| 1 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jan 116B: 17-22 |
|---|---|
| PMID | 12497607 |
| Title | Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia: linkage disequilibrium mapping using SNPs evenly distributed across the gene region. |
| Abstract | The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia-susceptibility genes. We have been conducting systematic studies of the association between glutamate receptors and schizophrenia. We report on a positive association of some haplotypes of the AMPA receptor subunit GluR4 gene (GRIA4) with schizophrenia. We genotyped 100 Japanese schizophrenics and 100 controls for six single nucleotide polymorphism (SNP) markers distributed at intervals of about 50 kb in the GRIA4 region, and estimated the degree of linkage disequilibrium (LD) between the SNPs. We constructed haplotypes of the SNPs in LD using the EM algorithm to test their association with schizophrenia. Significant associations were detected for the combination of SNP4-5 (chi(2) = 12.54, df = 3, P = 0.0057, P = 0.029 with Bonferroni correction) and for the combination of SNP3-4-5 (chi(2) = 18.9, df = 7, P = 0.0085, P = 0.043 with Bonferroni correction). These results suggest that at least one susceptibility locus for schizophrenia is located within or very close to the GRIA4 region in Japanese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2003 Jan 116B: 17-22 |
| PMID | 12497607 |
| Title | Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia: linkage disequilibrium mapping using SNPs evenly distributed across the gene region. |
| Abstract | The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia-susceptibility genes. We have been conducting systematic studies of the association between glutamate receptors and schizophrenia. We report on a positive association of some haplotypes of the AMPA receptor subunit GluR4 gene (GRIA4) with schizophrenia. We genotyped 100 Japanese schizophrenics and 100 controls for six single nucleotide polymorphism (SNP) markers distributed at intervals of about 50 kb in the GRIA4 region, and estimated the degree of linkage disequilibrium (LD) between the SNPs. We constructed haplotypes of the SNPs in LD using the EM algorithm to test their association with schizophrenia. Significant associations were detected for the combination of SNP4-5 (chi(2) = 12.54, df = 3, P = 0.0057, P = 0.029 with Bonferroni correction) and for the combination of SNP3-4-5 (chi(2) = 18.9, df = 7, P = 0.0085, P = 0.043 with Bonferroni correction). These results suggest that at least one susceptibility locus for schizophrenia is located within or very close to the GRIA4 region in Japanese. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Neurosci. Lett. 2004 Oct 369: 168-72 |
| PMID | 15450689 |
| Title | No genetic association between polymorphisms in the AMPA receptor subunit GluR4 gene (GRIA4) and schizophrenia in the Chinese population. |
| Abstract | The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. It has recently been reported that some haplotypes in the AMPA receptor subunit GluR4 Gene (GRIA4), which is located on chromosome 11q22, are positively associated with schizophrenia in the Japanese population. In order to assess the role of GRIA4 in schizophrenia, we examined three reported positive SNPs (single nucleotide polymorphisms): rs609239, rs641574 and rs659840 at the GRIA4 locus in schizophrenic cases (n = 372) and controls (n = 392) of the Chinese population. Although we had observed similar allele and genotype frequencies compared with that in the Japanese population, no evidence was found for association with the disease in the analysis of either single nucleotide polymorphisms (all P-values > 0.300) or haplotype relative risk (all P-values > 0.088). Our results suggest that the three SNPs of GRIA4 are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Neurosci. Lett. 2004 Oct 369: 168-72 |
| PMID | 15450689 |
| Title | No genetic association between polymorphisms in the AMPA receptor subunit GluR4 gene (GRIA4) and schizophrenia in the Chinese population. |
| Abstract | The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. It has recently been reported that some haplotypes in the AMPA receptor subunit GluR4 Gene (GRIA4), which is located on chromosome 11q22, are positively associated with schizophrenia in the Japanese population. In order to assess the role of GRIA4 in schizophrenia, we examined three reported positive SNPs (single nucleotide polymorphisms): rs609239, rs641574 and rs659840 at the GRIA4 locus in schizophrenic cases (n = 372) and controls (n = 392) of the Chinese population. Although we had observed similar allele and genotype frequencies compared with that in the Japanese population, no evidence was found for association with the disease in the analysis of either single nucleotide polymorphisms (all P-values > 0.300) or haplotype relative risk (all P-values > 0.088). Our results suggest that the three SNPs of GRIA4 are unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 745-53 |
| PMID | 18163426 |
| Title | Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients. |
| Abstract | Impairment of glutamatergic neurotransmission is one of the major hypotheses proposed to explain the neurobiology of schizophrenia. Therefore, the genes involved in the glutamate neurotransmitter system could be considered potential candidate genes for schizophrenia susceptibility. A systematic study on alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor genes has been carried out and the results obtained from the analysis on GRIA2, GRIA3 and GRIA4 are reported. No evidence of association with schizophrenia was found for the GRIA2 and GRIA4 genes; strong evidence of association with schizophrenia was found for GRIA3. This X-linked gene showed a different behavior in the two genders; a positive association with schizophrenia was observed among females but not in males. Female carriers of rs1034428 A allele were found to have a 2.19-fold higher risk of developing schizophrenia compared to non-carriers and 3.28-fold higher risk for developing a non-paranoid phenotype. The analysis at the haplotype level showed that susceptibility to schizophrenia was associated with the specific haplotype rs989638-rs1034428-rs2227098 CAC (P = 0.0008). We conclude that, of the three AMPA genes analyzed here, only GRIA3 seems to be involved in the pathogenesis of schizophrenia, but only in females. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Mol. Psychiatry 2009 Aug 14: 804-19 |
| PMID | 18521090 |
| Title | Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. |
| Abstract | A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Psychiatr. Genet. 2009 Feb 19: 6-13 |
| PMID | 19125103 |
| Title | Association analysis of the glutamic acid decarboxylase 2 and the glutamine synthetase genes (GAD2, GLUL) with schizophrenia. |
| Abstract | As dysfunction of glutamatergic neurotransmission is one of the plausible hypotheses for the pathogenesis of schizophrenia, genes involved in the glutamate neurotransmitter system are candidates for schizophrenia susceptibility. The aim of this study is to clarify the contribution of two genes encoding glutamate metabolic enzymes: the glutamic acid decarboxylase 2 gene (GAD2) and the glutamine synthetase gene (GLUL), in schizophrenia. We genotyped 300 Japanese schizophrenia patients and 300 healthy controls for 14 single nucleotide polymorphisms (SNPs) in GAD2 (approximately 91 kb in size) and six SNPs in GLUL (approximately 14 kb in size). We examined 'single-point' association as well as pairwise haplotype association for all SNPs with schizophrenia. We observed no significant 'single-point' associations with the disease in any of the 20 SNPs after correction for multiple testing using False Discovery Rate. We also observed no significant haplotype associations with False Discovery Rate. Furthermore, we analyzed gene-gene interactions, including six glutamate receptor genes we have reported previously in the association studies of GRIA4, GRIN2D, GRIK3, GRIK4, GRIK5, and GRM3, using the multifactor dimensionality reduction method. The best interaction model, however, did not show the statistical significance. These results suggest that GAD2 and GLUL do not play a major role in schizophrenia pathogenesis and there is no gene-gene interaction between the eight genes in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Genes Brain Behav. 2010 Nov 9: 899-909 |
| PMID | 20662939 |
| Title | Comprehensive behavioural study of GluR4 knockout mice: implication in cognitive function. |
| Abstract | Fast excitatory transmission in the mammalian central nervous system is mediated by AMPA-type glutamate receptors. The tetrameric AMPA receptor complexes are composed of four subunits, GluR1-4. The GluR4 subunit is highly expressed in the cerebellum and the early postnatal hippocampus and is thought to be involved in synaptic plasticity and the development of functional neural circuitry through the recruitment of other AMPA receptor subunits. Previously, we reported an association of the human GluR4 gene (GRIA4) with schizophrenia. To examine the role of the GluR4 subunit in the higher brain function, we generated GluR4 knockout mice and conducted electrophysiological and behavioural analyses. The mutant mice showed normal long-term potentiation (LTP) in the CA1 region of the hippocampus. The GluR4 knockout mice showed mildly improved spatial working memory in the T-maze test. Although the retention of spatial reference memory was intact in the mutant mice, the acquisition of spatial reference memory was impaired in the Barnes circular maze test. The GluR4 knockout mice showed impaired prepulse inhibition. These results suggest the involvement of the GluR4 subunit in cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Pharmacogenet. Genomics 2011 Apr 21: 206-16 |
| PMID | 20859245 |
| Title | Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. |
| Abstract | The 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 Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Neurosci. Lett. 2012 Jan 506: 170-4 |
| PMID | 22094384 |
| Title | Influence of GRIA1, GRIA2 and GRIA4 polymorphisms on diagnosis and response to antipsychotic treatment in patients with schizophrenia. |
| Abstract | The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. One hundred forty five patients with MD, 221 in-patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. No significant association was found with the diagnosis of schizophrenia. We observed an association between rs3813296 genotype and improvement on PANSS negative scores. Our findings provide no evidence for an association between SNPs within GRIA1, GRIA2 and GRIA4 under investigation and schizophrenia susceptibility, although rs3813296 (GRIA2) could be associated with improvement on PANSS negative scores. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J Clin Psychiatry 2012 Mar 73: 367-71 |
| PMID | 21813073 |
| Title | Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone. |
| Abstract | We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy. Patients with schizophrenia (DSM-IV) were assessed during 2006 and 2007 for response/nonresponse (defined as ? 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score. The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: -12.5 versus -20.9). In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone. clinicaltrials.gov Identifier: NCT00337662. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Biol. Psychiatry 2015 Jun 77: 959-68 |
| PMID | 25433904 |
| Title | Altered glutamate protein co-expression network topology linked to spine loss in the auditory cortex of schizophrenia. |
| Abstract | Impaired glutamatergic signaling is believed to underlie auditory cortex pyramidal neuron dendritic spine loss and auditory symptoms in schizophrenia. Many schizophrenia risk loci converge on the synaptic glutamate signaling network. We therefore hypothesized that alterations in glutamate signaling protein expression and co-expression network features are present in schizophrenia. Gray matter homogenates were prepared from auditory cortex gray matter of 22 schizophrenia and 23 matched control subjects, a subset of whom had been previously assessed for dendritic spine density. One hundred fifty-five selected synaptic proteins were quantified by targeted mass spectrometry. Protein co-expression networks were constructed using weighted gene co-expression network analysis. Proteins with evidence for altered expression in schizophrenia were significantly enriched for glutamate signaling pathway proteins (GRIA4, GRIA3, ATP1A3, and GNAQ). Synaptic protein co-expression was significantly decreased in schizophrenia with the exception of a small group of postsynaptic density proteins, whose co-expression increased and inversely correlated with spine density in schizophrenia subjects. We observed alterations in the expression of glutamate signaling pathway proteins. Among these, the novel observation of reduced ATP1A3 expression is supported by strong genetic evidence indicating it may contribute to psychosis and cognitive impairment phenotypes. The observations of altered protein network topology further highlight the complexity of glutamate signaling network pathology in schizophrenia and provide a framework for evaluating future experiments to model the contribution of genetic risk to disease pathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | J. Psychopharmacol. (Oxford) 2015 Apr 29: 372-82 |
| PMID | 25691503 |
| Title | Understanding responder neurobiology in schizophrenia using a quantitative systems pharmacology model: application to iloperidone. |
| Abstract | The concept of targeted therapies remains a holy grail for the pharmaceutical drug industry for identifying responder populations or new drug targets. Here we provide quantitative systems pharmacology as an alternative to the more traditional approach of retrospective responder pharmacogenomics analysis and applied this to the case of iloperidone in schizophrenia. This approach implements the actual neurophysiological effect of genotypes in a computer-based biophysically realistic model of human neuronal circuits, is parameterized with human imaging and pathology, and is calibrated by clinical data. We keep the drug pharmacology constant, but allowed the biological model coupling values to fluctuate in a restricted range around their calibrated values, thereby simulating random genetic mutations and representing variability in patient response. Using hypothesis-free Design of Experiments methods the dopamine D4 R-AMPA (receptor-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor coupling in cortical neurons was found to drive the beneficial effect of iloperidone, likely corresponding to the rs2513265 upstream of the GRIA4 gene identified in a traditional pharmacogenomics analysis. The serotonin 5-HT3 receptor-mediated effect on interneuron gamma-aminobutyric acid conductance was identified as the process that moderately drove the differentiation of iloperidone versus ziprasidone. This paper suggests that reverse-engineered quantitative systems pharmacology is a powerful alternative tool to characterize the underlying neurobiology of a responder population and possibly identifying new targets. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Mol Genet Genomic Med 2016 Jan 4: 18-27 |
| PMID | 26788534 |
| Title | Evaluation of genetic association of neurodevelopment and neuroimmunological genes with antipsychotic treatment response in schizophrenia in Indian populations. |
| Abstract | Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27-2.52), P = 7.62 × 10(-4); rs4586: OR (95% CI) = 1.74 (1.24-2.43), P = 1.13 × 10(-3)] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36-0.78), P = 1.44 × 10(-3)] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19-0.65), P = 7.68 × 10(-4)] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23-0.79), P = 6.81 × 10(-3); rs17716295, OR (95% CI) = 1.78 (1.15-2.75), P = 8.71 × 10(-3)] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |