The Maoa Internal Multi-locus Mode Of Action And Dna Methylation Status And Mental Disorders In The Study

Schizophrenia and major depressive disorder are two common severe psychiatric diseases. The joint prevalence is about 2% of the population. These disorders suffer the youth, bring heavy economical and social burdens to families and societies.Decades of studies have shown that, both schizophrenia and major depressive disorder are typical complex disorders. Although the genetic factors account for much of the etiology of these two diseases and the heredity of schizophrenia and major depressive disorder could up to 81% and 66% respectively, the candidate gene is still unknown by both association and linkage studies. Previous psychiatric research mainly focuses on analyzing single polymorphism or haplotype. Similar gene-environmental factor interaction in schizophrenia and major depressive disorder does not result in same disease out-come. Then comes a question that why similar genetic predisposition and environmental factors among individuals produce different disease pathogenesis? Is this disease development involves different gene-gene or gene-environmental interaction? Few studies dissect the interaction among genetic locus or possible regulatory effect between them and seldom have study consider the inter-gene regulation effect when analyzing the disease pathogenesis. Therefore, to determine the genetic effect in paranoid schizophrenia or major depressive disorder, researchers could evaluate the impact of multiple genetic loci on the development of psychiatric disease, especially the interaction between them. In previous study, we tested the entire dopamine metabolic pathway and found that the combined effect of single nucleotide polymorphism in the gene coding monoamine oxidase A, the enzyme involved in the breakdown of dopamine, and gender conferred a genetic susceptibility to paranoid schizophrenia. According to the genetic characteristic of schizophrenia, major depressive disorder and our previous achievements, we carried out two researches in this thesis:1) to examine the multiple genetic interaction effects under the association of MAOA gene with schizophrenia and major depressive disorder; 2) to further explore the interaction model under different psychiatric disorder.In the first part of this study, we scanned all possible functional SNPs within MAOA gene by PCR-based genotyping analysis in 555 patients with paranoid schizophrenia,512 major depressive disorder patients and 567 controls from a Han Chinese population. We also determined the interaction model of susceptible genetic markers, and their effect on psychotic symptoms and gene expression. We found that the MAOA gene could confer disease susceptibility in both paranoid SCZ and MDD in a Chinese population; we also found that the MAOA gene influence the disease susceptibility in two different ways, in which the MAOA gene could increase the risk of paranoid SCZ via the multiple variants interaction within the gene and in MDD, the cis-regulatory effect of VNTR on SNPs is likely to contribute to the development of MDD. These interactions can modify disease susceptibility through alteration of the gene expression level.Furthermore, with the effects of analyzing genetic background of psychiatry disease, environmental factors should also be considered, under which mechanism it confer disease risk remained unknown. Epigenetic modifications provide an alternative explanation for environmental interaction with genetic factors and phenotypic discordance of psychiatric diseases. Studies in epigenetics have shown that the modification in brain could influence many neuronal development functions.In the second part of this study, we firstly scanned 2 kb MAOA gene promoter region to explore the correlation of DNA methylation state and disease susceptibility. We found that in female population,14 CG dinucleotides show significant methylation difference between control and paranoid SCZ patients (global P= 1.59E-63); in male population,13 CG dinucleotides showed differential methylation (global P= 9.52E-46).In the first part of this study, we not only guarantee the repeatability of genetic study, but also support the genetic results by functional evidence, which could give a systematic view of the effect of MAOA gene with severe psychiatric disorders. In the second part of this study, we start from the work from DNA methylation, by scanning MAOA gene promoter methylation state; we confirmed the association of DNA methylation with paranoid schizophrenia and bring new idea for the researches of psychiatric disorders.