Zhao X, Qin S, Shi Y, Zhang A, Zhang J, Bian L et al. Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray. Schizophr Res 93: 374-384

Bio-X Life Science Research Center, Shanghai Jiao Tong University, Hao Ran Building, Shanghai 200030, China.
Schizophrenia Research (Impact Factor: 3.92). 07/2007; 93(1-3):374-84. DOI: 10.1016/j.schres.2007.02.023
Source: PubMed


Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (P<0.001). These findings suggest that the GABRB2 and GAD1 genes alone and the combined effects of the polymorphisms in the four GABAergic system genes may confer susceptibility to the development of schizophrenia in the Chinese population.

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    • "Accumulating data indicate that GABAergic function is disrupted in schizophrenia. Significant associations have been detected between variation of several GABAergic genes and schizophrenia, including the genes encoding the 67 kDa isoform of glutamic acid dehydrogenase (GAD67) (Straub et al., 2007; Zhao et al., 2007), and the GABA-A receptor subunits GABA-Aα1, GABA-Aα6 (Petryshen et al., 2005), GABA-Aβ2 (Lo et al., 2004, 2007; Yu et al., 2006; Zhao et al., 2007), and GABA-Aγ2 "
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    ABSTRACT: GABAergic dysfunction has been strongly implicated in the pathophysiology of schizophrenia. In this study, we analyzed the expression levels of several GABAergic genes in the anterior cingulate cortex (ACC) of postmortem subjects with schizophrenia (n=21) and a comparison group of individuals without a history of psychiatric illness (n=18). Our analyses revealed a significant sex by diagnosis effect, along with significant differences in GABAergic gene expression based on medication status. Analyses revealed that in male groups, the expression of GABAergic genes was generally lower in schizophrenia cases compared to the controls, with significantly lower expression levels of GABA-Aα5, GABA-Aβ1, and GABA-Aε. In females, the expression of GABAergic genes was higher in the schizophrenia cases, with significantly higher expression of the GABA-Aβ1 and GAD67 genes. Analysis of the effect of medication in the schizophrenia subjects revealed significantly higher expression of GABA-Aα1-3, GABA-Aβ2, GABA-Aγ2, and GAD67 in the medicated group compared to the unmedicated group. These data show that sex differences in the expression of GABAergic genes occur in the ACC in schizophrenia. Therefore, our data support previous findings of GABAergic dysfunction in schizophrenia and emphasize the importance of considering sex in analyses of the pathophysiology of schizophrenia. Sex differences in the GABAergic regulation of ACC function may contribute to the differences observed in the symptoms of male and female patients with schizophrenia. In addition, our findings indicate that antipsychotic medications may alter GABAergic signaling in the ACC, supporting the potential of GABAergic targets for the development of novel antipsychotic medication. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 02/2015; 167(1). DOI:10.1016/j.schres.2015.01.025 · 3.92 Impact Factor
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    • "and GABBR2 gene (5q34) have been established as susceptibility loci for schizophrenia (Lindholm et al., 1999; Petryshen et al., 2005). However, one study has found a weak linkage between the GABBR1 gene and schizophrenia (Zai et al., 2005), while two other studies have found no connection (Imai et al., 2002; Zhao et al., 2007). In two microarray studies of suicides, increased expression of GABBR1 and GABBR2 mRNA was observed (Klempan et al., 2009; Sequiera et al., 2009). "
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    ABSTRACT: Postmortem and genetic studies have clearly demonstrated changes in GABA(B) receptors in neuropsychiatric disorders such as autism, bipolar disorder, major depression, and schizophrenia. Moreover, a number of recent studies have stressed the importance of cerebellar dysfunction in these same disorders. In the current study, we examined protein levels of the two GABA(B) receptor subunits GABBR1 and GABBR2 in lateral cerebella from a well-characterized cohort of subjects with schizophrenia (n=15), bipolar disorder (n=14), major depression (n=13) and healthy controls (n=12). We found significant reductions in protein for both GABBR1 and GABBR2 in lateral cerebella from subjects with schizophrenia, bipolar disorder and major depression when compared with controls. These results provide further evidence of GABAergic dysfunction in these three disorders as well as identify potential targets for therapeutic intervention.
    Schizophrenia Research 02/2011; 128(1-3):37-43. DOI:10.1016/j.schres.2010.12.025 · 3.92 Impact Factor
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    • "A certain threshold, defined as the ratio of cases to controls, determines the risk group to which a factor combination is assigned [15]. Using MDR, many studies have observed that complex interactions among multiple genes may make a genetic contribution to complex disorders [16-18], including SZ [19-21]. Here, we explored the epistasis, or gene × gene interaction, between the two genes via MDR. "
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    ABSTRACT: The blood-derived RNA levels of the adenylosuccinate synthase (ADSS) and ataxia telangiectasia mutated (ATM) genes were found to be down- and up-regulated, respectively, in schizophrenics compared with controls, and ADSS and ATM were among eight biomarker genes to discriminate schizophrenics from normal controls. ADSS catalyzes the first committed step of AMP synthesis, while ATM kinase serves as a key signal transducer in the DNA double-strand breaks response pathway. It remains unclear whether these changes result from mutations or polymorphisms in the two genes. Six SNPs in the ADSS gene and three SNPs in the ATM gene in a Chinese population of 488 schizophrenics and 516 controls were genotyped to examine their association with schizophrenia (SZ). Genotyping was performed using the Sequenom platform. There was no significant difference in the genotype, allele, or haplotype distributions of the nine SNPs between cases and controls. Using the Multifactor Dimensionality Reduction (MDR) method, we found that the interactions among rs3102460 in the ADSS gene and rs227061 and rs664143 in the ATM gene revealed a significant association with SZ. This model held a maximum testing accuracy of 60.4% and a maximum cross-validation consistency of 10 out of 10. These findings suggest that the combined effects of the polymorphisms in the ADSS and ATM genes may confer susceptibility to the development of SZ in a Chinese population.
    BMC Medical Genetics 01/2009; 9(1):119. DOI:10.1186/1471-2350-9-119 · 2.08 Impact Factor
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