| 1 | Mol. Psychiatry 2004 Jun 9: 603-8 |
|---|---|
| PMID | 14699426 |
| Title | Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia. |
| Abstract | Disturbances in GABAergic system have been observed in schizophrenics. In the present study, population association analysis was performed on 19 SNPs in the alpha(1), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B2I7G1584T, rs1816071, rs194072, rs252944 and rs187269, were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2004 Jun 9: 603-8 |
| PMID | 14699426 |
| Title | Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia. |
| Abstract | Disturbances in GABAergic system have been observed in schizophrenics. In the present study, population association analysis was performed on 19 SNPs in the alpha(1), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B2I7G1584T, rs1816071, rs194072, rs252944 and rs187269, were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Biol. Psychiatry 2005 Sep 58: 440-5 |
| PMID | 15993854 |
| Title | Association analysis of chromosome 5 GABAA receptor cluster in Japanese schizophrenia patients. |
| Abstract | Several investigations suggest that abnormalities in gamma-amino butyric acid (GABA) neurotransmission systems may be related to the pathophysiology of schizophrenia. A GABA(A) receptor gene cluster on 5q31-35 (beta2 [GABRB2], alpha6 [GABRA6], alpha1 [GABRA1], and gamma2 [GABRG2] subunit genes) is one of the most attractive candidate regions for schizophrenia susceptibility. We performed 1) systematic polymorphism search of GABRB2, GABRA6, and GABRA1, in addition to our colleague's study of GABRG2; 2) evaluation of linkage disequilibrium (LD) within this cluster with 35 single nucleotide polymorphisms (SNPs); 3) "selection of haplotype-tagging (ht) SNPs"; and 4) two-stage association analysis that comprised first-set screening analysis of all htSNPs (288 Japanese schizophrenia patients and 288 control subjects) and second-set replication analysis of the positive htSNPs (901 schizophrenic patients and 806 control subjects). In the first-set scan, we found a significant association of two htSNPs in GABRA1, but no association of GABRB2, GABRA6, and GABRG2. In the following second-set analysis, however, we could not confirm these significant associations. These results indicate that this gene cluster may not play a major role in Japanese schizophrenia. They also raised an alert with regard to preliminary genetic association analysis using a small sample size. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Biol. Psychiatry 2005 Sep 58: 440-5 |
| PMID | 15993854 |
| Title | Association analysis of chromosome 5 GABAA receptor cluster in Japanese schizophrenia patients. |
| Abstract | Several investigations suggest that abnormalities in gamma-amino butyric acid (GABA) neurotransmission systems may be related to the pathophysiology of schizophrenia. A GABA(A) receptor gene cluster on 5q31-35 (beta2 [GABRB2], alpha6 [GABRA6], alpha1 [GABRA1], and gamma2 [GABRG2] subunit genes) is one of the most attractive candidate regions for schizophrenia susceptibility. We performed 1) systematic polymorphism search of GABRB2, GABRA6, and GABRA1, in addition to our colleague's study of GABRG2; 2) evaluation of linkage disequilibrium (LD) within this cluster with 35 single nucleotide polymorphisms (SNPs); 3) "selection of haplotype-tagging (ht) SNPs"; and 4) two-stage association analysis that comprised first-set screening analysis of all htSNPs (288 Japanese schizophrenia patients and 288 control subjects) and second-set replication analysis of the positive htSNPs (901 schizophrenic patients and 806 control subjects). In the first-set scan, we found a significant association of two htSNPs in GABRA1, but no association of GABRB2, GABRA6, and GABRG2. In the following second-set analysis, however, we could not confirm these significant associations. These results indicate that this gene cluster may not play a major role in Japanese schizophrenia. They also raised an alert with regard to preliminary genetic association analysis using a small sample size. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Biochem. Biophys. Res. Commun. 2005 Sep 334: 817-23 |
| PMID | 16023997 |
| Title | Positive association of the human GABA-A-receptor beta 2 subunit gene haplotype with schizophrenia in the Chinese Han population. |
| Abstract | A converging body of evidence implicates the gamma-amino butyric acid neurotransmitter system in the pathogenesis of schizophrenia. Recently, Lo et al. reported strong positive association between schizophrenia and GABRB2, demonstrated by single markers and haplotypes of five markers in introns of GABRB2, rs6556547, rs1816071, rs194072, rs252944, and rs187269. To validate this linkage disequilibrium report, we genotyped these five SNPs and additional rs1816072 in 352 Chinese Han family trios. Though we failed to detect any positive results in single markers, we did find a significant haplotypic association (global p = 0.00157-0.00588) which had not been identified in Lo's study. Our data indicated that the haplotype 'GACTCT' (p = 0.00215, frequency = 53.6%) was overtransmitted which suggests that GABRB2 is in linkage disequilibrium with schizophrenia in the Chinese Han population. The difference between the two studies may be due to the respective analytic power of the two designs. These two independent studies highlighting linkage disequilibrium support the potential involvement of GABRB2 or a nearby gene in the genetic etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Mol. Psychiatry 2005 Dec 10: 1074-88, 1057 |
| PMID | 16172613 |
| Title | Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. |
| Abstract | We previously performed a genome-wide linkage scan in Portuguese schizophrenia families that identified a risk locus on chromosome 5q31-q35. This finding was supported by meta-analysis of 20 other schizophrenia genome-wide scans that identified 5q23.2-q34 as the second most compelling susceptibility locus in the genome. In the present report, we took a two-stage candidate gene association approach to investigate a group of gamma-aminobutyric acid (GABA) A receptor subunit genes (GABRA1, GABRA6, GABRB2, GABRG2, and GABRP) within our linkage peak. These genes are plausible candidates based on prior evidence for GABA system involvement in schizophrenia. In the first stage, associations were detected in a Portuguese patient sample with single nucleotide polymorphisms (SNPs) and haplotypes in GABRA1 (P=0.00062-0.048), GABRP (P=0.0024-0.042), and GABRA6 (P=0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P=0.0015-0.043). Supportive evidence for association was also obtained for a previously reported GABRB2 risk haplotype. Exploratory analyses of the effects of associated GABRA1 haplotypes on transcript levels found altered expression of GABRA6 and coexpressed genes of GABRA1 and GABRB2. Comparison of transcript levels in schizophrenia patients and unaffected siblings found lower patient expression of GABRA6 and coexpressed genes of GABRA1. Interestingly, the GABRA1 coexpressed genes include synaptic and vesicle-associated genes previously found altered in schizophrenia prefrontal cortex. Taken together, these results support the involvement of the chromosome 5q GABAA receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Clin. Biochem. 2006 Mar 39: 210-8 |
| PMID | 16472798 |
| Title | Analysis of GABRB2 association with schizophrenia in German population with DNA sequencing and one-label extension method for SNP genotyping. |
| Abstract | schizophrenia (SCZ) is a complex mental disease that affects approximately 1% of the population. In this study, six SNPs in GABRB2 were genotyped for a case-control association study with the cycloid psychosis subtype of SCZ in the German population using two methods for SNP genotyping. The SNPs were genotyped by direct DNA sequencing, as well as a novel one-label extension method. The results were analyzed for association with SCZ. Significant association was found for SNPs rs1816071 and rs1816072 with SCZ susceptibility. This is consistent with our previous finding of association of SNPs in GABRB2 with SCZ susceptibility in Han Chinese. There was a total agreement between the genotyping results from one-label extensions and the results of direct DNA sequencing, thus validating the accuracy of the one-label extension method of SNP genotyping. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Mol. Psychiatry 2006 Dec 11: 1092-105 |
| PMID | 16983389 |
| Title | Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. |
| Abstract | Single nucleotide polymorphisms in type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform beta(2L), 13.4% in the short isoform beta(2S) and 15.8% in the sum of the two isoforms beta(2T) in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of beta(2L), beta(2S) and beta(2T), and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of beta(2T). Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABA(A) receptors expressed in HEK293 human cells containing beta(2L) underwent a steeper current rundown upon repetitive GABA activation than receptors containing beta(2S). The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA(A) receptor beta2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Mol. Psychiatry 2006 Dec 11: 1092-105 |
| PMID | 16983389 |
| Title | Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. |
| Abstract | Single nucleotide polymorphisms in type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform beta(2L), 13.4% in the short isoform beta(2S) and 15.8% in the sum of the two isoforms beta(2T) in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of beta(2L), beta(2S) and beta(2T), and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of beta(2T). Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABA(A) receptors expressed in HEK293 human cells containing beta(2L) underwent a steeper current rundown upon repetitive GABA activation than receptors containing beta(2S). The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA(A) receptor beta2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Mol. Psychiatry 2006 Dec 11: 1092-105 |
| PMID | 16983389 |
| Title | Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. |
| Abstract | Single nucleotide polymorphisms in type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform beta(2L), 13.4% in the short isoform beta(2S) and 15.8% in the sum of the two isoforms beta(2T) in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of beta(2L), beta(2S) and beta(2T), and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of beta(2T). Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABA(A) receptors expressed in HEK293 human cells containing beta(2L) underwent a steeper current rundown upon repetitive GABA activation than receptors containing beta(2S). The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA(A) receptor beta2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Schizophr. Res. 2007 Jul 93: 374-84 |
| PMID | 17412563 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Psychiatr. Genet. 2007 Feb 17: 43-5 |
| PMID | 17167345 |
| Title | No evidence for an association between variants at the gamma-amino-n-butyric acid type A receptor beta2 locus and schizophrenia. |
| Abstract | The alpha1/beta2/gamma2-containing heteropentamer is the most abundant gamma-amino-n-butyric acid type A receptor subtype in mammalian brains and the corresponding genes, the GABRA1, GABRB2, and GABRG2 genes, are located in chromosomal region 5q34 that several genome wide scans have implicated as a susceptibility region for schizophrenia. Given this positional and functional evidence, Lo et al. (Mol Psychiatry 2004; 9: 603-608) performed systematic linkage disequilibrium mapping of the GABAAR gene cluster on 5q34 in 130 schizophrenic patients and 170 controls, all of Chinese Han origin. In the single locus and haplotype analyses, single nucleotide polymorphisms in the GABRB2 gene showed highly significant association. The estimated effect caused by GABRB2 varied between odds ratios of 2.27 and 5.12. In order to re-examine their findings, we analyzed the most significantly associated single nucleotide polymorphism in the GABRB2 gene in a sample of 367 patients with schizophrenia and 360 controls, all of German descent. Our sample had a sufficient power to detect the effects described. Neither single marker nor haplotype analysis revealed a significant association with the disease status. Thus, our results do not support the hypothesis that genetic variation at the GABRB2 locus plays a major role in schizophrenic patients of European descent and that such variation would explain the previously observed linkage findings at this chromosomal region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Psychiatr. Genet. 2007 Feb 17: 43-5 |
| PMID | 17167345 |
| Title | No evidence for an association between variants at the gamma-amino-n-butyric acid type A receptor beta2 locus and schizophrenia. |
| Abstract | The alpha1/beta2/gamma2-containing heteropentamer is the most abundant gamma-amino-n-butyric acid type A receptor subtype in mammalian brains and the corresponding genes, the GABRA1, GABRB2, and GABRG2 genes, are located in chromosomal region 5q34 that several genome wide scans have implicated as a susceptibility region for schizophrenia. Given this positional and functional evidence, Lo et al. (Mol Psychiatry 2004; 9: 603-608) performed systematic linkage disequilibrium mapping of the GABAAR gene cluster on 5q34 in 130 schizophrenic patients and 170 controls, all of Chinese Han origin. In the single locus and haplotype analyses, single nucleotide polymorphisms in the GABRB2 gene showed highly significant association. The estimated effect caused by GABRB2 varied between odds ratios of 2.27 and 5.12. In order to re-examine their findings, we analyzed the most significantly associated single nucleotide polymorphism in the GABRB2 gene in a sample of 367 patients with schizophrenia and 360 controls, all of German descent. Our sample had a sufficient power to detect the effects described. Neither single marker nor haplotype analysis revealed a significant association with the disease status. Thus, our results do not support the hypothesis that genetic variation at the GABRB2 locus plays a major role in schizophrenic patients of European descent and that such variation would explain the previously observed linkage findings at this chromosomal region. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | PLoS ONE 2007 -1 2: e462 |
| PMID | 17520021 |
| Title | Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene. |
| Abstract | The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor beta(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2), especially its long isoform. Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | PLoS ONE 2007 -1 2: e462 |
| PMID | 17520021 |
| Title | Positive selection within the Schizophrenia-associated GABA(A) receptor beta(2) gene. |
| Abstract | The gamma-aminobutyric acid type-A (GABA(A)) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABA(A) receptor beta(2) subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced beta(2) isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of beta(2), especially its long isoform. Electrophysiological analysis showed that this long beta(2) isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABA(A) receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Biol. Psychiatry 2007 Mar 61: 653-60 |
| PMID | 16950232 |
| Title | GABRB2 association with schizophrenia: commonalities and differences between ethnic groups and clinical subtypes. |
| Abstract | Single nucleotide polymorphisms (SNPs) and haplotypes in intron 8 of type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were initially found to be associated with schizophrenia in Chinese. This finding was subjected to cross-validation in this study with Japanese (JP) and German Caucasian (GE) subjects. Single nucleotide polymorphisms discovery and genotyping were carried out through resequencing of a 1839 base pair (bp) region in GABRB2. Tagging SNPs (tSNPs) were selected based on linkage disequilibrium (LD), combinations of which were analyzed with Bonferroni correction and permutation for disease association. Random resampling was applied to generate size- and gender-balanced cases and control subjects. Out of the 17 SNPs (9.2/kilobase [kb]) revealed, 6 were population-specific. Population variations in LD were observable, and at least two low LD points were identified in both populations. Although disease association at single SNP level was only shown in GE, strong association was demonstrated in both JP (p = .0002 - .0191) and GE (p = .0033 - .0410) subjects, centering on haplotypes containing rs1816072 and rs1816071. Among different clinical subtypes, the most significant association was exhibited by systematic schizophrenia. Cross-population validation of GABRB2 association with schizophrenia has been obtained with JP and GE subjects, with the genotype-disease correlations being strongest in systematic schizophrenia, the most severe subtype of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Pharmacogenet. Genomics 2008 Apr 18: 317-23 |
| PMID | 18334916 |
| Title | Pathway-based association analysis of genome-wide screening data suggest that genes associated with the gamma-aminobutyric acid receptor signaling pathway are involved in neuroleptic-induced, treatment-resistant tardive dyskinesia. |
| Abstract | Neuroleptic-induced tardive dyskinesia (TD) is an involuntary movement disorder that develops in patients who have undergone long-term treatment with antipsychotic medications, and its etiology is unclear. In this study, a genome-wide association screening was done to identify the pathway(s) in which genetic variations influence susceptibility to neuroleptic-induced TD. Screening with Sentrix Human-1 Genotyping BeadChip (Illumina, San Diego, California, USA) was done for 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD. A total of 40 573 single nucleotide polymorphisms that were not in linkage disequilibrium with each other and were located in the exonic and intronic regions of 13 307 genes were analyzed. After gene-based corrections, P values for allelic associations were subjected to canonical pathway-based analyses with Ingenuity Pathway Analysis software (Ingenuity Systems, Inc., Redwood City, California, USA). Eight genes (ABAT, ALDH9A1, GABRA3, GABRA4, GABRB2, GABRAG3, GPHN, and SLC6A11) contained polymorphisms with gene-based corrected allelic P values of less than 0.05. They were aggregated significantly in 33 genes belonging to the gamma-aminobutyric acid (GABA) receptor signaling pathway (P=0.00007, corrected P=0.01). Associations were replicated in an independent sample of 36 patients with TD and 136 patients without TD for polymorphisms in SLC6A11 (GABA transporter 3) (P=0.0004 in the total sample), GABRB2 (beta-2 subunit of GABA-A receptor) (P=0.00007 in the total sample), and GABRG3 (gamma-3 subunit of GABA-A receptor) (P=0.0006 in the total sample). The results suggest that the GABA receptor signaling pathway may be involved in genetic susceptibility to treatment-resistant TD, at least in a subgroup of Japanese patients with schizophrenia. The present results suggest that benzodiazepines may be considered as possible treatment option for TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Nat. Genet. 2008 Jul 40: 827-34 |
| PMID | 18583979 |
| Title | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. |
| Abstract | In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Schizophr. Res. 2008 Sep 104: 96-107 |
| PMID | 18715757 |
| Title | Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. |
| Abstract | Genetic association studies on schizophrenia (SZ) have been repeatedly performed over the last two decades, resulting in a consensus that results are generally inconsistent. This consensus has begun to change as a result of meta-analyses (e.g., [Glatt, S.J. and Jonsson, E.G., 2006. The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 149-154.]). The schizophreniaGene database (http://www.schizophreniaforum.org/res/sczgene/default.asp) has been a leader in meta-analyses of SZ association data, by dynamically and comprehensively cataloging all public genetic association studies, and preparing meta-analyses of case-control data. There are 19 "top" candidate genes from these analyses (access on December 20, 2007), showing the highest effect sizes and nominally significant associations of at least one variant in the meta-analyses of all ethnic samples or of samples of Caucasian ancestry. We selected 40 polymorphisms in 12 selected "top" genes for additional meta-analyses, which had at least one familial association data. We found gene-wide (correction for the number of meta-analyses for each gene) significant allelic association evidence for seven genes in the combined samples. The odds ratios (ORs) of the associated minor risk alleles range from 1.072 to 1.121, for DRD4, MTHFR, PPP3CC and TP53. For protective allele associations, the ORs are between 0.842 and 0.886, for DAO, IL1B, and SLC6A4. In population-based sub-analyses, we found significant results in four genes in Asians (ORs between 1.084 and 1.309 for DRD4, GABRB2, PPP3CC, and TP53), and one gene in European (OR of 0.888 for SLC6A4). The association of rs1816072 of GABRB2 with SZ in Asians was significant (adjusted P=0.048 after correction for 80 tests). No significant heterogeneity between case-control and family-based study designs was detected in 35 out of 40 polymorphisms. Our results further support eight potential SZ candidate genes and suggest that family data can reasonably be included in the meta-analysis of genetic associations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Arch. Gen. Psychiatry 2008 Jan 65: 53-61 |
| PMID | 18180429 |
| Title | Family-based association study of lithium-related and other candidate genes in bipolar disorder. |
| Abstract | Association studies in bipolar disorder have been focused on a relatively narrow pool of candidate genes based on a limited understanding of the underlying pathophysiologic features. Recent developments suggest that a broader pool of genes may be associated with this disorder. To examine the association between genes related to the lithium mechanism of action, as well as other positional and functional candidates, with bipolar I disorder. We examined a dense set of haplotype-tagging single-nucleotide polymorphisms using a gene-based test of association. Three hundred seventy-nine parent-affected offspring trios. No genes specifically chosen to probe the action of lithium were associated with bipolar disorder. However, gene-based analysis of sialyltransferase 4A (SIAT4A), tachykinin receptor 1 (TACR1), and gamma-aminobutyric acid(A) beta2 receptor subunit (GABRB2) yielded evidence of association (empirical P value, <.005). Among 3 genes associated with schizophrenia or bipolar disorder in multiple previous studies, including dysbindin (DTNBP1), neuregulin (NRG1), and disrupted-in-schizophrenia 1 (DISC1), only DISC1 showed evidence of association in this cohort. In a secondary analysis of these 6 genes among parent-proband trios with a history of psychosis, evidence of the association with SIAT4A was strengthened. These results suggest novel candidates and 1 gene (DISC1) previously associated with schizophrenia that merit further study in bipolar disorder. However, polymorphisms in major lithium-signaling genes do not appear to contribute substantially to bipolar liability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Biochem. Soc. Trans. 2009 Dec 37: 1415-8 |
| PMID | 19909288 |
| Title | GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations. |
| Abstract | The SCZ (schizophrenia)-associated GABA(A) receptor (gamma-aminobutyric acid type A receptor) beta(2) subunit gene GABRB2 was recently associated with BPD (bipolar disorder). Although weaker than its association with SCZ, significant association of GABRB2 with BPD was found in both German and Chinese, especially for the haplotypes rs1816071-rs187269 and rs1816072-rs187269 for which the M-M variants showed higher frequency in disease than the control. Significant genotype-dependent reduction in GABRB2 expression was shown for BPD, but to a lesser extent than that for SCZ. Temporal effects on GABRB2 expression were observed. Moreover, for the homozygous major genotypes of rs1816071, rs1816072 and rs187269, expression increased with time in CON but decreased in SCZ and BPD. The genotypes of these three SNPs (single nucleotide polymorphisms) were further correlated with antipsychotics dosage in SCZ cohorts. The findings highlight the importance of GABRB2 in neuropsychiatric disease aetiology, with respect to haplotype association, as well as reduction of and temporal effects on gene expression in both SCZ and BPD, but to a lesser extent in the latter, supporting the suggestion that functional psychosis can be conceptualized as a continuous spectrum of clinical phenotypes rather than as distinct categories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | PLoS ONE 2009 -1 4: e6977 |
| PMID | 19763268 |
| Title | Alternative-splicing in the exon-10 region of GABA(A) receptor beta(2) subunit gene: relationships between novel isoforms and psychotic disorders. |
| Abstract | Non-coding single nucleotide polymorphisms (SNPs) in GABRB2, the gene for beta(2)-subunit of gamma-aminobutyric acid type A (GABA(A)) receptor, have been associated with schizophrenia (SCZ) and quantitatively correlated to mRNA expression and alternative splicing. Expression of the Exon 10 region of GABRB2 from minigene constructs revealed this region to be an "alternative splicing hotspot" that readily gave rise to differently spliced isoforms depending on intron sequences. This led to a search in human brain cDNA libraries, and the discovery of two novel isoforms, beta(2S1) and beta(2S2), bearing variations in the neighborhood of Exon-10. Quantitative real-time PCR analysis of postmortem brain samples showed increased beta(2S1) expression and decreased beta(2S2) expression in both SCZ and bipolar disorder (BPD) compared to controls. Disease-control differences were significantly correlated with SNP rs187269 in BPD males for both beta(2S1) and beta(2S2) expressions, and significantly correlated with SNPs rs2546620 and rs187269 in SCZ males for beta(2S2) expression. Moreover, site-directed mutagenesis indicated that Thr(365), a potential phosphorylation site in Exon-10, played a key role in determining the time profile of the ATP-dependent electrophysiological current run-down. This study therefore provided experimental evidence for the importance of non-coding sequences in the Exon-10 region in GABRB2 with respect to beta(2)-subunit splicing diversity and the etiologies of SCZ and BPD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Curr. Med. Chem. 2010 -1 17: 1300-16 |
| PMID | 20166940 |
| Title | Primate-accelerated evolutionary genes: novel routes to drug discovery in psychiatric disorders. |
| Abstract | Novel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | PLoS ONE 2010 -1 5: e9547 |
| PMID | 20221451 |
| Title | A recombination hotspot in a schizophrenia-associated region of GABRB2. |
| Abstract | schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2) subunit of GABA(A) receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d)) over mutation rate (theta), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | PLoS ONE 2010 -1 5: e9547 |
| PMID | 20221451 |
| Title | A recombination hotspot in a schizophrenia-associated region of GABRB2. |
| Abstract | schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2) subunit of GABA(A) receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes. In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d)) over mutation rate (theta), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Neurosci Biobehav Rev 2010 May 34: 958-77 |
| PMID | 20060416 |
| Title | Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance. |
| Abstract | schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Mol. Psychiatry 2011 May 16: 557-68 |
| PMID | 20404824 |
| Title | Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor ?(2) subunit. |
| Abstract | schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2 or rs2290732 (G/A) in the neighboring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the disease-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could have an impact on the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Mol. Psychiatry 2011 May 16: 557-68 |
| PMID | 20404824 |
| Title | Imprinting in the schizophrenia candidate gene GABRB2 encoding GABA(A) receptor ?(2) subunit. |
| Abstract | schizophrenia is a complex genetic disorder, the inheritance pattern of which is likely complicated by epigenetic factors yet to be elucidated. In this study, transmission disequilibrium tests with family trios yielded significant differences between paternal and maternal transmissions of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 and its haplotypes. The minor allele (T) of rs6556547 was paternally undertransmitted to male schizophrenic offsprings, and this parent-of-origin effect strongly suggested that GABRB2 is imprinted. 'Flipping' of allelic expression in heterozygotes of SNP rs2229944 (C/T) in GABRB2 or rs2290732 (G/A) in the neighboring GABRA1 was compatible with imprinting effects on gene expression. Clustering analysis of GABRB2 mRNA expressions suggested that imprinting brought about the observed two-tiered distribution of expression levels in controls with heterozygous genotype at the disease-associated SNP rs1816071 (A/G). The deficit of upper-tiered expressions accounted for the lowered expression levels in the schizophrenic heterozygotes. The occurrence of a two-tiered distribution furnished support for imprinting, and also pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, the two schizophrenia-associated SNPs rs6556547 and rs1816071 overlapped with a CpG dinucleotide, thereby opening the possibility that CpG methylation status of these sites could have an impact on the risk of schizophrenia. Thus multiple lines of evidence pointed to the occurrence of imprinting in the GABRB2 gene and its possible role in the development of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Transl Psychiatry 2012 -1 2: e146 |
| PMID | 22872161 |
| Title | Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome. |
| Abstract | The 22q11.2 microdeletion is one of the highest genetic risk factors for schizophrenia. It is not well understood which interactions of deleted genes in 22q11.2 regions are responsible for the pathogenesis of schizophrenia, but catechol-O-methytransferase (COMT) is among the candidates. Df1/+ mice are 22q11.2 deletion syndrome (22q11DS) model mice with a hemizygous deletion of 18 genes in the 22q11-related region. Df1/+ mice showed enhanced response to the dopamine D1 agonist, SKF38393, and the N-methyl-D-aspartate antagonist, MK801, which can be normalized by a GABA(A) receptor agonist, bretazenil, or a GABA(A) ?2/?3 receptor agonist, SL651498. Here, we demonstrated the curing effects of virus-mediated reintroduction of Comt to the prefrontal cortex (PFC) in Df1/+ mice. In contrast, both Comt overexpression and Comt inhibition caused an abnormal responsiveness to Bretazenil, a GABA(A) receptor agonist in control mice. Comt overexpression increased MK801-induced interneuronal activation and GABA release in the PFC. The expression levels of GABA-related genes such as GABRB2 (GABA(A)receptor ?2), Gad2 (glutamic acid decarboxylase 65 (Gad65)) and Reln (Reelin) correlate with a Comt expression level in PFC. Our data suggest that Comt-mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of Df1/+ mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Schizophr. Res. 2012 Feb 134: 260-6 |
| PMID | 22206711 |
| Title | Epigenetic regulation on GABRB2 isoforms expression: developmental variations and disruptions in psychotic disorders. |
| Abstract | To improve the understanding of psychotic abnormalities and their non-Mendelian inheritance patterns, the epigenetic regulation of the psychotic disorder-associated GABRB2, gene for the type A ?-aminobutyric acid receptor ?(2)-subunit, was investigated. Expression of GABRB2, and the epigenetic regulatory enzymes histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) in mouse and postmortem human brains was analyzed using real-time PCR. Results showed that expression of GABRB2 isoforms significantly increased over time in both mouse and human, especially for the long splicing isoform. In the brains of non-psychiatric controls (CON), a significant positive correlation of GABRB2 expression with age was observed in individuals with MM genotypes of the single nucleotide polymorphisms (SNPs) rs187269 and rs1816072. This was reversed to a significant negative correlation in schizophrenics (SCZ). A similar reversal was also displayed by bipolar disorder (BPD) patients. In parallel, a significant co-variation of HDAC1 with GABRB2 expression observed in CON remained significant in BPD but not in SCZ; comparably, a significant co-variation of HDAC2 with GABRB2 expression observed in CON became non-significant in both SCZ and BPD. Moreover, co-variations of DNMT1 and DNMT3B with GABRB2, not observable in CON, became significant in BPD. These findings demonstrated that GABRB2 expression was under epigenetic regulation that varied with development, genotype and disease status, and these regulatory mechanisms were observably disrupted in SCZ and BPD. This study provided insight into the complex inheritance patterns of psychiatric disorders, and pointed to the involvement of epigenetic dysregulation in the disease process of major psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | PLoS ONE 2013 -1 8: e62322 |
| PMID | 23638040 |
| Title | Social cognitive role of schizophrenia candidate gene GABRB2. |
| Abstract | The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | PLoS ONE 2013 -1 8: e62322 |
| PMID | 23638040 |
| Title | Social cognitive role of schizophrenia candidate gene GABRB2. |
| Abstract | The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | PLoS ONE 2013 -1 8: e62322 |
| PMID | 23638040 |
| Title | Social cognitive role of schizophrenia candidate gene GABRB2. |
| Abstract | The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs) were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS) or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis) to psychological (altruism) spectrum of social cognition suggesting GABRB2 involvement in human cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Nord J Psychiatry 2014 Feb 68: 123-8 |
| PMID | 23795861 |
| Title | Gaba transporter SLC6A11 gene polymorphism associated with tardive dyskinesia. |
| Abstract | Gamma-aminobutyric acid (GABA) insufficiency has been reported to be related to the tardive dyskinesia (TD) susceptibility. Inada et al. (Pharmacogenet Genomics 2008;18:317-23) identified eight genes belonging to GABA receptor signaling pathway that may be involved in TD susceptibility by genome-wide screening and they replicated associations in an independent sample for polymorphisms in SLC6A11 (GABA transporter 3), GABRG3 (c-3 subunit of GABA-A receptor) and GABRB2 (?-2 subunit of GABA-A receptor). In this study, we tried to replicate their finding in a larger Korean sample and find if any of the genes was associated with the susceptibility to TD. We selected three polymorphisms in SLC6A11 (rs4684742), GABRG3 (rs2061051) and GABRB2 (rs918528) from the previous study. We carried out a case-control study (105 TD and 175 non-TD schizophrenic patients) to identify the association between the three candidate polymorphisms and susceptibility to TD and their epistatic interactions by using the multifactor dimensionality reduction (MDR) algorithm. Among the three variants, SCL6A11 genotypes distribution showed a significant difference between the TD and non-TD patients (P = 0.049). However, GABRG3 and GABRB2 genotype distributions were not associated with TD (P = 0.268 and P = 0.976, respectively). Further, our analyses provided significant evidence for gene-gene interactions (SCL6A11, GABRG3 and GABRB2) in the development of TD. The odds ratio increased to 2.53 (CI = 1.515-4.217, P = 0.0003) when the genetic susceptibility to TD was analyzed with the three genes considered altogether through MDR approach. These results suggest that GABA receptor signaling pathway was associated with the increased susceptibility to TD in Korean schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Nan Fang Yi Ke Da Xue Xue Bao 2015 Feb 35: 256-9 |
| PMID | 25736124 |
| Title | [Association of single nucleotide polymorphisms in the promoter of GABAA receptor ?2 subunit gene with schizophrenia]. |
| Abstract | To investigate the genetic association between schizophrenia and the polymorphism of GABA(A) receptor ?2 subunit (GABRB2) gene. A population association analysis was performed of 5 single nucleotide polymorphisms (SNPs) in the proximal promoter of GABRB2 gene by PCR and sequencing of the genomic DNA in a cohort of 172 schizophrenics and 167 controls of Chinese Han nationality. One out of the 5 SNPs, namely rs3811996, was found to be significantly associated with schizophrenia especially in the male cohorts, where the heterozygous genotypes (A/G) and minor allele G displayed lower frequencies in case group than in the controls. We found a new risk, SNP rs3811996, for paranoia schizophrenia, which further supports the importance of genetic variations of GABRB2 in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Nan Fang Yi Ke Da Xue Xue Bao 2015 Feb 35: 256-9 |
| PMID | 25736124 |
| Title | [Association of single nucleotide polymorphisms in the promoter of GABAA receptor ?2 subunit gene with schizophrenia]. |
| Abstract | To investigate the genetic association between schizophrenia and the polymorphism of GABA(A) receptor ?2 subunit (GABRB2) gene. A population association analysis was performed of 5 single nucleotide polymorphisms (SNPs) in the proximal promoter of GABRB2 gene by PCR and sequencing of the genomic DNA in a cohort of 172 schizophrenics and 167 controls of Chinese Han nationality. One out of the 5 SNPs, namely rs3811996, was found to be significantly associated with schizophrenia especially in the male cohorts, where the heterozygous genotypes (A/G) and minor allele G displayed lower frequencies in case group than in the controls. We found a new risk, SNP rs3811996, for paranoia schizophrenia, which further supports the importance of genetic variations of GABRB2 in the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | PLoS ONE 2015 -1 10: e0142049 |
| PMID | 26561861 |
| Title | GABRB2 Haplotype Association with Heroin Dependence in Chinese Population. |
| Abstract | Substance dependence is a frequently observed comorbid disorder in schizophrenia, but little is known about genetic factors possibly shared between the two psychotic disorders. GABRB2, a schizophrenia candidate gene coding for GABAA receptor ?2 subunit, is examined for possible association with heroin dependence in Han Chinese population. Four single nucleotide polymorphisms (SNPs) in GABRB2, namely rs6556547 (S1), rs1816071 (S3), rs18016072 (S5), and rs187269 (S29), previously associated with schizophrenia, were examined for their association with heroin dependence. Two additional SNPs, rs10051667 (S31) and rs967771 (S32), previously associated with alcohol dependence and bipolar disorder respectively, were also analyzed. The six SNPs were genotyped by direct sequencing of PCR amplicons of target regions for 564 heroin dependent individuals and 498 controls of Han Chinese origin. Interestingly, it was found that recombination between the haplotypes of all-derived-allele (H1; OR = 1.00) and all-ancestral-allele (H2; OR = 0.74) at S5-S29 junction generated two recombinants H3 (OR = 8.51) and H4 (OR = 5.58), both conferring high susceptibility to heroin dependence. Additional recombination between H2 and H3 haplotypes at S1-S3 junction resulted in a risk-conferring haplotype H5 (OR = 1.94x109). In contrast, recombination between H1 and H2 haplotypes at S3-S5 junction rescued the risk-conferring effect of recombination at S5-S29 junction, giving rise to the protective haplotype H6 (OR = 0.68). Risk-conferring effects of S1-S3 and S5-S29 crossovers and protective effects of S3-S5 crossover were seen in both pure heroin dependent and multiple substance dependence subgroups. In conclusion, significant association was found with haplotypes of the S1-S29 segment in GABRB2 for heroin dependence in Han Chinese population. Local recombination was an important determining factor for switching haplotypes between risk-conferring and protective statuses. The present study provide evidence for the schizophrenia candidate gene GABRB2 to play a role in heroin dependence, but replication of these findings is required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | J. Mol. Neurosci. 2016 May 59: 36-47 |
| PMID | 26894264 |
| Title | Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats. |
| Abstract | The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-C? and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, GABRB2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (?-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (?-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (?-1) receptor and CREB1 in the NAc, probably via activating PKA signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |