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ABSTRACT: We resequenced the exonic regions of DLGAP3 gene, which encodes SAP90/PSD95-associated protein 3, in 215 schizophrenic patients and 215 non-psychotic controls. Seven known single-nucleotide polymorphisms (SNPs) were identified, but not associated with schizophrenia. Nevertheless, we identified several rare missense mutations and some of them might be associated with the pathogenesis of schizophrenia.
Psychiatry research. 02/2013;
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ABSTRACT: Schizophrenia is a severe chronic mental disorder with high genetic components in its etiology. Several studies indicated that synaptic dysfunction is involved in the pathophysiology of schizophrenia. Postsynaptic synapse-associated protein 90/postsynaptic density 95-associated proteins (SAPAPs) constitute a part of the N-methyl-d-aspartate receptor-associated postsynaptic density proteins, and are involved in synapse formation. We hypothesized that genetic variants of the SAPAPs might be associated with schizophrenia. Thus, we systemically sequenced all the exons of the discs, large (Drosophila) homolog-associated protein 1 (DLGAP1) gene that encodes SAPAP1 in a sample of 121 schizophrenic patients and 120 controls from Taiwan. We totally identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259) and one rare missense mutation (c.1922A>G) in this sample. SNP- and haplotype-based analyses showed no association of these SNPs with schizophrenia. The c.1922A>G mutation that changes the amino acid lysine to arginine at codon 641 was found in one out of 121 patients, but not in 275 control subjects, suggesting it might be a patient-specific mutation. Nevertheless, bioinformatic analysis showed this mutation does not affect the function of the DLGAP1 gene and appears to be a benign variant. Hence, its relationship with the pathogenesis remains to be investigated.
Psychiatry research. 08/2012;
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ABSTRACT: Early growth response genes (EGR1, 2, 3, and 4) encode a family of nuclear proteins that function as transcriptional regulators. They are involved in the regulation of synaptic plasticity, learning, and memory, and are implicated in the pathogenesis of schizophrenia.
We conducted a genetic association analysis of 14 SNPs selected from the EGR1, 2, 3, and 4 genes of 564 patients with schizophrenia and 564 control subjects. We also conducted Western blot analysis and promoter activity assay to characterize the EGR genes associated with schizophrenia
We did not detect a true genetic association of these 14 SNPs with schizophrenia in this sample. However, we observed a nominal over-representation of C/C genotype of rs9990 of EGR2 in female schizophrenia as compared to female control subjects (p=0.012, uncorrected for multiple testing). Further study showed that the average mRNA level of the EGR2 gene in the lymphoblastoid cell lines of female schizophrenia patients was significantly higher than that in female control subjects (p=0.002). We also detected a nominal association of 4 SNPs (rs6747506, rs6718289, rs2229294, and rs3813226) of the EGR4 gene that form strong linkage disequilibrium with schizophrenia in males. Reporter gene assay showed that the haplotype T-A derived from rs6747506 and rs6718289 at the promoter region had significantly reduced promoter activity compared with the haplotype A-G.
Our data suggest a tendency of gender-specific association of EGR2 and EGR4 in schizophrenia, with an elevated expression of EGR2 in lympoblastoid cell lines of female schizophrenia patients and a reduced EGR4 gene expression in male schizophrenia patients.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 06/2012; 39(1):149-55. · 3.25 Impact Factor
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ABSTRACT: Schizophrenia is a highly heritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, a SNP rs12807809 located upstream of the neurogranin (NRGN) gene achieved genome-wide significance in this disorder.
In order to find the causal variants of NRGN gene in schizophrenia, we searched for genetic variants in the promoter region and all the exons (including both UTR ends and rs12807809) using direct sequencing in a sample of patients with schizophrenia (n=346) and non-psychotic controls (n=345), both being Han Chinese from Taiwan, and conducted an association and functional study.
We identified 7 common polymorphisms in the NRGN gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 5 rare variants in 6 out of 346 patients, including 3 rare variants located at the promoter region (g.-620A>G, g.-578C>G, and g.-344G>A) and 2 rare variants located at 5' UTR (c.-74C>G, and c.-41G>A). No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing g.-620G, g.-578G, g.-344A, c.-74G, and c.-41A was significantly lower as compared to the wild type construct (P<0.01 for g.-578G; P<0.001 for the other constructs). In silico analysis also demonstrated their influences on the regulatory function of NRGN gene.
Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and provides genetic clues that indicate the involvement of NRGN in this disorder.
Biological Psychiatry 02/2012; 137(1-3):7-13. · 8.28 Impact Factor
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ABSTRACT: In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia.
We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study.
We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants.
Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.
Biological Psychiatry 12/2011; 134(2-3):239-45. · 8.28 Impact Factor
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ABSTRACT: Dopamine receptor partial agonists have been proposed as potential candidate agents to treat psycho-stimulant abuse. Aripiprazole is a dopamine D2/D3 receptor partial agonist that is currently used as an antipsychotic drug in clinical settings. This study aimed to examine whether aripiprazole can suppress the methamphetamine-induced locomotor response in mice that is used as an indicator for potential clinical use. In ICR mice pre-exposed to methamphetamine (1mg/kg subcutaneous injection once daily for 7 days), we found that mice receiving repetitive treatments with aripiprazole (1, 5, and 10mg/kg, respectively; intraperitoneal injection once daily for 1 week) showed a significantly enhanced locomotor response upon re-exposure to methamphetamine (0.5mg/kg), compared with animals that received a vehicle treatment. Furthermore, we found that methamphetamine-naïve mice receiving repetitive treatment with aripiprazole (5mg/kg intraperitoneal injection once daily for 1 week) also showed a significantly enhanced locomotor response to acute challenge with methamphetamine (0.5mg/kg), compared with animals receiving the vehicle treatment. The enhanced locomotor response to methamphetamine in both methamphetamine-pre-exposed and methamphetamine-naïve mice lasted at least four weeks in this study. Our data suggest that aripiprazole may enhance the effects of methamphetamine, so caution should be exercised when prescribing to individuals with histories of stimulant use.
Behavioural brain research 01/2011; 216(2):621-5. · 3.22 Impact Factor
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ABSTRACT: Hypofunction of N-methyl-D-aspartate (NMDA) receptor-mediated signal transduction has been implicated in the pathophysiology of schizophrenia. Post-synaptic density protein 95 (PSD95) plays a critical role in regulating the trafficking and activity of the NMDA receptor and altered expression of the PSD95 has been detected in the post-mortem brain of patients with schizophrenia. The study aimed to examine whether the DLG4 gene that encodes the PSD95 may confer genetic susceptibility to schizophrenia. We re-sequenced the core promoter, all the exons, and 3' untranslated regions (UTR) of the DLG4 gene in 588 Taiwanese schizophrenic patients and conducted an association study with 539 non-psychotic subjects. We did not detect any rare mutations at the protein-coding sequences of the DLG4 gene associated with schizophrenia. Nevertheless, we identified four polymorphic markers at the core promoter and 5' UTR and one single nucleotide polymorphism (SNP) at the 3'UTR of the DLG4 gene in this sample. Genetic analysis showed an association of a haplotype (C-D) derived from 2 polymorphic markers at the core promoter (odds ratio = 1.26, 95% confidence interval = 1.06-1.51, p = 0.01), and a borderline association of the T allele of the rs13331 at 3'UTR with schizophrenia (odds ratio = 1.19, 95% confidence interval = 0.99-1.43, p = 0.06). Further reporter gene assay showed that the C-D-C-C and the T allele of the rs13331 had significant lower activity than their counter parts. Our data indicate that the expression of the DLG4 gene is subject to regulation by the polymorphic markers at the core promoter region, 5' and 3'UTR of the gene, and is associated with the susceptibility of schizophrenia.
PLoS ONE 01/2010; 5(12):e15107. · 4.09 Impact Factor
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