A naturally occurring null variant of the NMDA type glutamate receptor NR3B subunit is a risk factor of schizophrenia

Hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been implicated in the pathogenesis of schizophrenia. Here, we investigated the significance of a common human genetic variation of the NMDAR NR3B subunit that inserts 4 bases within the coding region (insCGTT) in the patho...

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Bibliographic Details
Published in:PloS one 2015-03, Vol.10 (3), p.e0116319-e0116319
Main Authors: Matsuno, Hitomi, Ohi, Kazutaka, Hashimoto, Ryota, Yamamori, Hidenaga, Yasuda, Yuka, Fujimoto, Michiko, Yano-Umeda, Satomi, Saneyoshi, Takeo, Takeda, Masatoshi, Hayashi, Yasunori
Format: Article
Language:English
Subjects:
Adult
Case-Control Studies
Coding
Female
Gene expression
Gene Frequency
Gene polymorphism
Genetic analysis
Genetic Association Studies
Genetic diversity
Genetic Predisposition to Disease
Genotype
Glutamate
Glutamic acid receptors (ionotropic)
Humans
Inhibition (psychology)
Inserts
Male
Medicine
Mental disorders
Middle Aged
N-methyl-D-aspartate
N-Methyl-D-aspartic acid receptors
Neural coding
Pathogenesis
Patients
Personality
Polymorphism
Polymorphism, Single Nucleotide
Psychiatry
Receptors, N-Methyl-D-Aspartate - genetics
Risk factors
Schizophrenia
Schizophrenia - genetics
Schizophrenia - pathology
University graduates
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Summary:Hypofunction of the N-methyl-D-aspartate type glutamate receptor (NMDAR) has been implicated in the pathogenesis of schizophrenia. Here, we investigated the significance of a common human genetic variation of the NMDAR NR3B subunit that inserts 4 bases within the coding region (insCGTT) in the pathogenesis of schizophrenia. The cDNA carrying this polymorphism generates a truncated protein, which is electrophysiologically non-functional in heterologous expression systems. Among 586 schizophrenia patients and 754 healthy controls, insCGTT was significantly overrepresented in patients compared to controls (odds ratio = 1.37, p = 0.035). Among 121 schizophrenia patients and 372 healthy controls, genetic analyses of normal individuals revealed that those carrying insCGTT have a predisposition to schizotypal personality traits (F1,356 = 4.69, p = 0.031). Furthermore, pre-pulse inhibition, a neurobiological trait disturbed in patients with schizophrenia, was significantly impaired in patients carrying insCGTT compared with those with the major allele (F1,116 = 5.72, p = 0.018, F1,238 = 4.46, p = 0.036, respectively). These results indicate that a naturally occurring null variant in NR3B could be a risk factor of schizophrenia.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0116319