No evidence for an association between variants at the γ-amino-n-butyric acid type A receptor β2 locus and schizophrenia

Jamra, Rami Abou; Becker, Tim; Klopp, Norman; Dahdouh, Faten; Schulze, Thomas G.; Groß, Magdalena; Deschner, Monika; Schmäl, Christine; Illig, Thomas; Rietschel, Marcella; Propping, Peter; Cichon, Sven; Nöthen, Markus M.; Schumacher, Johannes

doi:10.1097/ypg.0b013e32801118cd

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…GABRB2 codes for the β 2 subunit of GABA A receptor, and is part of a cluster of genes on chromosome 5q34 for the GABA A receptor, the major inhibitory neurotransmitter-gated channel receptor family in the central nervous system (CNS) [5]. Our initial findings from Han Chinese have since been validated by additional samples from the Chinese [6], Portuguese [7], German [7]–[9] and Japanese [9] populations, although conflicting results from Japanese [10] and German [11] populations have also been reported.…”

Section: Introductionmentioning

confidence: 88%

Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

et al. 2007

PLoS ONE

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The gamma-aminobutyric acid type-A (GABAA) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABAA receptor β2 subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced β2 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 β2, especially its long isoform. Electrophysiological analysis showed that this long β2 isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABAA receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.

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Section: Introductionmentioning

confidence: 88%

Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

et al. 2007

PLoS ONE

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“…Positive associations between GABRB2 polymorphisms and SCZ were found in Asian [ 20 – 22 ] and Caucasian populations [ 21 , 23 ]. However, other studies reported no association between GABRB2 and SCZ in Asian [ 24 , 25 ] or Caucasian population [ 26 ]. The results of previous two meta-analyses of GABRB2 with SCZ were inconsistent [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of GABRB2 polymorphisms and the risk of schizophrenia combined with GWAS data of the Han Chinese population and psychiatric genomics consortium

Zhang¹,

Li²,

Yu³

et al. 2018

PLoS ONE

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Schizophrenia (SCZ) is a severe psychiatric disorder with evidence of a strong genetic component in the complex etiologies. Some studies indicated that gamma-aminobutyric acid (GABA)A receptor β2 subunit gene (GABRB2) was associated with SCZ. Other studies reported a negative association. Moreover, the results of two previous meta-analyses of GABRB2 with SCZ were inconsistent and the sample sizes were limited. Therefore, an updated meta-analysis combined with genome-wide association study (GWAS) data of the Han Chinese population and Psychiatric Genomics Consortium (PGC) was performed. Available case–control and family-based genetic data were extracted from association studies, and the GWAS data were included. The findings showed no association between six single-nucleotide polymorphisms of GABRB2 (rs6556547, rs1816071, rs1816072, rs194072, rs252944, and rs187269) and SCZ in a total of 51,491 patients and 74,667 controls. The ethnic subgroup analysis revealed no significant association in Asian populations. Since the PGC data of SCZ (SCZ-PGC, 2014) contained 3 studies of Asian populations (1866 patients and 3418 controls), only the data of European samples in SCZ-PGC were used for the meta-analysis of the Caucasian population in the present study. The result still showed no association in the Caucasian population. In conclusion, the present meta-analysis on combined data from GWASs of the Han Chinese population and PGC suggested that GABRB2 polymorphisms might not be associated with SCZ.

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“…Several candidate genes in the region have been considered including epsin 4 (CLINT1), and the GABAA locus between 160-170Mb, although the results are equivocal (Ikeda et al, 2005;Liu et al, 2005;Petryshen 2005;Pimm et al, 2005;Tang et al, 2006;Jamra et al, 2007;Lo et al, 2007). Recently, Fanous et al, (2007) presented data showing a modest association in SZ to a haplotype in the neurogenin 1 gene, which maps to ~134.9Mb.…”

Section: Introductionmentioning

confidence: 99%

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia

Pedrosa

Stefanescu

Margolis

et al. 2008

Schizophrenia Research

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Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome mapped in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members -α, β, and γ -which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHα enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allelespecific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

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No evidence for an association between variants at the γ-amino-n-butyric acid type A receptor β2 locus and schizophrenia

Cited by 6 publications

References 13 publications

Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene

Meta-analysis of GABRB2 polymorphisms and the risk of schizophrenia combined with GWAS data of the Han Chinese population and psychiatric genomics consortium

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia

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