Resequencing of the vesicular glutamate transporter 2 gene (VGLUT2) reveals some rare genetic variants that may increase the genetic burden in schizophrenia.
OBJECTIVE
Vesicular glutamate transporters (VGLUT1-3) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. In mesencephalic dopamine neuron culture, the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3, have been demonstrated. As related to the dysregulated glutamatergic hypothesis of schizophrenia, the gene encoding VGLUT2 is the most plausible candidate involved in the pathogenesis of this illness.


METHODS
We searched for genetic variants in the promoter region and 12 exons (including UTR ends) of the VGLUT2 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=375) and non-psychotic controls (n=366) from Taiwan, and conducted a case-control association study.


RESULTS
We identified 8 common SNPs in the VGLUT2 gene. SNP and haplotype-based analyses showed no association with schizophrenia. Besides, we identified 9 rare variants in 13 out of 375 patients, including 3 variants located at the promoter region, 2 synonymous variants located at protein coding regions, and 4 variants located at UTR ends. No rare variants were found in the control subjects. Collectively, these rare variants were significantly overrepresented in the patient group (3.5% versus 0, p value of Fisher's exact test=2.3x10(-5)), suggesting they may contribute to the pathogenesis of schizophrenia.


CONCLUSIONS
Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutations hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.
Shen
Yu-Chih
YC
Department of Psychiatry, Tzu Chi General Hospital and University, Hualien, Taiwan.
Liao
Ding-Lieh
DL
Lu
Chao-Lin
CL
Chen
Jen-Yeu
JY
Liou
Ying-Jay
YJ
Chen
Tzu-Ting
TT
Chen
Chia-Hsiang
CH
D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D013624:Taiwan; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics*
D050599:Vesicular Glutamate Transport Protein 2