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神经-精神疾病的影像遗传学研究
其他题名Imaging genetic for Neuropsychiatric diseases
范明
学位类型工学博士
导师蒋田仔
2011-01-16
学位授予单位中国科学院研究生院
学位授予地点中国科学院自动化研究所
学位专业模式识别与智能系统
关键词Meta分析 载脂蛋白e 皮层厚度 全基因组关联研究 拷贝数量变异 Meta Analysis Apolipoprotein e Cortical Thickness Genome Wide Association Study Copy Number Variants
摘要神经-精神疾病严重困扰患者的生活和工作,给家庭和社会带来沉重的负担。医生、遗传学家、神经影像工作者都从不同角度开展神经-精神疾病的相关研究,期望从致病机理上能有新的理解。本文针对这个问题从候选基因的筛选和影像学统计分析两个角度开展研究,主要贡献如下: 1.对于抑郁症、双相情感障碍有很多候选风险性基因,但是研究结果存在不一致的情况。我们分析了抑郁症和双相情感障碍危险性基因单胺氧化酶(MAOA)的关联研究情况,对该基因的三个常见多态(uVNTR,T941G,CA)与该疾病的已发表的关联研究数据开展了系统性的Meta分析。本文的Meta分析提示MAOA基因多态性对抑郁症和双相情感障碍的亚组中存在显著关联。从Meta分析中也发现该基因的多态性可能对这两种疾病有性别和种族差异。 2.对于阿尔茨海默病来说,广泛报导的危险性位点为载脂蛋白E基因的ε4等位基因。但是该基因的另一个ε2等位基因对阿尔茨海默病的保护性作用还缺乏相关的研究。本文的目的是分析载脂蛋白E的不同等位基因对皮层厚度的影响。载脂蛋白E等位基因可分为ε2+、ε3ε3、及ε4+,通过基因型的组间比较、以及纵向数据分析来讨论这些位点与皮层厚度的关系。实验的结果与ε2等位基因的保护性作用,ε3的中性作用以及ε4的危险性因素一致。 3.除了载脂蛋白E以外,也有其他的位点为阿尔茨海默病的危险性基因。本文选取一定的阿尔茨海默病人和健康对照组(共397例),通过全基因组关联研究以及重复性试验来筛选候选基因位点。我们利用了基于单核苷酸多态性以及拷贝数量变异的数据。然后,我们分析了这些候选位点对皮层厚度的影响,发现其中的位点(rs439401)对阿尔茨海默病有潜在的保护性作用,以及和载脂蛋白E基因有可能的交互性作用。同时,我们开展了全基因组拷贝数量位点检测和关联研究,通过该方法发现了2个拷贝数量变异。其中位于15q13.3的删除位点与CHRNA7基因有关,可能为阿尔茨海默病的危险性因素;另外的位点位于CCDC50基因区域,可能为阿尔茨海默病的保护性因素。
其他摘要The human neuropsychiatric disease has a large impact on the life and work of the patients’s life, and brings a huge burden through the family and the society. Doctors, geneticists, neuroimage researchers have done a lot of work in various aspects, aiming to find a new point of view for these diseases. We have studied this problem through the candidate gene exploring and clarifying and image statistical analysis. Our contributions are at bellows: 1. For the association of risk gene with major depression, the published studies have controversial results. To evaluate the controversial, putative associations between the three common polymorphisms (promoter uVNTR,T941G,(CA) repeat) of MAOA and mood disorders (major depressive or bipolar disorders) by systematically meta-analyzing published case-control association studies. Our meta-analysis suggests a significant association of the MAOA gene with major depressive disorder and bipolar disorder within specific groups, indicating that these three polymorphisms of the MAOA gene may be associated with mood disorders by gender and ethnicity. 2. Previous studies have consistently suggested that the ε4 allele of apolipoprotein E (APOE) gene, a major risk factor for Alzheimer’s disease (AD). However, whether the ε2 allele, a possible protective factor for AD, will express its protective effect in terms of cortical thickness in healthy elderly carriers is unclear. The goal of this study is to clarify the effects of APOE genotypes on cortical thickness in nondemented elderly subjects. We used cognitively normal and elderly subjects, who were grouped into ε2 carriers, ε3 homozygotes, and ε4 carriers. We performed comparision for group differences in different genotypes and comparision with longitudinal data. These findings suggest that the different alleles of the APOE gene have distinct neuroanatomic effects in elderly healthy subjects and may play specific roles in the development of AD. 3. The present study aims to examine genetic factors in addition to Apolipoprotein E (APOE) for late onset Alzheimer’s disease (LOAD), and check their functional effects thought cortical thickness. To identify candidate loci associated with AD, we peformed the genome wide association analysis (GWAS). We used genome data for single nucleotide polymorphism and copy number variation data. Subsequently, we examine these genetic effects observed from GWAS on cortical thickness. We concluded that rs439401 might have a so called...
馆藏号XWLW1488
其他标识符200718014628034
语种中文
文献类型学位论文
条目标识符http://ir.ia.ac.cn/handle/173211/6319
专题毕业生_博士学位论文
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GB/T 7714
范明. 神经-精神疾病的影像遗传学研究[D]. 中国科学院自动化研究所. 中国科学院研究生院,2011.
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