2004 - Schizophrenia and Glutamate abstracts
1: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12604-9. Epub 2004 Aug 13. Related Articles, Links
Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.
Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR.
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health/NIH/DHHS, Building 10, Center Drive, Bethesda, MD 20892, USA.
GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. In a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02).
We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNPs, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription.
These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.
PMID: 15310849 [PubMed - indexed for MEDLINE]
ncbi.nlm.nih.gov
Same article with different words ....
Schizophrenia Gene Variant Linked to Risk Traits
Researchers at the NIH's National Institute of Mental Health (NIMH) have identified a relationship between a small section of one gene, the brain chemical messenger glutamate, and a collection of traits known to be associated with schizophrenia. The finding confirms the gene responsible for management of glutamate is a promising candidate in determining risk for schizophrenia. The study, conducted by Michael Egan, M.D., Daniel Weinberger, M.D., and colleagues, will be in the August 24th issue of the Proceedings of the National Academy of Sciences, published online the week of August 9, 2004.
Glutamate is a key neurotransmitter long thought to play a role in schizophrenia. The gene identified in this study makes the glutamate receptor (GRM3) which is responsible for regulating glutamate in synapses — spaces in between brain cells — where chemicals like glutamate transfer information from cell to cell. The amount of glutamate remaining in the synapse may have a downstream impact on cognition.
"Because of the small effects of individual genes in complex genetic disorders like schizophrenia, it is difficult to make significant associations with any one particular marker. However, this study brings us closer to unlocking the genetic clues that increase the risk for schizophrenia," said NIMH Director Thomas R. Insel, M.D.
Researchers know that schizophrenia affects several regions in the front part of the brain that are involved in higher order thinking and decision-making and neurotransmitter systems like glutamate. Many of the genes already identified as likely candidates for the disorder have been thought to affect the glutamate system. The study implicates the GRM3 gene as well.
GRM3 alters glutamate transmission, brain physiology and cognition, increasing the risk for schizophrenia. To pinpoint the section of the gene responsible for these changes, scientists are exploring a region where the gene may differ by one letter at a location called SNP4. The normal variation is spelled with either an 'A' — the more common of the two — or a 'G'. Patients with schizophrenia are more likely to inherit an 'A' from either parent, indicating the 'A' variant slightly increases risk. The 'A' variant is also associated with the pattern of traits linked with the disorder. This was true in patients, their healthy siblings, and normal volunteers.
In the study, people with an 'A' variant have differences in measures of brain glutamate. In a postmortem study of brain tissue, the 'A' variant was associated with lower levels of the chemical that promotes gene expression for the protein responsible for regulating the level of glutamate in the cell. N-acetylaspartate, a measure of cell health evaluated through the use of MRI spectroscopy, was lower in 'A' participants. 'A' carriers had poorer performance on several cognitive tests of prefrontal and hippocampal function than people with the 'G' variant. The 'G' marker was associated with relatively more 'efficient' processing in the prefrontal cortex. Those who inherit the 'G' variant scored higher on verbal and cognitive tests than those who have two of the 'A' variant. Scientists think the less common 'G' variant may exert a protective effect against the disease.
People with schizophrenia and their healthy siblings share the inefficient brain physiology, and cognition patterns, which suggests a link to genetic risk, though the disease itself is most likely caused by a combination of genetic and environmental factors. The gene seems to affect the mechanism of memory encoding only as there was no genotype effect seen during retrieval in the memory tests.
Although scientists could not be certain that the 'A/G' difference accounts for all the affects on brain function, there may be yet undiscovered variations located near SNP4 on the GRM3 gene. It is unclear as to why the higher-risk 'A' variant is more common in humans. Researchers speculate that it may provide a counterbalancing advantage, perhaps related to reduced glutamate in the cells.
Also participating in the research were: Drs. Richard Straub, Terry Goldberg, Joseph Callicott, Ahmad Hariri, Venkata Mattay, Thomas Hyde, Cynthia Shannon-Weickert, Mayada Akil, Radha Krishna Vakkalanka, Rishi Balkissoon, Joel Kleinman; Alessandro Bertolino, NIMH and Universita Study Bari, Italy; Jeremy Crook, NIMH and ES Cell International; Imtiaz Yakub, and Richard Gibbs, Baylor College of Medicine.
NIMH is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.
nih.gov
2005 Article
1: Schizophr Res. 2005 Feb 1;73(1):21-6. Related Articles, Links
A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population.
Chen Q, He G, Chen Q, Wu S, Xu Y, Feng G, Li Y, Wang L, He L.
Bio-X Life Science Research Center, Shanghai Jiao Tong University, Shanghai 200030, China; Department of Pathophysiology, Medical school of Soochow University, Suzhou 215007, China.
Recent studies of the association between the metabotropic glutamate receptor 3 gene (GRM3) and schizophrenia have produced conflicting results, although GRM3 is a promising candidate gene. Fujii et al. found a single nuclear polymorphism (SNP) for within this gene, rs1468412 to have a positive association to schizophrenia in Japanese patients. To investigate this further, we genotyped 7 SNPs around GRM3 including rs1468412, in 752 Chinese patients with schizophrenia and 752 controls using Taqman technology. We did not detect any association between rs1468412 and schizophrenia, however we found differences in the allele frequency distribution of SNP rs2299225 (p=0.0297, odds ration [OR]=1.44, 95% confidence interval 1.05-1.99) between cases and controls. Moreover, the overall frequency of haplotypes constructed from three SNPs including rs2299225 showed significant differences between cases and controls (p=0.0017).
Our results partially support the previous studies in other ethnic groups and indicate that the GRM3 gene may play an important role in the etiology of schizophrenia in the Han Chinese.
PMID: 15567072 [PubMed - in process]
ncbi.nlm.nih.gov
1: Psychiatr Genet. 2003 Jun;13(2):71-6. Related Articles, Links
Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia.
Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y.
Division of Disease Genes, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Japan.
OBJECTIVES: Glutamatergic dysfunction is one of the major hypotheses of schizophrenia pathophysiology. We have been conducting systematic studies on the association between glutamate receptors and schizophrenia. We focused on the metabotropic glutamate receptor type 3 gene (GRM3) as a candidate for schizophrenia susceptibility. METHODS: We genotyped Japanese schizophrenics (n=100) and controls (n=100) for six single nucleotide polymorphisms (SNPs) located in the GRM3 region at intervals of approximately 50 kb. Statistical differences in genotype, allele and haplotype frequencies between cases and controls were evaluated by the chi2 test and Fisher's exact probability test at a significance level of 0.05. Haplotype frequencies were estimated by the EM algorithm. RESULTS: A case-control association study identified a significant difference in allele frequency distribution of a SNP, rs1468412, between schizophrenics and controls (P=0.011). We also observed significant differences in haplotype frequencies estimated from SNP frequencies between schizophrenics and controls. The haplotype constructed from three SNPs, including rs1468412, showed a significant association with schizophrenia (P=8.30 x 10-4). CONCLUSIONS: Our data indicate that at least one susceptibility locus for schizophrenia is situated within or very close to the GRM3 region in the Japanese patients.
PMID: 12782962 [PubMed - indexed for MEDLINE] |
