The glutamatergic system is the most common excitatory neurotransmitter system in the central nervous system. N-methyl-D-aspartate (NMDA) receptors form an integral part of this system, and their dysregulation has been linked to the aetiology of numerous psychiatric phenotypes. Mounting evidence from pharmacology, postmortem studies, clinical interventions, and animal models indicates that the genes encoding these NMDA receptors, particuarly GRIN1 and GRIN2A, may play an important role in susceptibility to schizophrenia.
In a study to be published in the journal Biological Psychiatry, Xinzhi Zhao and colleagues from the Shanghai Institute of Mental Health have genotyped numerous polymorphisms in both genes in a large sample of 2455 Han Chinese subjects. A highly significant association was detected at the 5′ end of the GRIN1 gene. Analysis of single variants and multiple-locus haplotypes indicates that the association is mainly mediated by the single nucleotide polymorphism (SNP) rs11146020, which was found to be strongly associated with schizophrenia. No association was found with polymorphisms in the GRIN2A gene, suggesting that this locus may not play a role in schizophrenia.
These results provide support for the hypothesis that NMDA receptors are an important factor in the development of schizophrenia. It is interesting that SNP rs11146020 is located in 5′ untranslated region of GRIN1, and the authors speculate that it may influence gene expression by affecting transcription, the stability of mRNA, or translational efficiency.
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