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David M Hougaard - One of the best experts on this subject based on the ideXlab platform.
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Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2011Co-Authors: Ditte Demontis, Mette Nyegaard, Henriette N Buttenschøn, Anne Hedemand, Carsten B Pedersen, Jakob Grove, Tracey J Flint, Merete Nordentoft, Thomas Werge, David M HougaardAbstract:N-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.
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Association of GRIN1 and GRIN2A-D with schizophrenia and genetic interaction with maternal herpes simplex virus-2 infection affecting disease risk.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2011Co-Authors: Ditte Demontis, Mette Nyegaard, Henriette N Buttenschøn, Anne Hedemand, Carsten B Pedersen, Jakob Grove, Tracey J Flint, Merete Nordentoft, Thomas Werge, David M HougaardAbstract:N-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, Pnominal = 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, Pnominal = 0.0001 and rs1806205, Pnominal = 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. © 2011 Wiley Periodicals, Inc.
James L. Kennedy - One of the best experts on this subject based on the ideXlab platform.
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Gene-gene interaction analyses between NMDA receptor subunit and dopamine receptor gene variants and clozapine response.
Pharmacogenomics, 2011Co-Authors: Rudi Hwang, Renan P. Souza, Arun K. Tiwari, Clement C. Zai, Daniel J. Müller, Steven G. Potkin, Jeffrey A. Lieberman, Herbert Y Meltze, James L. KennedyAbstract:Aims: To investigate the possible association and gene–gene interaction effects of polymorphisms in NMDA receptor subunit (GRIN1, GRIN2A and GRIN2B) and dopamine receptor (DRD1, DRD2 and DRD3) genes with clozapine response. Materials & methods: GRIN1 rs11146020 (G1001C), GRIN2A GT-repeat and GRIN2B rs10193895 (G-200T) polymorphisms were tested for association in a Caucasian (n = 183) and an African–American (n = 49) sample using χ2 and ANOVA tests. Logistic regression and two-way ANOVA were used to explore gene–gene interaction effects with dopamine receptor gene variants. Results & conclusion: This study does not support the involvement of the NMDA receptor subunit gene polymorphisms in clozapine response. All tests for an association were negative. Gene–gene interaction analyses however yielded promising leads, including an observed effect between DRD1 rs686 and DRD3 Ser9Gly polymorphisms on clozapine response (p = 0.002). Original submitted 29th September 2010; Revision submitted 4th November 2010.
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N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses.
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2003Co-Authors: Livia Martucci, Albert H.c. Wong, Joseph Trakalo, Tasha Cate-carter, Gregory W.h. Wong, Fabio Macciardi, James L. KennedyAbstract:The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses.
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N-methyl-d-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses
American Journal of Medical Genetics, 2003Co-Authors: Livia Martucci, Albert H.c. Wong, Joseph Trakalo, Tasha Cate-carter, Gregory W.h. Wong, Fabio Macciardi, James L. KennedyAbstract:The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5′ untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: χ2 = 2.19, P = 0.14; GRIN1/10: χ2 = 1.5, P = 0.22. For the case-control sample: GRIN1/1: χ2 = 0.013, P = 0.908; GRIN1/10: χ2 = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (χ2 = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses. © 2003 Wiley-Liss, Inc.
Aaron M. Jasnow - One of the best experts on this subject based on the ideXlab platform.
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GRIN1 deletion in CRF neurons sex-dependently enhances fear, sociability, and social stress responsivity
Psychoneuroendocrinology, 2015Co-Authors: T. Lee Gilman, Jeffrey P. Damert, Jeremy D. Meduri, Aaron M. JasnowAbstract:The corticotropin releasing factor (CRF) system plays a critical role in responses to stressful stimuli, and is expressed in many areas of the brain involved in processing fear, anxiety, and social behaviors. To better understand the mechanisms by which the CRF system modulates responses to stressful events and social stimuli, we employed a mouse model that selectively disrupts NMDA receptor function via NMDA receptor subunit NR1 (GRIN1) knockout specifically in Cre-expressing CRF neurons. These animals (Cre+/ fGRIN1+ ) were compared with littermates lacking Cre expression (Cre−/ fGRIN1+ ). Following cue discrimination fear condition- ing, male Cre+/ fGRIN1+ mice showed increased fear expression to the tone paired with a foot shock (CS+) while still discriminating the CS+ from a tone never paired with a foot shock (CS−). In contrast to males, female mice learned and discriminated fear cues equivalently across the genotypes. Similarly, no genotype differences in sociability or social novelty were observed in female mice, but Cre+/ fGRIN1+ males displayed greater naive sociability and preference for social novelty than Cre−/ fGRIN1+ littermates. Furthermore, the level of social withdrawal exhibited by male Cre+/ fGRIN1+ mice susceptible to social defeat stress relative to same genotype controls was significantly more pronounced than that displayed by susceptible Cre−/ fGRIN1+ mice compared to control Cre−/ fGRIN1+ mice. Together, these results demonstrate increased fear, social, and stress responsiveness specifically in male Cre+/ fGRIN1+ mice. Our findings indicate that NMDA- mediated glutamatergic regulation of CRF neurons is important for appropriately regulating fear and social responses, likely functioning to promote survival under aversive circumstances. © 2015 Elsevier Ltd. All rights reserved.
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GRIN1 receptor deletion within CRF neurons enhances fear memory.
PloS one, 2014Co-Authors: Georgette M. Gafford, Aaron M. Jasnow, Kerry J. ResslerAbstract:Corticotropin releasing factor (CRF) dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD). CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA). Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre) (Martin et al., 2010). In these studies, mice that have the gene that encodes NR1 (GRIN1) flanked by loxP sites (floxed) were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt GRIN1 within CRF containing neurons (Cre+/fGRIN1+). We find that disruption of GRIN1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of GRIN1 was decreased in Cre+/fGRIN1+ mice as measured by RTPCR. Cre+/fGRIN1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGRIN1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the GRIN1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGRIN1+) into the CeA of floxed GRIN1 mice. Cre driven deletion of GRIN1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of GRIN1 within CeA CRF neurons strongly enhances fear memory.
Huijun Liu - One of the best experts on this subject based on the ideXlab platform.
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Significant association between the genetic variations in the 5' end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia.
Biological psychiatry, 2006Co-Authors: Xinzhi Zhao, Guoyin Feng, Yongyong Shi, Ruqi Tang, Wuyan Chen, Jixia Liu, Jianguo Shi, Lijuan Yan, Huijun LiuAbstract:Background N-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A , are both good candidate genes for schizophrenia. Method We genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case–control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann–Whitney U test was performed. Results A highly significant association was detected at the 5′ end of GRIN1 . Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case–control study: p = .0000013, odds ratio=.61, 95% confidence interval .50–.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms. Conclusions Our results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5′ untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study.
Guoyin Feng - One of the best experts on this subject based on the ideXlab platform.
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Significant association between the genetic variations in the 5' end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia.
Biological psychiatry, 2006Co-Authors: Xinzhi Zhao, Guoyin Feng, Yongyong Shi, Ruqi Tang, Wuyan Chen, Jixia Liu, Jianguo Shi, Lijuan Yan, Huijun LiuAbstract:Background N-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A , are both good candidate genes for schizophrenia. Method We genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case–control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann–Whitney U test was performed. Results A highly significant association was detected at the 5′ end of GRIN1 . Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case–control study: p = .0000013, odds ratio=.61, 95% confidence interval .50–.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms. Conclusions Our results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5′ untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study.
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An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray.
European journal of human genetics : EJHG, 2005Co-Authors: Shengying Qin, X.z. Zhao, Yuxi Pan, Jianhua Liu, Guoyin Feng, Jiying Bao, Zhizhou ZhangAbstract:Dysfunction 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.
