基于基因组与脑影像的五种精神疾病遗传与神经机制研究

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	基于基因组与脑影像的五种精神疾病遗传与神经机制研究
	王天奇
	2017
学位类型	工学硕士
中文摘要	常见的精神疾病，包括注意力缺陷多动障碍，自闭症，双向情感障碍，抑郁症和精神分裂症等，是高度可遗传的多基因疾病。有证据表明这五种疾病既有共同的又有特异性的遗传和神经机制。本文希望能通过分析脑影像和基因组数据为理解常见的五种精神疾病的神经和遗传机制提供帮助。本文首先研究了跨疾病多基因风险分数和上述五种精神疾病的多基因风险分数与功能连接的相关性。本文在两个分别由360和323名健康被试组成的独立数据集上分别研究了跨疾病和特定疾病的多基因风险分数是否与功能连接的个体差异有关。本文在两个数据集上发现了一致的双侧岛叶功能连接变化：与左侧辅助运动区和左侧颞上回的功能连接与跨疾病多基因风险分数显著负相关；与左侧岛叶以及右侧颞中回和颞上回之间的功能连接与自闭症多基因风险分数显著正相关；与双侧中脑，后扣带，楔叶和楔前叶之间的功能连接与双向情感障碍多基因风险分数相关；与左侧角回和左侧背外侧前额叶之间的功能连接与精神分裂症多基因风险分数相关。本文没有发现与注意力缺陷多动障碍和抑郁症多基因风险分数相关的功能连接变化。本研究的结果表明对于疾病共享的及特异性的功能连接变化有影响的遗传因素是可以在健康人群中被检测到的，同时还说明多基因风险对精神疾病的主要神经生理表型有影响。本文结果还说明了研究跨疾病和特异性的功能连接和多基因风险分数之间的相关性可能可以帮助我们理解这些精神疾病的神经通路。然后本文研究了大脑皮层表面积和体积的遗传度，同时研究了具有显著遗传度的内表型是否与五种常见精神疾病共享相似的遗传变异。本文首先计算了139个内表型全基因组遗传度，之后使用与精神疾病相关的单核苷酸多态性的子集计算了具有显著全基因组遗传度的内表型的遗传度，最后通过置换检验来确定表型遗传度在与精神疾病相关的单核苷酸多态性子集中是否具有富集效应。研究结果发现23个内表型具有显著的遗传度，但是并未发现任何内表型遗传度在与精神疾病相关的单核苷酸多态性子集中的富集效应。该结果说明大脑结构受遗传因素影响，为大脑结构作为影像遗传研究的内表型提供了证据支持。
英文摘要	Major psychiatric disorders, including attention deficit hyperactivity disorder, autism, bipolar disorder, major depression disorder and schizophrenia, are highly heritable and polygenic disorders. Evidence suggests that these five disorders have both shared and distinct genetic risks and neural mechanisms. The present work aims to help understand the neural and genetic mechanisms of these five major psychiatric disorders based on brain imaging and genomics. At first, the relationships between cross-disorder polygenic risk scores and polygenic risk scores for specific psychiatric disorders and functional connectivity were examined. Two independent general populations (N = 360 and N = 323) were separately examined to investigate whether the cross-disorder PGRS and PGRS for a specific disorder were associated with individual variability in functional connectivity. Consistent altered functional connectivity was found with the bilateral insula: for the left supplementary motor area and the left superior temporal gyrus with the cross-disorder PGRS, for the left insula and right middle and superior temporal lobe associated with the PGRS for autism, for the bilateral midbrain, posterior cingulate, cuneus, and precuneus associated with the PGRS for BD, and for the left angular gyrus and the left dorsolateral prefrontal cortex associated with the PGRS for schizophrenia. No significant functional connectivity was found associated with the PGRS for ADHD and MDD. Our findings indicated that genetic effects on the cross-disorder and disorder-specific neural connectivity of common genetic risk loci are detectable in the general population. Our findings also indicated that polygenic risk contributes to the main neurobiological phenotypes of psychiatric disorders and that identifying cross-disorder and specific functional connectivity related to polygenic risks may elucidate the neural pathways for these disorders. In addition, the heritability of cortical surface area and gray matter volume of different regions in the brain was estimated. And the aim of this work was to find out whether there is a shared genetic basis of brain anatomy and these five psychiatric disorders. At first, the whole-genome heritability of 139 endophenotypes were estimated. And then the SNPs were divided into two sets with one sets including SNPs which were significantly associated with specific psychiatric disorders and then joint analysis was performed to estimate the heritability. Finally, permutation test was performed to test whether observed partial heritability is significantly higher than expectation. 23 of these 139 endophenotypes were found with significant heritability. But none of these partitioning of heritability showed a significantly enriched contribution of the sets including SNPs significantly associated with these five psychiatric disorders for brain phenotypes. The results may support that the brain anatomy is modulated by genetic factors and provide evidence that brain anatomy is a promising endophenotype for imaging genetics.
关键词	遗传和神经机制精神疾病影像遗传
文献类型	学位论文
条目标识符	http://ir.ia.ac.cn/handle/173211/14726
专题	毕业生_硕士学位论文
推荐引用方式 GB/T 7714	王天奇. 基于基因组与脑影像的五种精神疾病遗传与神经机制研究[D]. 北京. 中国科学院大学,2017.

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基于基因组与脑影像的五种精神疾病遗传与神（2662KB）	学位论文		限制开放	CC BY-NC-SA