An Association Study Between Paranoid Schizophrenia And Genes In The Gamma-aminobutyric Acid Receptor And Transporter

Objective:Schizophrenia is the most common mental disorder with a lifetime risk of about 1%in the general population.Since the disorder causes heavy economical and social burdens to families and societies,it is very important to establish a procedure of treating and preventing schizophrenia,and the investigation of the susceptibility genes for schizophrenia becomes noticeable generally.Though its molecular etiology remains unknown,the data from twin,adoption and family studies have clearly demonstrated that schizophrenia is a representative complex disorder.Its pathogenesy involved genetics and environmental factors and its heritability about 80%.Gamma-aminobutyric acid is one of the most important inhibitory neurotransmitters in the mammalian central nervous system.In 50%of central synapse,GABA play an important role in controlling the excitability of neuron,which depend on specific receptors.In addition, gamma-aminobutyric,aminoglutaminic acid and dopamine could interact at different anatomic levels and affect dopamine function.Although a defect in neurotransmission involving GABA in schizophrenia was first proposed by Roberts in 1972,followed by extensive investigations on the GABAergic system in schizophrenia subjects.And many studies found gamma-aminobutyric acid system disfunction in schizophrenia patients.Candidate gene strategy wad taken in our early work and we systematically screened SNPs of metabolic enzyme genes on metabolic pathway of gamma-aminobutyric acid.Results showed that the correlation between gamma-aminobutyric acid metabolic enzyme genes and schizophrenia were not been found.So,we continue to study GABA signal transduction pathway loacating downstream of GABA system,and systematically to analyze the association between the gamma-aminobutyric acid receptor or transporter genes and paranoid schizophrenia.Methods:In the present study,case-control study was taken.A total of 80 patients with paranoid schizophrenia meeting ICD-10 criteria and 108 matched normal controls were recruited from Beijing,north China.All subjects were unrelated Han Chinese and gave written informed consent.It was selected that 86 reported single nucleotide polymorphisms(SNPs)in the coding or untranslated regions of the 20 genes involved in the gamma-aminobutyric acid receptor and transporter from the public databases,and genotyped them by polymerase chain reaction(PCR) and direct sequencing of PCR products.In all,59 SNPs in 18 genes showed polymorphic＞5%in the sample population and were used for data analysis.Results:(1)No significant differences were observed in genotypic or allelic frequencies of these SNPs between the patients and controls.(2)No significant assocition was found between genetype and phenotypes in paranoid schizophrenia.(3)A weak association was found between rs976156(A)-rs1497568(C),rs2256882(A)-rs3810651(T)haplotypes and paranoid schizophrenia. (4)Using Multifactor dimensionality reduction method,one combination that sex/GABRE-E5 (rs2256882)/GABRQ-E9(rs3810651)were detected to be significantly susceptible to paranoid schizophrenia.Conclution:We conclude the combination of GABRE,GABRQ and gender may play a major role in paranoid schizophrenia pathogenesis in the sample population.GABRG1 gene is one possible suspected gene for paranoid schizophrenia.