湖南人群精神分裂症的遗传易感性研究
文献类型：学位论文
| 作者 | 马亮 |
| 学位类别 | 博士 |
| 答辩日期 | 2014-03 |
| 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 NDUFS7 全基因组关联分析 CREB1信号通路 正选择 关联分析 meta-analysis |
| 其他题名 | Study of genetic susceptibility to schizophrenia based on Han Chinese population from Hunan Province |
| 学位专业 | 遗传学 |
| 中文摘要 | 精神分裂症是一类严重的慢性神经精神疾病，终身患病率高达1%，遗传力约为80%-85%。尽管全球该病具有一致的流行率和较高的遗传力，但精神分裂症的遗传基础至今未完全明朗。大规模的精神分裂症基因组研究会隐藏群体特异的易感位点，本论文一方面验证来自大规模的汉族人群和欧洲人群的全基因组关联研究得到的达到基因组显著水平的位点，探索精神分裂症易感位点的群体一致性。另一方面针对特定的系统（线粒体）和信号通路（CERB1）进行精细研究。大量研究表明，线粒体功能紊乱和精神疾病的发生有很大关联。NDUFS7是线粒体复合体I的一个重要组成部分，该基因最近被报道与双向情感障碍有关，而精神分裂症和双向情感障碍的遗传组成有很大的重叠性。为了检测该基因是否与精神分裂症的易感性有关，我们选择了NDUFS7基因区域内的3个tagSNPs，对330个湖南汉族人群精神分裂症病人和330个匹配的正常对照进行测序分型、频率比较。结果在病人和对照群体等位基因、基因型和单倍型中均没有发现显著差异的位点，提示该基因可能和精神分裂症没有显著的关联性。最近报道了两个大规模的我国汉族人群的全基因组关联研究，两个研究共确定了9个SNPs达到基因组显著水平。尽管这两个研究均采用汉族人群的样本，但他们发现的基因组显著位点没有重叠。为了对这9个位点进行验证，我们在湖南汉族人群（976个精神分裂症患者和1043个匹配的正常对照）中进行病例对照检测，但没有发现显著关联的位点，提示精神分裂症异质性很大。CREB1是一个cAMP应答的转录因子，在神经发育中发挥重要作用。最近，CREB1信号通路被大量报道与精神分裂症遗传易感性有关。我们假设CREB1信号通路在人类复杂脑皮层进化过程中经历了正选择，基因在自然选择压力下会发生快速进化，该过程可能导致一些“进化漏洞”的发生，进而导致大脑疾病如精神分裂症的易感性。正选择检测结果显示NRG1、CNNM2、DGCR2和OPCML与灵长类特异的进化有关，选择时间可能发生于百万年前。除此之外，我们发现NRG1和CREB1在人类走出非洲的时期（约3万年前）也经历了自然选择。随后，为了验证是否CREB1信号通路的快速进化与精神疾病的易感性有关，我们在2019个湖南汉族人群（976个精神分裂症患者和1043个匹配的正常对照）中对CREB1信号通路的常见SNPs进行分型和比较。结果发现两个SNPs（rs4379857, P=0.009, OR=0.833, 95% CI: 0.725-0.956; rs2238751, P=0.023, OR=0.798, 95% CI: 0.657-0.969）显著与精神分裂症相关。表观互作分析共检测到1889个可能的SNP-SNP互作，其中有70个显著与精神分裂症相关（P<0.05）。但所有这些显著关联信号在多重校正后均不显著。另外，我们对NRG1和DGCR2基因区域内在多个人群中进行过关联分析的9个常见SNPs进行全面的meta-analysis，但仍未发现显著的关联信号。有趣的是，我们发现位于CREB1、CNNM2-NT5C2和DGCR2区域内很多单倍型显著与精神分裂症关联，其中，只有位于CREB1区域的大量稀有单倍型经过校正后依然显著。由于CREB1可以通过对神经发育的大量基因进行转录调节，进而影响大脑功能或精神症状，因此，我们推测该基因在人类进化过程中发生了快速进化，在增加人类认知能力的同时也可能产生一些“进化漏洞”，在一定的环境作用下可导致疾病。另外，该研究显示精神分裂症遗传易感性的群体异质性非常大，CREB1信号通路中不同基因在不同群体中对精神分裂症的易感性有所不同。综上所述，我们在一个独立的湖南汉族人群中对一个线粒体核编码基因（NDUFS7）、9个汉族人群精神分裂症GWAS阳性位点和CREB1信号通路的常见SNPs进行病例对照研究。结果发现CREB1区域内富集了大量与精神分裂症显著关联的稀有单倍型，同时该基因在人类走出非洲的人群分化时期受到较强的自然选择压力。不过我们没有发现和精神分裂症显著关联的常见变异。这些结果证实了精神分裂症遗传研究瓶颈的存在，即一个独立群体的精神分裂症易感位点和基因在其它人群中往往得不到完全一致的重复，如何解决该瓶颈将可能是未来主要的研究方向。 |
| 英文摘要 | Schizophrenia is a severe and chronic neuropsychiatric disorder, with a lifetime prevalence of approximately 1%. The heritability was estimated to be between 80% and 85%. Despite of a consistent prevalence and high heritability globally, the genetic underpinnings of schizophrenia have not been sufficiently resolved. Population specific susceptable loci were not revealed in large-scale schizophrenia genomic study, in the thesis, we would testify the loci that reached genome-wide level in large-scale genome-wide association study of Han Chinese populations and European populations for exploring the consistency of susceptable loci among popuations. On the other hand, we focused on special biosystem (mitochondrial) and signal pathway (CREB1) to explore the exact mechanisms of schizophrenia.Accumulating evidence suggests that mitochondrial dysfunction contributes to the pathogenesis of psychiatric diseases. NADH dehydrogenase Fe-S protein 7 (NDUFS7), a subunit of respiratory chain complex I, has been recently reported to be associated with bipolar disorder. In order to test if this gene would confer a wide variety of psychiatric disorders, we performed a case-control association analysis of three tag single nucleotide polymorphisms (SNPs) (rs2074896, rs2074897 and rs2074898) in the NDUFS7 gene by sequencing 330 Han Chinese patients with schizophrenia and 330 well matched healthy controls from Hunan Province, China. We found no significant difference in the frequency distributions of alleles, genotypes, and haplotypes between cases and controls, suggesting no active role of this gene in schizophrenia. Recently, two large Han Chinese genome-wide association studies (GWAS) were reported. A total of 9 SNPs that reached genome-wide significance level were identified, but none of these risk loci was overlapped in the two studies, although both of them use Han Chinese populations. To verify the nine SNPs, we employed a case-control study in an independent Han Chinese population from Hunan Province of China (976 schizophrenia patients and 1,043 matched healthy individuals), and identified no association of any claimed SNP with schizophrenia. This study implied the heterogeneity is strong in schizophrenia.CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We hypothesized that CSP has undergone positive selection during evolution of the complex brain cortex in human and some genes that have undergone natural selection in the past may predispose to schizophrenia in modern time. The positive selection analysis showed that NRG1, CNNM2, DGCR2 and OPCML were putatively linked to primate-specific evolution. They were predicted to have undergone positive selection around millions of years ago. Besides, we found the selection event on NRG1 and CREB1 occurred before the Out-of-Africa scenario (around 30,000 years ago). To further determine whether genetic variants of the CSP genes contributed to schizophrenia risk, 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 schizophrenia patients and 1043 healthy individuals) were analyzed, the results showed that two SNPs (rs4379857, P=0.009, OR=0.833, 95% CI: 0.725-0.956; rs2238751, P=0.023, OR=0.798, 95% CI: 0.657-0.969) were significantly associated with schizophrenia. Epistasis test showed that 70 of 1889 interaction combinations of these SNPs had nominal significant association with schizophrenia (P<0.05). However, none of these significances survived after multiple testing corrections. In addition, a comprehensive meta-analysis of NRG1 and DGCR2 were performed but yielded no susceptible SNPs. Nonetheless, we observed associations of CREB1, CNNM2-NT5C2 and DGCR2 haplotypes with schizophrenia, among them, only rare CREB1 haplotype could survive multiple corrections. Taken together, schizophrenia positive rare haplotypes were enriched in CREB1 region, |
| 语种 | 中文 |
| 公开日期 | 2014-06-04 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7877]  |
| 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 | 马亮. 湖南人群精神分裂症的遗传易感性研究[D]. 北京. 中国科学院研究生院. 2014. |
入库方式： OAI收割
来源：昆明动物研究所
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