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 metaanalysis 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 ¼ 0.00062-0.048), GABRP (P ¼ 0.0024-0.042), and GABRA6 (P ¼ 0.0065-0.0088). The GABRA1 and GABRP findings were replicated in the second stage in an independent German family-based sample (P ¼ 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 GABA A receptor gene cluster in schizophrenia, and suggest that schizophrenia-associated haplotypes may alter expression of GABA-related genes.

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…Consistent with this interpretation, a recent genetic study reported that variants in the GABA A receptor a1 subunit gene were associated with both schizophrenia and altered expression levels of GABA A receptor subunit mRNAs. 66 Furthermore, a targeted deletion of the GABA A receptor a1 subunit gene in mice resulted in altered cortical expression of other GABA A receptor subunits, such as increased a2 and decreased g2 protein levels, as well as decreased levels of SST mRNA. 67,68 Together, these findings suggest that the deficit in a1 subunit expression could be an upstream event to other GABA-related gene expression changes in the DLPFC of subjects with schizophrenia.…”

ErbB4 reduces synaptic GABA A currents independent of its receptor tyrosine kinase activity

“…17). Genome-wide linkage scans of Portuguese families identified a genomic region that includes GABRA1 (55), and haplotypes and SNPs in the gene are also associated with risk for SCZ, as well as alterations in the expression of GABAR subunits (56). Moreover, GABAR α1 transcript levels are lower in the postmortem brain of persons diagnosed with SCZ (19) and depression (57), suggesting a functional role of GABAR α1-containing receptors in the etiology of these disorders.…”

The myelin-pathogenesis puzzle in schizophrenia: a literature review

“…39 One of the most attractive candidate regions for schizophrenia on 5q31-35 that maps several GABA(A) receptor subunit genes, recently gained positive results for an association with the disorder. 40 However, further investigations are warranted considering that a concurrent study in a Japanese schizophrenic population failed to confirm this. 41 Further interest in schizophrenia susceptibility on this chromosome has been stirred by a case report of a segmental uniparental isodisomy on 5q32-qter (the offspring receives two chromosomal homologs from one parent) in a patient with childhood-onset schizophrenia.…”