Gene Promoter Dna Methylations and Their Relationships with Endophenotypes in Patients with Schizophrenia

Project: A - Government Institutionb - National Science and Technology Council

Project Details


Background Schizophrenia is a disabling mental disease affecting about 1% of the worldwide population. There is an overall heritability estimate of 68% for the underlying liability to schizophrenia. Molecular epigenetic studies can overcome the complexities of traditional genetic studies and provide a new framework for the search of etiological factors in schizophrenia. DNA methylation provides an example of an epigenetic process that affects gene expression. Several postmortem experiments have found that increased DNA methylation at the glutamic acid decarboxylase (GAD67) and reelin promoter, and hypomethylation of membrane-bound catechol-O-methyltransferase (MB-COMT) promoter gene in prefrontal cortex of schizophrenia patients. Because it is impossible to obtain brain tissue from schizophrenia patients clinically, the peripheral blood mononuclear cell (PBMC) can partly represent the brain gene expression. It has been reported to use PBMC as biomarkers for epigenetic abnormalities, such as histone acetylation and methylatoin, in schizophrenia. To our best knowledge, gene promoter DNA methylation abnormalities in schizophrenia have been limited to postmortem study. It warrants to studying the DNA methylation using schizophrenia’s PBMC. Recently, endophenotype strategy has emerged as an important tool in understanding the genetic architecture of schizophrenia. Some cognitive functions, such as attention and working memory (WM), have been used as candidate endophpenotypes for genetic studies in schizophrenia. Synchronized GABA neurotransmission in the dorsolateral prefrontal cortex is required for adequate attention and working memory, suggesting that impairments in GABA-mediated inhibition in the prefrontal cortex could contribute to the endophenotype presentations in schizophrenia. Study goals: Our study goals are 1) to compare GAD, reelin, and MB-COMT gene promoter DNA methylations between schizophrenia patients and control group; 2) to examine the correlation of GAD, reelin, and MB-COMT gene promoter DNA methylation and their gene expressions; 3) to test the correlations between DNA methylation and endophenotypes in schizophrenia. 4) to exam the medication effect on DNA methylation and gene expression in PBMC in schizophrenia; 5) to follow the gene promoter DNA methylation and gene expression change in one year. Methods: The study will be approved by Institutional Review Board of participated institutions before recruiting patients. We will recruit 60 patients with schizophrenia and 60 healthy control subjects after explaining the study goal and getting the informed consents. We will evaluate the performance of continuous performance test (CPT) and working memory subset in Chinese version of WAIS-III in both case and control subjects. We will assay reelin, GAD, and MB-COMT gene promoter DNA methylation using methylation specific PCR (MSP) and quantify these gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Patients will be followed in one year and receive the same evaluation. Anticipated results We hypothesize that 1) there are differences in percentage of reelin, GAD, and MB-COMT promoter methylation between patients with schizophrenia and control subjects; 2) the gene promoter methylation will affect gene expression; 3) there will be some correlation between promoter gene methylation, gene expression and the performance of endophenotypes; 4) there might no antipsychotic effect on epigenetic presentation; 5) there might be some change in promoter gene methylation, gene expression and the performance of endophenotypes.
Effective start/end date8/1/117/31/13


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