创伤后应激障碍表观遗传学数据整合与挖掘及数据库构建

	创伤后应激障碍表观遗传学数据整合与挖掘及数据库构建
其他题名	Data integration and mining for epigenetics studies of posttraumatic stress disorder and database construction
	赵光义
导师	张昆林
	2021-06
摘要	创伤后应激障碍（posttraumatic stress disorder, PTSD ）是一种常见的精神疾病，但由于个体和种族的差异，其发生和发展的机制一直未得到很好的阐明，同时由于环境因素在其中起到的决定性作用，已发表的大量遗传研究只取得了有限的结果。最近，越来越多的研究强调了表观遗传学在 PTSD 发病机制中的重要作用，然而研究方法的多样性以及人口学变量的差异使得这些研究存在结果异质性较高的问题，阻碍了对 PTSD 病理机制的进一步探索。本研究旨在对已有的 PTSD表观遗传学研究进行全面的检索和整合，在此基础上完成数据挖掘并进行可视化呈现。首先对关键词检索得到的文献进行略读和筛选，再对符合标准的文献进行精读并提取研究的统计结果和候选标志物，以及研究设计、诊断标准、关联基因等信息，整理汇总为 PTSD 表观遗传学核心数据。接下来，利用这些核心数据，对DNA甲基化、组蛋白修饰等重点研究的标志物关联的基因进行了通路分析、蛋白质交互作用网络分析等生物信息学分析，确定了重点分子，尝试解释了 PTSD表观遗传学相关基因的生物学机制，并把分析结果进行结构化整理形成扩展数据。最后，应用数据库技术和相关的计算机技术，搭建了 MySQL 关系型数据库对核心数据和扩展数据进行存储和关联，并搭建了 PTSDepigenetics 网站http://ptsdepigenetics.psych.ac.cn/ cn/）），提供对数据库和分析结果的检索功能。数据库共收录了 127 篇符合纳入排除标准的 PTSD 表观遗传学文献，包括110 篇研究和 1 7 篇综述，共整合提取出包括 369 个 DNA 甲基化位点在内的近 600个标志物，以及 261 个相关基因。整体趋势上，研究以横向设计、候选标志物研究及人类被试为主，在创伤类型、测量方法、研究结果等方面均存在较高的异质性。相关基因方面，有显著结果的基因多参与 HPA 轴调控或 5 羟色胺系统，FKBP5 、 NR3C1 、 BDNF 关联的有显著结果的研究和标志物最多。在补充了标志物和基因的基本信息后，进行了通路富集分析，发现了药物反应、类泛素加工、酗酒、免疫疾病等通路富集了较多的 PTSD 表观遗传学相关基因，提示了 PTSD与物质滥用、自身免疫疾病等其他心理生理疾病有共同的发病机制，疾病间的共病值得关注。蛋白质交互作用网络分析中，多个组蛋白去乙酰化酶（HDAC ）家族基因得到了较高的连接度，该家族基因在恐惧消退等应激反应中可能发挥重要作用。基于 MySQL 数据库构建的 PTSDepigene tics 网站，对整合及分析的数据进行了存储和展示，并可以为研究者提供方便快捷的检索功能，网站数据和功能将在未来不断更新。本研究对已有的PTSD 表观遗传学研究进行了详细的梳理和整合，并对PTSD 的发病机制提出了新的见解。希望 PTSDepigenetics 能为相关领域的研究者提供启发和便利。
其他摘要	The genesis and development of Posttraumatic stress disorder (PTSD), a common psychiatric disorder, has not been elucidated partly on account of individual and ethnic difference. Recently,the important role of epigenetics in PTSD pathogenesis has been highlighted by more and more studies,yet the differences of selected technology and demographic variables leading to high heterogeneity among these studies, which further hinder our in-depth exploration of the PTSD etiology,thus we aim to make a throughout search and integration of current epigenetic papers. After comprehensively screening and filtering the papers searched by keywords,literature met the inclusion criteria was read intensively, and details such as phenotype, sample information, biomarkers, and its association results for each epigenetic study were extracted as core data. We then conducted bioinformatics analysis using these core data, including pathway enrichment and protein-protein interaction network analysis for genes associated with DNA methylation and histone modification. Our work not only summarized the landscape of PTSD epigenetic studies and identified the focus molecule, but also discovered the biological mechanism of epigenetics一related genes, enlarging the overall candidates for future study. The analysis results were structured to form extended data. Finally, with the application of database and computer programming technology, all data were stored in a MySQL relational database and the website with searching function, PTSDepigenetics (http://ptsdepigenetics.psych.ac.cn/) was conducted. A total of 127 PTSD epigenetic articles that met the included in the database, including 110 studies and 17 inclusion criteria were reviews. Nearly 600 biomarkers containing 369 DNA methylation sites and 261 associated genes were extracted. Overall, the majority of the studies used the cross一sectional design, candidate study and human subjects. High heterogeneity was existed in trauma types, measurement methods and research results. In terms of associated genes, genes with significant results were mostly involved in the regulation of the HPA axis or the serotonin system. FKBPS, NR3C1，and BDNF had the largest number of associated studies and markers with significant statistical results. After adding the basic information of the markers and genes, some pathways enriched more associated genes were found by pathway enrichment analysis, such as Response to drug, Ub1 conjugation, Alcoholism, and Immune system diseases. These findings prompted PTSD may have common pathogenesis with substance abuse and autoimmune diseases, and comorbidities between diseases were of concern. Genes in the histone deacetylase (HDAC) family obtained a high connective degree in protein-protein interaction network analysis, implied important role in stress response such as fear extinction. The PTSdepigenetics website built based on MySQL database stores and displays the integrated and analyzed data, and can provide researchers with convenient and fast retrieval functions. The data and functions of the website will be continuously updated in the future. In this study, the existing PTSD epigenetic studies were sorted out and integrated in detail, and a new insight into the pathogenesis of PTSD was proposed. We hope PTSDepigenetics could help researchers better understand the underlying mechanism of PTSD etiology.
关键词	创伤后应激障碍表观遗传学数据整合与挖掘数据库
学位类型	硕士
语种	中文
学位名称	硕士论文
学位专业	应用心理
学位授予单位	中国科学院心理研究所
学位授予地点	中国科学院心理研究所
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/39543
专题	中国科学院心理健康重点实验室
推荐引用方式 GB/T 7714	赵光义. 创伤后应激障碍表观遗传学数据整合与挖掘及数据库构建[D]. 中国科学院心理研究所. 中国科学院心理研究所,2021.

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