线粒体相关遗传因子变异与汉族人群精神分裂症遗传易感性分析
文献类型：学位论文
| 作者 | 李晓 |
| 学位类别 | 硕士 |
| 答辩日期 | 2015-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 姚永刚 |
| 关键词 | 精神分裂症 线粒体 遗传关联研究 家系 功能验证 |
| 其他题名 | Genetic polymorphisms of mitochondrial related genetic factors and susceptibility to schizophrenia in Han Chinese population |
| 学位专业 | 生物工程 |
| 中文摘要 | 精神分裂症是一类常见的精神类疾病，也是目前发病率最高的一种精神类疾病。全球精神分裂症的终生患病率高达1%，给社会与家庭带来沉重的负担。精神分裂症由遗传和环境因素共同影响而发病，其中遗传因素占据主要作用，其遗传力高达81%。尽管遗传学研究报道了许多与精神分裂症遗传易感性相关的基因与遗传多态位点，但这些结果仍然不能够有效的揭示精神分裂症的遗传机制。 大脑是人类最耗能的器官之一，其能量消耗约占人体总能耗的20%，因此对能量代谢异常较为敏感。作为细胞的能量工厂，线粒体与精神分裂症的关系受到广大研究者的关注。线粒体DNA（mtDNA）在亲子代之间的传递遵循母系遗传规律。许多研究报道，精神分裂症具有母系遗传特征。线粒体异常也在许多精神分裂症患者中出现。尸检发现，在精神分裂症患者脑部出现一系列线粒体相关的变化，包括线粒体形态和数目异常、患者脑部能量代谢异常、氧化磷酸化相关的酶活性异常以及线粒体相关基因表达变化等。临床上也不乏发病家族史表现出母系遗传特征的家系，但其发病机制尚不清楚。综合分析线粒体相关遗传因子与精神分裂症的关系，有望为探索精神分裂症遗传易感性提供新的证据。本研究拟对中国汉族精神分裂症患者的核基因编码的线粒体基因多态性以及线粒体自身DNA（mtDNA）变异的潜在危害进行分析，试图探讨这些线粒体相关的遗传因子与精神分裂症遗传易感性之间的关系，为该病的临床咨询和诊治提供依据。 线粒体复合物I是线粒体电子传递链上的第一个复合物，其14个核心组分中，7个亚基由核基因编码。由于其在能量代谢中的重要作用，一些研究者猜想线粒体复合物I可能与精神分裂症的病理生理学有一定相关性。我们对核编码的线粒体复合物I基因（NDUFS1、NDUFS2、NDUFS3、NDUFS7、NDUFS8、NDUFV1和NDUFV2）构建连锁不平衡图谱，选取了48个标签单核苷酸多态性位点（tag SNPs），在918个精神分裂症病例和1042个对照样本中进行基因分型。最终46个SNPs位点得到成功分型。我们在病例和对照组之间对成功分型的46个SNPs位点进行了基因型、等位基因和单倍型频率差异的比较。此外，我们还利用精神病基因组协会（Psychiatric Genomic Corsortium, PGC）的欧洲人群数据对这46个SNPs位点进行了分析。遗憾的是，我们的分析没有找到与精神分裂症显著相关的位点，提示这7个核编码基因的常见SNPs位点可能与精神分裂症的遗传易感性不相关。 此外，我们对有母系遗传特征的精神分裂症家系样本进行了mtDNA变异的功能研究。首先对所采集到的11个家系样本进行了mtDNA测序，筛选可能有害的mtDNA变异。我们对其中最具有潜在危害的变异m.15395A>G进行了线粒体指标的检测，包括线粒体质量（mitomass）水平、mtDNA拷贝数、细胞的氧消耗水平、胞内ATP水平以及活性氧自由基（ROS）水平。实验结果显示m.15395A>G突变携带者的线粒体质量（mitomass）、mtDNA拷贝数以及线粒体复合物IV偶联的氧消耗水平显著低于对照，表明该突变可能影响了线粒体功能，继而对精神分裂症的发病有所贡献。 综上所述，我们检测了线粒体复合物I的七个核编码基因的常见变异与精神分裂症的相关性，同时还对一个mtDNA变异m.15395A>G的功能进行了研究。本论文结果显示，线粒体复合物I的7个核编码基因的常见多态性位点可能与精神分裂症的遗传易感性不相关；而线粒体自身的mtDNA变异m.15395A>G可能会通过影响线粒体的相关功能而对精神分裂症的发生产生影响。 |
| 英文摘要 | Schizophrenia is a common psychiatric disorder with a worldwide prevalence of about 1%. The pathogenesis of schizophrenia is very complex with active involvement of both genetic and environmental factors. Schizophrenia has a high heritability of approximately 80%. Although there have been a large amount of genetic loci being reported to confer susceptibility to schizophrenia, these results can explain only a small proportion of the heritability of this disease. The relationship between mitochondrion and schizophrenia has been received wide attention in recent years. Mitochondrial DNA (mtDNA) is maternally inherited. There were lines of evidence showing maternal inheritance in schizophrenia and involvement of mitochondria in the pathogenesis of psychiatric disorders were also reported. In postmortem studies, a series of mitochondrial related abnormalities were observed, including altered mitochondrial morphology and number, decreased energy metabolism in the brain of schizophrenia patients, altered enzymatic activity of oxidative phosphorylation (OXPHOS) and mitochondrial related gene expression. Clinical survey also identified a modest amount of families which presented martrilineal inheritance of schizophrenia, but the pathogenic mechanism remains unknown. A comprehensive analysis focusing on mitochondrial related genetic factors in schizophrenia may make effort to clarify the pathogenesis of schizophrenia. In this study, we aimed to investigate the role of mitochondrial related genetic factors in schizophrenia in two aspects: (1) genetic polymorphism of nuclear-encoded mitochondrial related genes and (2) mtDNA variation(s), with the hope to clarify the relationship between these mitochondrial related factors to schizophrenia and to provid directions for the clinical diagnosis and genetic consult of this disorder. Human brain is the largest energy consumer among all organs (it consumes about 20% energy used by the human body), which makes it more susceptible to disrupted cellular energy metabolism. Among the five mitochondrial complexes, NADH ubiquinone oxidoreductase (complex I) is the first complex of the mitochondrial electron transport system. Seven of the 14 “core” subunits of complex I were nuclear-encoded. Due to its pivotal role in energy metabolism, it has been speculated that mitochondrial complex I may be involved in the pathophysiology of schizophrenia. In this study, we selected 48 tag single nucleotide polymorphisms (SNPs) from the 7 nuclear-encoded core genes NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFV1 and NDUFV2 of mitochondrial complex I based on their linkage disequilibrium (LD) structures. Two SNPs (rs12798346 and rs3751084) were failed to be genotyped in our samples. Therefore, these two SNPs were excluded from our statistical analysis. In total, we genotyped 46 SNPs in 918 schizophrenia patients and 1042 healthy controls, and compared the genotype, allele and haplotype frequencies. We also analyzed these SNPs in a large sample set mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genetics Consortium (PGC). No significant associations were identified between these SNPs and schizophrenia in Han Chinese and the PGC data set. Our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not be involved in schizophrenia. We also performed functional characterization in schizophrenia families with a family history and maternal inheritance of the disease. We sequenced the entire mitochondrial genomes of probands from 11 families to screen potential harmful mtDNA variants. Among the identified nonsynonymous private variants, m.15395A>G in the MT-CYB gene was suggested to be harmful according to literature searching and in silico prediction. Potential function was characterized for this mtDNA variant. Mitochondrial parameters including cellular reactive oxygen species (ROS) level, cellular ATP level, mitochondrial |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10199]  |
| 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 | 李晓. 线粒体相关遗传因子变异与汉族人群精神分裂症遗传易感性分析[D]. 北京. 中国科学院研究生院. 2015. |
入库方式： OAI收割
来源：昆明动物研究所
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