Article

The GABA type A receptor α5 subunit gene is associated with bipolar I disorder

Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho 2-5-1, Okayama 700-8558, Japan.
Neuroscience Letters (Impact Factor: 2.06). 06/2005; 381(1-2):108-13. DOI: 10.1016/j.neulet.2005.02.010
Source: PubMed

ABSTRACT Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder.

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    • "This region is organized in cluster with three of the GABA A receptor subunit genes (GABRB3, GABRA5 and GABRG3) [24] [25]. Single nucleotide polymorphisms (SNPs) present in these genes have been associated in epilepsy susceptibility, drug resistance [37] [42], susceptibility to autistic [49] or with bipolar schizoaffective disorders [26] Specifically, GABRA5 was associated with bipolar I disorder [14] [49] [56]. In the mouse model, four lines of GABA A -receptor point mutated knock-in have attributed different diazepam pharmacological properties to different GABA A -receptor isoforms. "
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    • "Altered brain GABA A receptor function may account for some of the neuropsychiatric problems associated with PWS as there is increasing evidence that GABA neuronal dysfunction is implicated in various psychiatric disorders including psychosis (Guidotti et al., 2000; van Kammen et al., 1998), mood disorders (Sanacora et al., 1999), anxiety disorders (Goddard et al., 2001), and autism (Blatt et al., 2001; Dhossche et al., 2002). Genetic studies also suggest that polymorphisms of a GABA A receptor subunit gene (GABRB3) or a gene near this locus increases susceptibility to catatonia (Stöber et al., 2000, 2002), bipolar disorder (Papadimitriou et al., 1998; Otani et al., 2005), and autism (Nurmi et al., 2003; Shao et al., 2003). GABRB3 has been associated with a subtype of autism with high levels of repetitive behaviors and stereotyped patterns (insistence on sameness ) (Shao et al., 2003) and with a subtype of autism with savant skills, a characteristic often associated with the development of special skills (O'Conner and Hermelin, 1991). "
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