线粒体相关基因LRRK2、PINK1 与精神分裂症易感性研究
文献类型：学位论文
| 作者 | 龚伟 |
| 学位类别 | 硕士 |
| 答辩日期 | 2012-10 |
| 授予单位 | 中国科学技术大学 |
| 授予地点 | 北京 |
| 导师 | 姚永刚研究员 |
| 关键词 | 精神分裂症 schizophrenia 线粒体 mitochondria LRRK2 LRRK2 PINK1 PINK1 遗传易感性 genetic susceptibility 相关性 |
| 学位专业 | 遗传学 |
| 中文摘要 | 精神分裂症(schizophrenia)是一类常见的精神疾病，一般发病于青壮年时期， 与精神分裂症相关，基于这些位点所构建的单倍型中，单倍型GCAT (P=0.022，OR (95% CI) =1.225 [1.033-1.524]) 和ATCC (P=0.038 ， OR (95% CI) =0.819[0.677-0.989])显示出疾病相关性。PINK1 上的rs10916832 位点和精神分裂症相关(P=0.032，OR (95% CI) =1.229 [1.018-1.483])。基于检测的PINK1 基因上的5个SNP 构建的6 个主要单倍型中，单倍型TGAAC (P=0.003，OR (95% CI) =0.689[0.540-0.879])和CGAGC (P=0.005，OR (95% CI) =2.037 [1.229-3.376])在病例和对照间的频率分布差异具有显著性。本研究结果提示线粒体相关的帕金森病易感基因LRRK2和PINK1 上存在多个SNP 位点以及其单倍型对精神分裂症易感，提示二者可能是精神疾病和神经 |
| 英文摘要 | Schizophrenia is a common mental disorder which tends to occur in young adults. The patients suffer a long course of disease and repeated attacks. Most of them show multiple abnormalities of perception, thinking emotion and volitional behavior. Their mentations are always not accordant with surroundings and their inner experience. Schizophrenia has the highest morbidity among all mental disorders. According to the reports of WHO, the lifetime prevalence of schizophrenia is 1.3 percent and only a small number of patients can be cured. Because of its complex characteristics, schizophrenia patients and their families not only need to pay a lot for medicine, but also receive social discriminations. The studies of schizophrenia have been carried on for more than a century, but we still do not sufficiently understand the exact pathogenesis of schizophrenia. Researchers have made some progresses in several aspects, such as anatomy, neurotransmitters, neurodevelopment and genetics during different periods. There are accumulating genetic association studies for this disorder and we have accumulated a lot of data in the past several decades. Mitochondrial dysfunction has been proposed as a cause of schizophrenia. Mitochondria are the main energy source of various cellular processes which can be suppressed in the case of mitochondrial damage. In particular, the neurons need plenty of ATP for the neurite outgrowth, nerve conduction and neural network connection. Imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) revealed decreased cerebral metabolic rates in the frontal cortex, thalamus, temporal and the basal ganglia of patients with schizophrenia. In addition, reduced mitochondrial density and abnormal morphology were found by microscopic analysis of patient brain tissues. These findings suggest the potential role of mitochondrial damage in the onset of schizophrenia. Meanwhile, impairments of mitochondria were reported in many other psychosis and neurodegenerative diseases. All these results indicate the idea that mitochondrial dysfunction may be widespread in brain diseases. LRRK2 and PINK1 were widely reported as susceptible genes of Parkinson’s disease. These two genes play active roles in mitochondria. LRRK2 is a large protein with multiple domains and is located in cytoplasm and intracellular membranous structures including mitochondria. LRRK2 has both GTPase and kinase activities which interact with a lot of substrates. It can regulate mitochondrial dynamics and function through direct interaction with DLP1. Mutations that increase its kinase activity can induce mitochondrial fragmentation and cytotoxicity. PINK1 is a mitochondrial membrane integral protein with a Ser/Thr kinase domain. It can recruit parkin to the mitochondrial outer membrane and mediate the clearance of impaired mitochondria by autophagy. In this study, we hypothesized that genetic variants of LRRK2 and PINK1 genes confer genetic susceptibility to schizophrenia. We used the SNaPshot genotyping platform to detect the frequency distribution of 17 SNPs in LRRK2 and PINK1 genes in 507 schizophrenia patients and 480 normal controls from Hunan, China. Statistical results show that four tag SNPs in the introns of the LRRK2 gene (rs732374, P=0.044, OR (95% CI) =0.824 [0.683-0.994]; rs4473003, P=0.033, OR (95% CI) =1.230 [1.017-1.487]; rs7298930, P=0.033, OR (95% CI) =1.214 [1.016-1.452]; rs7307310, P=0.036, OR (95% CI) =0.815 [0.673-0.987]) are associated with schizophrenia. Two haplotypes GCAT (P=0.022, OR (95% CI) =1.225 [1.033-1.524]) and ATCC (P=0.038, OR (95% CI) =0.819 [0.677-0.989]) have a statistically significant difference between the case and control groups. The frequency distribution of rs10916832 of the PINK1 gene is significantly higher in patients with schizophrenia than that of controls (P=0.032, OR (95% CI) =1.229 [1.018-1.483]). A total of six haplotypes are constructed based on five SNPs genotyped for the PINK1 gene. Haplotypes TGAAC (P=0.003, OR (95% CI) =0.689 [0.540-0.879]) and CGAGC (P=0.005, OR (95% CI) =2.037 [1.229-3.376]) display significant difference between cases and controls. Our results indicate that SNPs and haplotypes of the two mitochondrial genes, LRRK2 and PINK1, are associated with schizophrenia. Genetic variants of the LRRK2 and PINK1 genes may confer both mental diseases and neurodegenerative diseases. Combine with previous studies, we speculate that the LRRK2 and PINK1 genes may induce mitochondrial energy metabolic dysfunction and impair the brain (which is the most sensitive organ to energy metabolism), leading to mental diseases and neurodegenerative diseases. Further validation study and function assay are essential to confirm our results. |
| 语种 | 中文 |
| 公开日期 | 2012-12-10 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7133]  |
| 专题 | 昆明动物研究所_重大疾病机理的遗传学 |
| 推荐引用方式 GB/T 7714 | 龚伟. 线粒体相关基因LRRK2、PINK1 与精神分裂症易感性研究[D]. 北京. 中国科学技术大学. 2012. |
入库方式： OAI收割
来源：昆明动物研究所
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