Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian central nervous system. It is involved in a wide spectrum of physiological functions, from sleep and sedation to convulsions. A defect in neurotransmission involving GABA in schizophrenia was first propsed in early 1970s, based on neuropathologcial evidence, yet there is a lack of molecular genetic evidence.
Recently, we carried out a pilot study on a region of the GABA-A receptor β2 subunit gene on chromosome 5 and found significant association for single nucleotide polymorphisms (SNPs) in the gene sequence with occurrence of schizophrenia. The current proposal aims to validate this important finding and to conduct a thorough scanning of the complete gene sequences of the GABA-A receptor subunit genes in this chromosomal region, including the three major subunits α1, β2 and γ2. We shall collect samples from Hong Kong Chinese subjects for a case-control study using haplotype maps and comparing the SNP haplotype frequencies in the receptor genes, and hence examine whether these genes are in association with schizophrenia, or other schizophrenia-spectrum disorders, including Alzheimer's disease presenting with psychotic symptoms.
Based on the observation that patients suffering from the catatonic subtype of schizophrenia respond particularly well to benzodiazepines, which bind specifically to GABA-A receptors, we shall also perform data analysis in terms of correlating SNP association with schizophrenia subtypes. Association of GABA-A receptor genes with schizophrenia would be a major step forward to determining whether these genes are susceptibility genes for schizophrenia, thereby paving the way to more effective diagnosis and treatment for this debilitating disease.