title: Resequencing and association study of vesicular glutamate transporter 1 gene (VGLUT1) with schizophrenia.
abstract: Dysregulation of glutamate neurotransmission is implicated in the pathphysiology of schizophrenia. Vesicular glutamate transporters (VGLUTs) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. Abnormal VGLUT1 expression has been linked to schizophrenia in postmortem brain studies. The purpose of this study was to investigate the involvement of the human VGLUT1 in the susceptibility to schizophrenia. In this study, we searched for genetic variants in the putative core promoter region and 12 exons (including UTR ends) of the VGLUT1 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=376) and non-psychotic controls (n=368) from Taiwan, and conducted a case-control association study. We identified two common SNPs (g.-248G>C (ss159695612) and c.2697C>A (rs1043558)) in the VGLUT1 gene. No differences in the allele and genotype frequencies were detected between the patients and control subjects. Besides, we identified eight patient-specific rare variants in 16 out of 376 patients, including two variants (g.-296A>G (ss159695611) and g.-32Cv>T (ss159695613)) at the core promoter region and 5'UTR, two missense variants (L516M (ss159695617) and P551S (ss159695618)) and three silent variants (E24E (ss159695614), L118L (ss159695615), and P133P (ss159695616)) at protein-coding regions, and one variant (c.2201G>A (ss159695619)) at the 3'UTR. No rare variants were found in 368 control subjects (4.3% versus 0, P=1.5x10(-5)). Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutation hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.
authors.affiliation: Department of Psychiatry, Tzu-Chi General Hospital and University, Hualien, Taiwan; Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Shen
authors.forename: Ding-Lieh
authors.initials: DL
authors.lastname: Liao
authors.forename: Jen-Yeu
authors.initials: JY
authors.lastname: Chen
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Wang
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Lai
authors.forename: Ying-Jay
authors.initials: YJ
authors.lastname: Liou
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Chen
authors.forename: Sy-Ueng
authors.initials: SU
authors.lastname: Luu
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Chen
mesh_terms: D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D013624:Taiwan; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics*
chemical_list: C493464:SLC17A7 protein, human; D050598:Vesicular Glutamate Transport Protein 1