Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia

Abstract

Studies suggest that GAD1 gene is a functional candidate susceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplotype levels. Altogether, we have found 17 variants including 10 SNPs in 5'-flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3'-untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5'-flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P = 0.0063, respectively; odds ratio = 1.83; 95% confidence interval: 1.26-2.65) and the male offsprings the trios (P = 0.0045, respectively; odds ratio = 2.21; 95% confidence interval: 1.37-3.56). Haplotype analysis suggested that rs3762556(C)-rs3791878(G)-rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P = 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the complexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcriptional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia.

Expression of GABA Signaling Molecules KCC2, NKCC1, and GAD1 in Cortical Development and Schizophrenia

“…Most schizophrenia studies focus on adults, but the pathogenesis probably involves early brain development (Marenco and Weinberger, 2000). Genetic variation in GAD1, the gene for the GABA synthetic enzyme GAD67, may be an etiologic factor in schizophrenia (Addington et al, 2005;Straub et al, 2007;Du et al, 2008).…”

The association between GAD1 gene polymorphisms and cerebral palsy in Chinese infants

“…A great many of evidences indicated that GAD1 played more and more important role in nerve system disease such as autism and schizophrenia. Many studies on the association between GAD1 and nerve system diseases have been conducted and their results proved that the abruption of GAD1 gene was an important risk factor to the happening of schizophrenia, autism and child bipolar I disorder [11][12][13][14]. There was also a study which demonstrated that GAD1 was associated with cortical gray matter volume loss in schizophrenia [15].…”

Modeling Interneuron Dysfunction in Schizophrenia

“…Several studies of the gene that encodes GAD67, GAD1, have yielded a number of single-nucleotide polymorphisms that are found more frequently in schizophrenic patients than controls [36,37,38]. The majority of single-nucleotide polymorphisms in each study was found in gene regulatory sequences suggesting a role in regulating gene expression and not protein function.…”