GRIN1 Research Articles

Possible association between genetic variants at the GRIN1 gene and schizophrenia with lifetime history of depressive symptoms in a German sample

Genetic variation in glutamatergic signalling pathways is believed to play a substantial role in the aetiology of schizophrenia. The N-methyl-D-aspartate receptor subunit gene GRIN1 has been proposed as a candidate gene for schizophrenia. We tested for a potential association between schizophrenia and four single nucleotide polymorphisms (rs4880213, rs11146020, rs6293, and rs10747050) and one microsatellite marker at GRIN1 in a German sample of 354 patients and 323 controls. We found significant associations in single-marker and haplotype-based analyses (P<0.05). Significance was more pronounced (P<0.01) in the subset of patients with a lifetime history of major depression, a subgroup of schizophrenia described previously as a promising phenotypic subtype in genetic studies of schizophrenia. Although significances did not withstand correction for multiple testing, the results of our exploratory analysis warrant further studies on GRIN1 and schizophrenia.

No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample

Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.

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

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.

In SilicoIdentification of Regulatory Elements of GRIN1 Genes

The ionotropic receptor of glutamate activated by N-methyl-D-aspartate (iGluR-NMDA) is a multiheteromeric complex constituted by at least three different types of subunits, encoded by seven different genes. The subunits of iGluR-NMDA have a complex system of regulation of their gene expression. Their expression is specific for each type of neural cell, as well as for the age of the organism. Moreover, there are reports that iGluR-NMDA expression is species-specific. Even though this macromolecular complex is very important in physiology and pathology of the central nervous system, knowledge to date about the regulatory elements controlling expression is scarce. We present the results of an in silico prediction of potential regulatory elements, some of which coincide with the few known experimentally. We also present the important differences regarding the presence and the localization of the regulatory elements among human, rat, and mouse species.

GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal

N-Methyl-D-aspartate (NMDA) receptors, members of the glutamate receptor channel superfamily, are generally inhibited by alcohol. The expression and alternative splicing of the obligatory NR1 subunit is altered by alcohol exposure, emphasizing the involvement of the NR1 subunit, which is coded by the GRIN1 gene, in alcohol-mediated effects. We performed an association study in patients with alcohol dependence with the GRIN1 locus. Two independent case control samples consisting of a total of 442 alcohol-dependent patients and 442 unrelated controls were included. There was no overall difference in allele or genotype frequency between patients and controls. However, the 2108A allele and A-containing genotypes were over-represented in the patients with a history of withdrawal-induced seizures when compared to healthy volunteers (allele: chi(2) = 5.412, df = 1, P = 0.020) or an independent sample of patients without a history of seizures (allele: chi(2) = 4.185, df = 1, P = 0.041). Age at onset, years of alcohol dependence, and a history of delirium tremens did not differ between genotype or allele groups. These findings support the hypothesis that the GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal. This novel finding warrants replication.

Association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia

Background The GRIN1 gene plays a fundamental role in many brain functions, and its involvement in the pathogenesis of the schizophrenia has been widely investigated. Non-synonymous polymorphisms have not been identified in the coding regions. To investigate the potential role of GRIN1 in the susceptibility to schizophrenia, we analyzed the G1001C polymorphism located in the promoter region in a case-control association study. Methods The G1001C polymorphism allele distribution was analyzed in a sample of 139 Italian schizophrenic patients and 145 healthy control subjects by a polymerase chain reaction amplification followed by digestion with a restriction endonuclease. Results We found that the C allele may alter a consensus sequence for the transcription factor NF-κB and that its frequency was higher in patients than in control subjects ( p = .0085). The genotype distribution also was different, with p = .034 (if C allele dominant, p = .0137, odds ratio 2.037, 95% confidence interval 1.1502-3.6076). Conclusions The association reported in this study suggests that the GRIN1 gene is a good candidate for the susceptibility to schizophrenia.

Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients.

Schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population.

Mutation analysis of the N-methyl- d-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia

Dysfunction of N-methyl- d-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl- d-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl- d-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.