多巴胺D2受体基因标志性SNP和单倍型的挑选及其与抑郁症易患性的关联及机制研究

The World Health Organization predicts that depressive disorder will be the second greatest contributor to the global burden of disease by 2020, however, the neurobiological mechanisms behind the disease and the risk factors for it are yet unknown. Previous study showed that major depressive disorder (MDD) had a genetic susceptibility, and it is related with the polymorphisms of candidate gene. DRD2 is an important receptor and its gene changes play an important role in the pathogenesis of MDD. However, any one SNP alone, even a functional SNP, also can’t represent the genetic characteristics of the whole gene. This subject is to study the susceptibility of all SNPs of the DRD2 gene to MDD. First, we use HapMap database to construct the DRD2 gene haplotype block in Chinese Han people, and select the Tag SNP and haplotype. And then use the high-throughput pyrosequencing quantitative genetic analysis system to verify the distribution of haplotype and tag SNPs in healthy Chinese Han population, and then collect the DNA samples of patients with MDD to analyze the relationship between the tag SNPs and haplotype with the individual susceptibility to MDD. Finally, we will use the site-directed mutagenesis to analyze the biological functional of haplotype and tag SNPs which related with susceptibility to MDD. This research is important to screen the susceptible individual as early as possible and to reduce the occurrence of MDD, and it will offer new ideas for clinical genetics of polygenic disease.

研究证实抑郁症具有遗传易患性，DRD2基因多态性是抑郁症易患性的重要分子机制。前期临床和生物信息学分析发现，DRD2基因在重度抑郁症的诊断和治疗中具有重要的意义。目前在中国汉族人群中共有79个SNPs位点。本课题以DRD2整个基因为单位，研究其标签SNPs与抑郁症易患性的内在联系。首先利用HapMap数据库构建中国汉族人DRD2基因单倍域，挑选出每个单倍域内有代表性的标签SNP及单体型；再利用高通量定量遗传分析系统，验证DRD2基因标签SNP及单体型在健康汉族人群中的分布；收集抑郁症临床病例DNA标本，分析标签SNP及单倍型与抑郁症易患性的关联性；最后利用定点突变等技术分析与抑郁症易患性相关的标签SNP及单倍型的生物学功能。本研究为抑郁症的预警诊断及早期针对性干预治疗提供有效的基因标志；也为临床多基因疾病遗传学研究提供新思路。

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