates a role for the NMDA-mediated glutamate transmission. The human gene coding for the 2B subunit of the NMDA receptor (GRIN2B) is considered a candidate based on its selective expression in brain. To evaluate the hypothesis that GRIN2B acts as a major gene in determining susceptibility to schizophrenia, a case-control association study was performed. Five single nucleotide polymorphisms (SNPs) were genotyped in 188 Italian patients and 156 control subjects. The association study showed a marginally significant excess of homozygosity for the polymorphism located in the 3'UTR region (P = 0.04). No other difference in genotype and allele frequencies was found in schizophrenics as compared to the control series. The case-control study was also carried out on estimated haplotypes, confirming a trend for association (P = 0.04). These results suggest that GRIN2B variations might be linked with susceptibility to schizophrenia. Replication studies on larger samples are warranted to further test this hypothesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 27-9
PMID15211626
TitleVariations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study.
AbstractA well established model for the pathophysiology of schizophrenia postulates a role for the NMDA-mediated glutamate transmission. The human gene coding for the 2B subunit of the NMDA receptor (GRIN2B) is considered a candidate based on its selective expression in brain. To evaluate the hypothesis that GRIN2B acts as a major gene in determining susceptibility to schizophrenia, a case-control association study was performed. Five single nucleotide polymorphisms (SNPs) were genotyped in 188 Italian patients and 156 control subjects. The association study showed a marginally significant excess of homozygosity for the polymorphism located in the 3'UTR region (P = 0.04). No other difference in genotype and allele frequencies was found in schizophrenics as compared to the control series. The case-control study was also carried out on estimated haplotypes, confirming a trend for association (P = 0.04). These results suggest that GRIN2B variations might be linked with susceptibility to schizophrenia. Replication studies on larger samples are warranted to further test this hypothesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9Am J Pharmacogenomics 2005 -1 5: 149-60
PMID15952869
TitleGenetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope.
AbstractNo 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Am. J. Hum. Genet. 2005 Dec 77: 918-36
PMID16380905
TitleBipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.
AbstractBipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
11Eur. J. Hum. Genet. 2005 Jul 13: 807-14
PMID15841096
TitleAn association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray.
AbstractDysfunction of the N-methyl-D-aspartate (NMDA) receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of several antagonists and on observation of genetic animal models. To conduct association analysis of the NMDA receptors in the Chinese population, we examined 16 reported SNPs across the NMDA receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B), five of which were identified in the Chinese population. In this study, we combined universal DNA microarray and ligase detection reaction (LDR) for the purposes of association analysis, an approach we considered to be highly specific as well as offering a potentially high throughput of SNP genotyping. The association study was performed using 253 Chinese patients with schizophrenia and 140 Chinese control subjects. No significant frequency differences were found in the analysis of the alleles but some were found in the haplotypes of the GRIN2B gene. The interactions between the GRIN1 and GRIN2B genes were evaluated using the multifactor-dimensionality reduction (MDR) method, which showed a significant genetic interaction between the G1001C in the GRIN1 gene and the T4197C and T5988C polymorphisms in the GRIN2B gene. These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GRIN2B genes might be involved in the etiology of schizophrenia.European Journal of Human Genetics (2005) 13, 807-814. doi:10.1038/sj.ejhg.5201418 Published online 20 April 2005.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Neurosci. Lett. 2006 Feb 394: 101-4
PMID16266783
TitleAnalysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes.
AbstractD-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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Neurosci. Lett. 2006 Feb 394: 101-4
PMID16266783
TitleAnalysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes.
AbstractD-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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14Schizophr. Res. 2006 Jun 84: 214-21
PMID16549338
TitleN-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.
AbstractThe NR2B protein is a critical structural and functional subunit of the NMDA glutamate receptor. The glutamate neurotransmitter system has been implicated in psychosis and schizophrenia, and so we looked for genetic association and measured gene expression in human DNA and brain samples, respectively, of the GRIN2B gene that codes for the NR2B protein. We tested three genetic polymorphisms: G-200T (5'UTR), A5806C and T5988C (both 3'UTR) in 180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms). We measured brain GRIN2B mRNA levels in schizophrenia, bipolar disorder and unaffected controls (n = 35 each). We detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15Schizophr Bull 2007 Nov 33: 1343-53
PMID17329232
TitleeIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia?
AbstractBipolar 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
16Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19
PMID17239033
TitleMolecular genetics of bipolar disorder and depression.
AbstractIn this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
17Genet. Med. 2007 Jan 9: 4-8
PMID17224684
TitleAssociation study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: a HuGE review and meta-analysis.
Abstractschizophrenia is a severe mental illness to which hypofunction of the N-methyl-D-aspartate receptors has been linked. Association studies have implicated the N-methyl-D-aspartate receptor 2B subunit gene (GRIN2B) as a candidate for schizophrenia. Subsequent studies have attempted to replicate the association, but the results have been mixed and thus inconclusive. It is necessary to explain the inconsistency of these results and to clarify the contribution of the GRIN2B gene to schizophrenia. The current meta-analysis covers all published association studies up to January 2006 using systematic allelic and genotypic analyses involving five polymorphisms. The results show evidence of a statistically significant association for GRIN2B. The association seems weaker, but nonetheless interesting. The meta-analysis supports the involvement of the glutamate system of the brain in the pathogenesis of schizophrenia. This may be the first systematic meta-analysis study focusing on GRIN2B.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
18Psychiatry Res 2007 Dec 153: 271-5
PMID17669510
TitleAssociation analysis of polymorphisms in the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) gene and tardive dyskinesia in schizophrenia.
AbstractTardive dyskinesia (TD) is a neurological disorder characterized by irregular, non-rhythmic, choreoathetotic and involuntary movements in single or multiple body regions. Chronic administration of typical antipsychotic agents, which predominantly act on dopamine receptors, implicates the dopamine system in susceptibility to TD. An alternative to this dopaminergic supersensivity hypothesis in understanding the pathogenesis of TD is the glutamatergic neurotoxicity hypothesis, which implicates the N-methyl-D-aspartate (NMDA) receptor in TD pathogenesis. In the present study, the association between three polymorphisms (T-200G, C366G and C2664T) of the GRIN2B gene, which encodes the 2B subunit of the NMDA receptor, and the occurrence and severity of TD were investigated in 273 Chinese schizophrenic patients receiving long-term antipsychotic treatment (TD: 142, non-TD: 133). There was no significant association between patients' genotype and allele frequencies and TD occurrence. Among the TD patients, the differences in the total scores on the Abnormal Involuntary Movement Scale (AIMS) among the three genotypes of each polymorphism were not significant. Because the three studied markers are in weak linkage disequilibrium with each other, haplotype-based association was not carried out. We conclude that genetic variations in the human GRIN2B gene probably do not play a major role in susceptibility to, or severity of TD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
19Psychiatry Res 2007 Dec 153: 271-5
PMID17669510
TitleAssociation analysis of polymorphisms in the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) gene and tardive dyskinesia in schizophrenia.
AbstractTardive dyskinesia (TD) is a neurological disorder characterized by irregular, non-rhythmic, choreoathetotic and involuntary movements in single or multiple body regions. Chronic administration of typical antipsychotic agents, which predominantly act on dopamine receptors, implicates the dopamine system in susceptibility to TD. An alternative to this dopaminergic supersensivity hypothesis in understanding the pathogenesis of TD is the glutamatergic neurotoxicity hypothesis, which implicates the N-methyl-D-aspartate (NMDA) receptor in TD pathogenesis. In the present study, the association between three polymorphisms (T-200G, C366G and C2664T) of the GRIN2B gene, which encodes the 2B subunit of the NMDA receptor, and the occurrence and severity of TD were investigated in 273 Chinese schizophrenic patients receiving long-term antipsychotic treatment (TD: 142, non-TD: 133). There was no significant association between patients' genotype and allele frequencies and TD occurrence. Among the TD patients, the differences in the total scores on the Abnormal Involuntary Movement Scale (AIMS) among the three genotypes of each polymorphism were not significant. Because the three studied markers are in weak linkage disequilibrium with each other, haplotype-based association was not carried out. We conclude that genetic variations in the human GRIN2B gene probably do not play a major role in susceptibility to, or severity of TD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
20Nat. Genet. 2008 Jul 40: 827-34
PMID18583979
TitleSystematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.
AbstractIn an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
21Fa Yi Xue Za Zhi 2008 Oct 24: 369-74, 377
PMID18979923
Title[The association between glutamate receptor gene SNP and schizophrenia].
AbstractGlutamate is a necessary excitatory neurotransmitter in human nervous system, which runs a biological function by binding with corresponding receptors. Psychiatric diseases occur when genes which encode receptors become dysfunctional. The authors have reviewed related literature and summarized the association between schizophrenia and glutamate receptor gene SNPs such as rs11146020 in GRIN1, 366C/G in GRIN2B, and rs1468412 in GRM3, etc. Due to controversial results in various studies, it is hypothesized that schizophrenia are complicated polygenic inherited diseases. Some sites such as 366C/G, 2664C/T and rs1408766 (C/T) possess with valuable genetic polymorphisms and might potentially contribute to personal identification and paternity testing. Studies in this field may have a potential significance in forensic psychiatry practice.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
22Psychiatr. Genet. 2010 Oct 20: 191-8
PMID20421849
TitleHabituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B).
AbstractTo identify the reliable connectivity between causal genes or variants with an abnormality expressed in a certain endophenotype has been viewed as a crucial step in unraveling the etiology of schizophrenia because of the considerable heterogeneity in this disorder.
According to this practical and scientific demand, we aimed to investigate the relationship between seven top-ranked variants in the SZgene database [120-bpTR in DRD4, rs1801028 and rs6277 in DRD2, rs1019385 (T200G) in GRIN2B, rs1800532 in TPH1, rs1801133 (C677T) in MTHFR, rs2619528 (P1765) in DTNBP1] and prepulse inhibition (PPI) and habituation after acoustic stimulus (HAB).
Both PPI and HAB were decreased significantly in patients with schizophrenia. In addition, we observed a significant effect of GRIN2B (human NMDA receptor 2B subunit gene, NR2B) genotype on HAB (P<0.05, not corrected).
Although these findings need to be replicated in other samples, an underlying mechanism of impaired biological reaction may be influenced by NMDA hypofunctioning in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
23Neurosci Biobehav Rev 2010 May 34: 958-77
PMID20060416
TitleGenetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance.
Abstractschizophrenia (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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
24Neurosci. Lett. 2010 Jul 478: 61-5
PMID20438806
TitleAssociation analysis of GRIN1 and GRIN2B polymorphisms and Parkinson's disease in a hospital-based case-control study.
AbstractHyperactivation of N-methyl-d-aspartate receptors (NMDARs) leads to neuronal excitotoxicity and is suggested to play a role in many brain disorders, including Alzheimer's disease and schizophrenia. However, the association between polymorphisms in the genes that code for NMDAR subunits, N-methyl-d-aspartate 1 and 2B (GRIN1 and GRIN2B) and Parkinson's disease (PD) remains unclear. In a hospital-based case-control study of PD, DNA samples were collected from 101 PD patients and 205 healthy controls. Genotyping assays were used to screen for polymorphisms in the GRIN1 (rs2301364 T>C, rs28489906 T>C, and rs4880213 T>C) and GRIN2B (C366G, C2664T, and rs1805476 T>G) genes, and logistic regression analysis was then used to assess the association between these single nucleotide polymorphisms (SNPs) and PD susceptibility. None of the 6 SNPs were significantly associated with PD risk on their own. However, in conjunction with putative low-risk genotypes for the GRIN1 gene, the GRIN2BC366G variant was significantly associated with reduced PD risk compared with the homozygous genotype 366CC (OR=0.38, 95%CI=0.17-0.93, P=0.033). A synergistic effect on risk reduction was observed in subjects who carried multiple polymorphisms of GRIN1 and the GRIN2BC366G polymorphism (OR=0.78, 95%CI=0.59-1.02, P(trend)=0.073). Our results suggest that polymorphisms in the GRIN1 and GRIN2B genes may serve as potential biomarkers for a reduced risk of PD among the Chinese population in Taiwan.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
25Brain Res. Bull. 2010 Sep 83: 108-21
PMID20417696
TitleN-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?
Abstractschizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-d-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and d-amino acid oxidase/G72 that regulate brain d-serine synthesis. Reductions in plasma and brain glycine, d-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
26AMIA Annu Symp Proc 2011 -1 2011: 1127-33
PMID22195173
TitleExploring schizophrenia drug-gene interactions through molecular network and pathway modeling.
AbstractIn this study, we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database. These drugs had interactions with 142 targets, whose corresponding genes were defined as drug targeted genes. To explore the complexity between these drugs and their related genes in schizophrenia, we constructed a drug-target gene network. These genes were overrepresented in several pathways including: neuroactive ligand-receptor pathways, glutamate metabolism, and glycine metabolism. Through integrating the pathway information into a drug-gene network, we revealed a few bridge genes connected the sub-networks of the drug-gene network: GRIN2A, GRIN3B, GRIN2C, GRIN2B, DRD1, and DRD2. These genes encode ionotropic glutamate receptors belonging to the NMDA receptor family and dopamine receptors. Haloperidol was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia. This study represents the first systematic investigation of drug-gene interactions in psychosis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
27Physiol. Behav. 2011 Aug 104: 334-9
PMID21382392
TitleStrain dependent effects of prenatal stress on gene expression in the rat hippocampus.
AbstractMultiple animal models have been developed to recapitulate phenotypes of the human disease, schizophrenia. A model that simulates many of the cognitive and sensory deficits of the disorder is the use of random variable prenatal stress (PS) in the rat. These deficits suggest a molecular origin in the hippocampus, a brain region that plays a role in the regulation of stress. To study both hippocampal gene expression changes in offspring of prenatally stressed dams and to address genetic variability, we used a random array of prenatal stressors in three different rat strains with diverse responses to stress: Fischer, Sprague-Dawley, and Lewis rats. Candidate genes involved in stress, schizophrenia, cognition, neurotrophic effects, and immunity were selected for assessment by real-time quantitative PCR under resting conditions and following a brief exposure to restraint stress. PS resulted in significant differences in gene expression in the offspring that were strain dependent. mRNA expression for the N-methyl-D-aspartate receptor subtype 2B (GRIN2B) was increased, and tumor necrosis factor-alpha (Tnf?) transcript was decreased in PS Sprague-Dawley and Lewis rats, but not in the Fischer rats. Expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus was increased after an acute stress in all controls of each strain, yet a decrease was seen after acute stress in the PS Sprague-Dawley and Lewis rats. Expression of the glucocorticoid receptor (Nr3c1) was decreased in the Fischer strain when compared to Lewis or Sprague-Dawley rats, though the Fischer rats had markedly higher ?7 nicotinic receptor (Chrna7) expression. The expression differences seen in these animals may be important elements of the phenotypic differences seen due to PS and genetic background.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
28PLoS Genet. 2011 Feb 7: e1001318
PMID21383861
TitleA population genetic approach to mapping neurological disorder genes using deep resequencing.
AbstractDeep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n ?= ?285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
29Cytogenet. Genome Res. 2011 -1 135: 228-40
PMID22085975
TitleDisentangling the myriad genomics of complex disorders, specifically focusing on autism, epilepsy, and schizophrenia.
AbstractAnalyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid 'diagnostic fatalism' (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
30Behav. Brain Res. 2011 Nov 225: 284-9
PMID21827795
TitleVariation in the NMDA receptor 2B subunit gene GRIN2B is associated with differential language lateralization.
AbstractVariations in the N-methyl-d-aspartate receptor 2B subunit gene (GRIN2B) have been associated with schizophrenia, a psychiatric disorder associated with reduced left-hemispheric language dominance. Here, we investigated, whether different polymorphisms in GRIN2B influence language lateralization and handedness in healthy individuals. In a cohort of 424 genetically unrelated participants we found significant association between the synonymous GRIN2B variation rs1806201 and language lateralization assessed using the dichotic listening task. Individuals carrying the heterozygous CT genotype exhibited more pronounced left-hemispheric language dominance as compared to both homozygous CC and TT individuals. Such an association was not identified for handedness. These findings suggest that variation in NMDA-receptors contributes to the interindividual variability of language lateralization.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
31Behav Brain Funct 2011 -1 7: 43
PMID21981786
TitleThe genetic validation of heterogeneity in schizophrenia.
Abstractschizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV.
Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors.
No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39).
The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
32Pharmacogenet. Genomics 2011 Apr 21: 206-16
PMID20859245
TitleGlutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol.
AbstractThe glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.
We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.
We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.
This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
33J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2011 Nov 879: 3169-83
PMID21992750
TitleAnalysis of free D-serine in mammals and its biological relevance.
AbstractD-Serine is a unique endogenous substance enriched in the brain at the exceptionally high concentrations as a free D-amino acid in mammals throughout their life. Peripheral tissues and blood contain low or trace levels of the D-amino acid. In the nervous systems, D-serine appears to act as an intrinsic coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDA receptor) based upon the following characteristics: (i) D-serine stereoselectively binds to and stimulates the glycine-regulatory site of the NMDA receptor consisting of GRIN1/GRIN2 subunits more potently than glycine with an affinity and ED50 at high nanomolar ranges, (ii) the selective elimination of D-serine in brain tissues attenuates the NMDA receptor functions, indicating an indispensable role in physiological activation of the glutamate receptor, and (iii) the distribution of D-serine is uneven and closely correlated with that of the binding densities of the various NMDA receptor sites, and especially of the GRIN2B subunit in the brain. Moreover, d-serine exerts substantial influence on the GRIN1/GRIN3-NMDA and ?2 glutamate receptor. In the brain and retina, metabolic processes of D-serine, such as biosynthesis, extracellular release, uptake, and degradation, are observed and some candidate molecules that mediate these processes have been isolated. The fact that the mode of extracellular release of D-serine in the brain differs from that of classical neurotransmitters is likely to be related to the detection of D-serine in both glial cells and neurons, suggesting that d-serine signals could be required for the glia-synapse interaction. Moreover, the findings from the basic experiments and clinical observations support the views that the signaling system of endogenous free D-serine plays important roles, at least, through the action on the NMDA receptors in the brain wiring development and the regulation of higher brain functions, including cognitive, emotional and sensorimotor function. Based upon these data, aberrant D-serine-NMDA receptor interactions have been considered to be involved in the pathophysiology of a variety of neuropsychiatric disorders including schizophrenia and ischemic neuronal cell death. The molecular and cellular mechanisms for regulating the D-serine signals in the nervous system are, therefore, suitable targets for studies aiming to elucidate the causes of neuropsychiatric disorders and for the development of new treatments for intractable neuropsychiatric symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
34Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Dec 156B: 913-22
PMID21919190
TitleAssociation of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
AbstractN-methyl-D-aspartate (NMDA) receptors are very important for proper brain development and several lines of evidence support that hypofunction of the NMDA receptors are involved in the pathophysiology of schizophrenia. Gene variation and gene-environmental interactions involving the genes encoding the NMDA receptors are therefore likely to influence the risk of schizophrenia. The aim of this study was to determine (1) whether SNP variation in the genes (GRIN1, GRIN2A, GRIN2B, GRIN2C, and GRIN2D) encoding the NMDA receptor were associated with schizophrenia; (2) whether GRIN gene variation in the offspring interacted with maternal herpes simplex virus-2 (HSV-2) seropositivity during pregnancy influencing the risk of schizophrenia later in life. Individuals from three independently collected Danish case control samples were genotyped for 81 tagSNPs (in total 984 individuals diagnosed with schizophrenia and 1,500 control persons) and antibodies against maternal HSV-2 infection were measured in one of the samples (365 cases and 365 controls). Nine SNPs out of 30 in GRIN2B were significantly associated with schizophrenia. One SNP remained significant after Bonferroni correction (rs1806194, P(nominal) ?= 0.0008). Significant interaction between maternal HSV-2 seropositivity and GRIN2B genetic variation in the offspring were observed for seven SNPs and two remained significant after Bonferroni correction (rs1805539, P(nominal) ?= 0.0001 and rs1806205, P(nominal) ?= 0.0008). The significant associations and interactions were located at the 3' region of GRIN2B suggesting that genetic variation in this part of the gene may be involved in the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
35Transl Psychiatry 2011 -1 1: e55
PMID22833210
TitleRare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.
AbstractPharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
36Genes Brain Behav. 2011 Jun 10: 410-7
PMID21281445
TitlePolymorphisms associated with normal memory variation also affect memory impairment in schizophrenia.
AbstractNeurocognitive dysfunction is a core feature of schizophrenia with particularly prominent deficits in verbal episodic memory. The molecular basis of this memory impairment is poorly understood and its relatedness to normal variation in memory performance is unclear. In this study, we explore, in a sample of cognitively impaired schizophrenia patients, the role of polymorphisms in seven genes recently reported to modulate episodic memory in normal subjects. Three polymorphisms (GRIN2B rs220599, GRM3 rs2189814 and PRKCA rs8074995) were associated with episodic verbal memory in both control and patients with cognitive deficit, but not in cognitively spared patients or the pooled schizophrenia sample. GRM3 and PRKCA acted in opposite directions in patients compared to controls, possibly reflecting an abnormal brain milieu and/or adverse environmental effects in schizophrenia. The encoded proteins balance glutamate signalling vs. excitotoxicity in complex interactions involving the excitatory amino acid transporter 2 (EAAT2), implicated in the dysfunctional glutamatergic signalling in schizophrenia. Double carrier status of the GRM3 and PRKCA minor alleles was associated with lower memory test scores and with increased risk of schizophrenia. Single nucleotide polymorphism (SNP) rs8074995 lies within the PRKCA region spanned by a rare haplotype associated with schizophrenia in a recent UK study and provides further evidence of PRKCA contribution to memory impairment and susceptibility to schizophrenia. Our study supports the utility of parsing the broad phenotype of schizophrenia into component cognitive endophenotypes that reduce heterogeneity and enable the capture of potentially important genetic associations.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
37Mol. Psychiatry 2012 Sep 17: 887-905
PMID22584867
TitleConvergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.
AbstractWe have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
38Cell 2012 Apr 149: 525-37
PMID22521361
TitleSequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.
AbstractBalanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci anda significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
39Schizophr. Res. 2012 Nov 141: 274-6
PMID22986046
TitleAbsence of de novo point mutations in exons of GRIN2B in a large schizophrenia trio sample.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
40PLoS ONE 2012 -1 7: e50970
PMID23226551
TitleAntipsychotic-induced movement disorders in long-stay psychiatric patients and 45 tag SNPs in 7 candidate genes: a prospective study.
AbstractFour types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1).
Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders.
Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained.
The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
41PLoS Comput. Biol. 2012 -1 8: e1002587
PMID22792057
TitleNetwork-assisted investigation of combined causal signals from genome-wide association studies in schizophrenia.
AbstractWith the recent success of genome-wide association studies (GWAS), a wealth of association data has been accomplished for more than 200 complex diseases/traits, proposing a strong demand for data integration and interpretation. A combinatory analysis of multiple GWAS datasets, or an integrative analysis of GWAS data and other high-throughput data, has been particularly promising. In this study, we proposed an integrative analysis framework of multiple GWAS datasets by overlaying association signals onto the protein-protein interaction network, and demonstrated it using schizophrenia datasets. Building on a dense module search algorithm, we first searched for significantly enriched subnetworks for schizophrenia in each single GWAS dataset and then implemented a discovery-evaluation strategy to identify module genes with consistent association signals. We validated the module genes in an independent dataset, and also examined them through meta-analysis of the related SNPs using multiple GWAS datasets. As a result, we identified 205 module genes with a joint effect significantly associated with schizophrenia; these module genes included a number of well-studied candidate genes such as DISC1, GNA12, GNA13, GNAI1, GPR17, and GRIN2B. Further functional analysis suggested these genes are involved in neuronal related processes. Additionally, meta-analysis found that 18 SNPs in 9 module genes had P(meta)<1 10??, including the gene HLA-DQA1 located in the MHC region on chromosome 6, which was reported in previous studies using the largest cohort of schizophrenia patients to date. These results demonstrated our bi-directional network-based strategy is efficient for identifying disease-associated genes with modest signals in GWAS datasets. This approach can be applied to any other complex diseases/traits where multiple GWAS datasets are available.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
42Front Pharmacol 2013 -1 4: 99
PMID23950745
TitleComorbid obsessive-compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors.
AbstractA large subgroup of around 25% of schizophrenia patients suffers from obsessive-compulsive symptoms (OCS) and about 12% fulfill the diagnostic criteria of an obsessive-compulsive disorder (OCD). The additional occurrence of OCS is associated with high subjective burden of disease, additional neurocognitive impairment, poorer social and vocational functioning, greater service utilization and high levels of anxiety and depression. Comorbid patients can be assigned to heterogeneous subgroups. One hypothesis assumes that second generation antipsychotics (SGAs), most importantly clozapine, might aggravate or even induce second-onset OCS. Several arguments support this assumption, most importantly the observed chronological order of first psychotic manifestation, start of treatment with clozapine and onset of OCS. In addition, correlations between OCS-severity and dose and serum levels and duration of clozapine treatment hint toward a dose-dependent side effect. It has been hypothesized that genetic risk-factors dispose patients with schizophrenia to develop OCS. One study in a South Korean sample reported associations with polymorphisms in the gene SLC1A1 (solute carrier family 1A1) and SGA-induced OCS. However, this finding could not be replicated in European patients. Preliminary results also suggest an involvement of polymorphisms in the BDNF gene (brain-derived neurotrophic factor) and an interaction between markers of SLC1A1 and the gene DLGAP3 (disc large associated protein 3) as well as GRIN2B (N-methyl-D-aspartate receptor subunit 2B). Further research of well-defined samples, in particular studies investigating possible interactions of genetic risk-constellations and pharmacodynamic properties, are needed to clarify the assumed development of SGA-induced OCS. Results might improve pathogenic concepts and facilitate the definition of at risk populations, early detection and monitoring of OCS as well as multimodal therapeutic interventions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
43Genetika 2013 Sep 49: 1106-13
PMID25508909
Title[Association polymorphic variants of GRIN2B gene with paranoid schizophrenia and response to common neuroleptics in Russians and Tatars from Bashkortostan Republic].
AbstractAn analysis of the association of paranoid schizophrenia seeking with polymorphic variants of GRIN2B gene was performed in order to identify genetic risk factors of disease development and genetic markers of the response to therapy by neuroleptics in Russian and Tatar patients from Bashkortostan Republic (BB). In the course of the analysis, we revealed the following: 1) genetic markers of increased risk of developing paranoid schizophrenia in various ethnic groups, including, in Tatars, the GRIN2B* T/*Tgenotype (p = 0.003; OR = 2.33) and GRIN2B*T allele (p = 0.001; OR = 2.36), rs1805247; in Russians, the GRIN2B*T/*T genotype (p = 0.038; OR = 2.12) and GRIN2B* T allele (p = 0.028; OR = 2.03), rs1805247, genotype GRIN2B*A/*A (p = 0.042; OR = 2.12), rs1805476; 2) genetic markers of the reduced risk of developing paranoid schizophrenia; 3) genetic markers of therapy response and the risk of side effects development during neuroleptics (haloperidol) treatment in Bashkortostan. The significant interethnic diversity of genetic factors related to the risk of this disease development was noted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
44Genetika 2013 Sep 49: 1106-13
PMID25486778
Title[Association polymorphic variants of GRIN2B gene with paranoid schizophrenia and response to common neuroleptics in Russians and Tatars from Bashkortostan Republic].
AbstractAn analysis of the association of paranoid schizophrenia seeking with polymorphic variants of GRIN2B gene was performed in order to identify genetic risk factors of disease development and genetic markers of the response to therapy by neuroleptics in Russian and Tatar patients from Bashkortostan Republic (BB). In the course of the analysis, we revealed the following: 1) genetic markers of increased risk of developing paranoid schizophrenia in various ethnic groups, including, in Tatars, the GRIN2B* T/*Tgenotype (p = 0.003; OR = 2.33) and GRIN2B*T allele (p = 0.001; OR = 2.36), rs1805247; in Russians, the GRIN2B*T/*T genotype (p = 0.038; OR = 2.12) and GRIN2B* T allele (p = 0.028; OR = 2.03), rs1805247, genotype GRIN2B*A/*A (p = 0.042; OR = 2.12), rs1805476; 2) genetic markers of the reduced risk of developing paranoid schizophrenia; 3) genetic markers of therapy response and the risk of side effects development during neuroleptics (haloperidol) treatment in Bashkortostan. The significant interethnic diversity of genetic factors related to the risk of this disease development was noted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
45Psychopharmacology (Berl.) 2013 Nov 230: 49-55
PMID23660601
TitleInfluence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine-induced obsessive-compulsive symptoms.
AbstractClinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology.
This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms.
A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y-BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped.
Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model (p?=?0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F 6, 137?=?7.650, p?These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
46Adv Med 2014 -1 2014: 317980
PMID26556409
TitleComorbid Obsessive-Compulsive Symptoms in Schizophrenia: Insight into Pathomechanisms Facilitates Treatment.
AbstractInsight into the biological pathomechanism of a clinical syndrome facilitates the development of effective interventions. This paper applies this perspective to the important clinical problem of obsessive-compulsive symptoms (OCS) occurring during the lifetime diagnosis of schizophrenia. Up to 25% of schizophrenia patients suffer from OCS and about 12% fulfil the diagnostic criteria of obsessive-compulsive disorder (OCD). This is accompanied by marked subjective burden of disease, high levels of anxiety, depression and suicidality, increased neurocognitive impairment, less favourable levels of social and vocational functioning, and greater service utilization. Comorbid patients can be assigned to heterogeneous subgroups. It is assumed that second generation antipsychotics (SGAs), most importantly clozapine, might aggravate or even induce second-onset OCS. Several epidemiological and pharmacological arguments support this assumption. Specific genetic risk factors seem to dispose patients with schizophrenia to develop OCS and risk-conferring polymorphisms has been defined in SLC1A1, BDNF, DLGAP3, and GRIN2B and in interactions between these individual genes. Further research is needed with detailed characterization of large samples. In particular interactions between genetic risk constellations, pharmacological and psychosocial factors should be analysed. Results will further define homogeneous subgroups, which are in need for differential causative interventions. In clinical practise, schizophrenia patients should be carefully monitored for OCS, starting with at-risk mental states of psychosis and longitudinal follow-ups, hopefully leading to the development of multimodal therapeutic interventions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
47Psychiatry Res 2014 Aug 218: 356-8
PMID24814139
TitleA recently-discovered NMDA receptor gene, GRIN3B, is associated with duration mismatch negativity.
AbstractThe study explored associations between mismatch negativity and N-methyl-d-aspartic acid receptor subunit genes, GRIN1, GRIN2B and GRIN3B in healthy subjects and schizophrenia. Nineteen single-nucleotide polymorphisms were genotyped in 138 schizophrenia patients and 103 healthy subjects. Rs2240158 of GRIN3B was significantly associated with mismatch negativity in healthy subjects.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
48Mol. Psychiatry 2014 Aug 19: 872-9
PMID24126926
TitleExcess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.
Abstractschizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
49Addict Biol 2014 Sep 19: 955-64
PMID23855403
TitleDeep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence.
AbstractThe N-methyl-D-aspartate (NMDA) glutamate receptors play important roles in the pathophysiology of substance dependence (SD), but no strong genetic evidence has associated common variants in NMDAR-related genes to SD. We hypothesized that rare variants (RVs) with minor allele frequency <1% in the NMDAR-related genes might exert large effects on SD risk. We sequenced 34?544?bp of coding and flanking intronic regions of 17 genes involved in the NMDA system in 760 subjects, all with co-occurring alcohol dependence, cocaine dependence and opioid dependence (OD), and 760 healthy control subjects. One hundred percent of the target regions were sequenced at >1000 coverage. We identified 454 variants, including 380 RVs. Based on case-control allele count differences, we genotyped 11 exonic RVs in 6751 additional subjects, and the 1520 subjects from the sequencing stage for validation. All alleles of the 11 RVs called in the sequencing stage were confirmed. We found a statistically significant association of the 11 RVs with OD in African Americans (P?=?0.00080). Results from gene-based association tests showed that the association signal derived mostly from DISC1 (P?=?0.0010) and GRIN2B (P?=?0.00085). DISC1 is a well-validated schizophrenia risk gene. This is the first demonstration that RVs affect the risk of OD and the first demonstration of biological convergence of schizophrenia and OD risk-via DISC1.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
50Sci Rep 2015 -1 5: 12984
PMID26257337
TitlePolymorphisms in MicroRNA Genes And Genes Involving in NMDAR Signaling and Schizophrenia: A Case-Control Study in Chinese Han Population.
AbstractDisturbances in glutamate signaling caused by disruption of N-methyl-D-aspartate-type glutamate receptor (NMDAR) have been implicated in schizophrenia. Findings suggested that miR-219, miR-132 and miR-107 could involve in NMDAR signaling by influencing the expression of pathway genes or the signaling transmission and single nucleotide polymorphisms (SNPs) within miRNA genes or miRNA target sites could result in their functional changes. Therefore, we hypothesized that SNPs in miRNAs and/or their target sites were associated with schizophrenia. 3 SNPs in hsa-pri-miR-219/132/107 and 6 SNPs in 3'UTRs of GRIN2A/2B/3A and CAMK2G were selected and genotyped in a case-control study of 1041 schizophrenia cases and 953 healthy controls in Chinese Han population. In the present study, GRIN2B rs890 showed significant associations with schizophrenia. Further functional analyses showed that the rs890 variant C allele led to significantly lower luciferase activity, compared with the A allele. MDR analysis showed that a 4-locus model including rs107822, rs2306327, rs890 and rs12342026 was the best model. These findings suggest that GRIN2B may be associated with schizophrenia and interaction effects of the polymorphisms in hsa-miR-219, CAKM2G, GRIN2B and GRIN3A may confer susceptibility to schizophrenia in the Chinese Han population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
51PLoS ONE 2015 -1 10: e0125925
PMID26020650
TitleAssociation Study of N-Methyl-D-Aspartate Receptor Subunit 2B (GRIN2B) Polymorphisms and Schizophrenia Symptoms in the Han Chinese Population.
Abstractschizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamatergic system is the major excitatory neurotransmitter system in the central nervous system, and is mediated by N-methyl-D-aspartate (NMDA) receptors. Disturbances in this system have been hypothesized to play a major role in SZ pathogenesis. Several studies have revealed that the NMDA receptor subunit 2B (GRIN2B) potentially associates with SZ and its psychiatric symptoms. In this study, we performed a case-control study to identify polymorphisms of the GRIN2B gene that may confer susceptibility to SZ in the Han Chinese population. Thirty-four single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was observed in allele and genotype between SZ and controls at rs2098469 (?2 = 8.425 and 4.994; p = 0.025 and 0.014, respectively). Significant associations were found in the allele at rs12319804 (?2 = 4.436; p = 0.035), as well as in the genotype at rs12820037 and rs7298664 between SZ and controls (?2 = 11.162 and 38.204; p = 0.003 and 4.2710(-8), respectively). After applying the Bonferroni correction, rs7298664 still had significant genotype associations with SZ (p = 1.7110(-7)). In addition, rs2098469 genotype and allele frequencies, and 12820037 allele frequencies were nominally associated with SZ. Three haplotypes, CGA (rs10845849-rs12319804-rs10845851), CC (rs12582848-rs7952915), and AAGAC (rs2041986-rs11055665-rs7314376-rs7297101-rs2098469), had significant differences between SZ and controls (?2 = 4.324, 4.582, and 4.492; p = 0.037, 0.032, and 0.034, respectively). In addition, three SNPs, rs2098469, rs12820037, and rs7298664, were significantly associated with cognition factors PANSS subscores in SZ (F = 16.799, 7.112, and 13.357; p = 0.000, 0.017, and 0.000, respectively). In conclusion, our study provides novel evidence for an association between GRIN2B polymorphisms and SZ susceptibility and symptoms in the Han Chinese population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
52Transl Psychiatry 2015 -1 5: e541
PMID25849980
TitleLPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage.
AbstractGenetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage--an identified risk factor for schizophrenia--using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction--in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex--were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of GRIN2B, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
53Schizophr. Res. 2016 Jan 170: 30-40
PMID26597662
TitleGenetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.
AbstractThe Consortium on the Genetics of schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
54Biol. Psychiatry 2016 Feb -1: -1
PMID27086544
TitleReceptor Tyrosine Kinase MET Interactome and Neurodevelopmental Disorder Partners at the Developing Synapse.
AbstractAtypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high-confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development.
Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development. The candidates were translated into interactome networks and analyzed bioinformatically. Additionally, three independent quantitative proximity ligation assays in cultured neurons and four independent immunoprecipitation analyses of synaptosomes validated protein interactions.
Approximately 11% (8/72) of MET-interacting proteins, including SHANK3, SYNGAP1, and GRIN2B, are associated with NDDs. Proteins in the MET interactome were translated into a novel MET interactome network based on human protein-protein interaction databases. High-confidence genes from different NDD datasets that encode synaptosomal proteins were analyzed for being enriched in MET interactome proteins. This was found for autism but not schizophrenia, bipolar disorder, major depressive disorder, or attention-deficit/hyperactivity disorder. There is correlated gene expression between MET and its interactive partners in developing human temporal and visual neocortices but not with highly expressed genes that are not in the interactome. Proximity ligation assays and biochemical analyses demonstrate that MET-protein partner interactions are dynamically regulated by receptor activation.
The results provide a novel molecular framework for deciphering the functional relations of key regulators of synaptogenesis that contribute to both typical cortical development and to NDDs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
55Hum Psychopharmacol 2016 Mar 31: 121-34
PMID26876050
TitleGenetic association analysis of N-methyl-d-aspartate receptor subunit gene GRIN2B and clinical response to clozapine.
AbstractApproximately 30% of patients with schizophrenia fail to respond to antipsychotic therapy and are classified as having treatment-resistant schizophrenia. Clozapine is the most efficacious drug for treatment-resistant schizophrenia and may deliver superior therapeutic effects partly by modulating glutamate neurotransmission. Response to clozapine is highly variable and may depend on genetic factors as indicated by twin studies. We investigated eight polymorphisms in the N-methyl-d-aspartate glutamate receptor subunit gene GRIN2B with response to clozapine.
GRIN2B variants were genotyped using standard TaqMan procedures in 175 European patients with schizophrenia deemed resistant or intolerant to treatment. Response was assessed using change in Brief Psychiatric Rating Scale scores following six months of clozapine therapy. Categorical and continuous response was assessed using chi-squared test and analysis of covariance, respectively.
No associations were observed between the variants and response to clozapine. A-allele carriers of rs1072388 responded marginally better to clozapine therapy than GG-homozygotes; however, the difference was not statistically significant (p?=?0.067, uncorrected).
Our findings do not support a role for these GRIN2B variants in altering response to clozapine in our sample. Investigation of additional glutamate variants in clozapine response is warranted. Copyright 2016 John Wiley & Sons, Ltd.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
56Aust N Z J Psychiatry 2016 Mar 50: 275-83
PMID26013316
TitleChanges in cortical N-methyl-d-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide.
AbstractIn humans, depending on dose, blocking the N-methyl-d-aspartate receptor (NMDAR) with ketamine can cause psychomimetic or antidepressant effects. The overall outcome for drugs such as ketamine depends on dose and the number of its available binding sites in the central nervous system, and to understand something of the latter variable we measure NMDAR in the frontal pole, dorsolateral prefrontal, anterior cingulate and parietal cortices from people with schizophrenia, bipolar disorder, major depressive disorders and age/sex matched controls.
We measured levels of NMDARs (using [(3)H]MK-801 binding) and NMDAR sub-unit mRNAs (GRINs: using in situ hybridisation) as well as post-synaptic density protein 95 (anterior cingulate cortex only; not major depressive disorders: an NMDAR post-synaptic associated protein) in bipolar disorder, schizophrenia and controls.
Compared to controls, levels of NMDAR were lower in the outer laminae of the dorsolateral prefrontal cortex (-17%, p?=?0.01) in people with schizophrenia. In bipolar disorder, levels of NMDAR binding (laminae IV-VI; -19%, p?GRIN2B mRNA were higher in parietal cortex (+20%, p?These data suggest that differences in cortical NMDAR expression and post-synaptic density protein 95 are present in psychiatric disorders and suicide completion and may contribute to different responses to ketamine.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics