title: A naturally occurring null variant of the NMDA type glutamate receptor NR3B subunit is a risk factor of schizophrenia.
abstract: 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.
authors.affiliation: Brain Science Institute, RIKEN, Wako, Saitama, 351-0198, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Matsuno
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ohi
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, 565-0871, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan; Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Hidenaga
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Molecular Neuropsychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Yano-Umeda
authors.affiliation: Brain Science Institute, RIKEN, Wako, Saitama, 351-0198, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Saneyoshi
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Brain Science Institute, RIKEN, Wako, Saitama, 351-0198, Japan; Saitama University Brain Science Institute, Saitama University, Saitama, 338-8570, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology
chemical_list: C501155:NR3B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate