健康与遗传心理学研究室知识库

创伤后应激障碍（posttraumatic stress disorder, PTSD）是一种可被表征的发生重大创伤事件（诸如战争，自然灾害或其他应激事件）后的临床现象。早期双生子研究和家庭研究表示 PTSD 受到遗传因素的影响，随着基因分型技术和 基因组测序技术的发展以及成本降低，研究可以从基因分子层面探索 PTSD 易 感性的遗传结构。基因变异是指个体 DNA 序列引起的一种或多种遗传变化，这些遗传变异使得一部分人更易患上 PTSD。近十几年来，PTSD 遗传学研究数量逐年增长，但是鉴于研究之间在设计类型、样本人口学变量、创伤类型、诊断工具等方面存在较大差异而使整个领域研究间异质性高、结果较难重复和比较的矛盾现象，阻碍了对 PTSD 遗传结构的进一步探索。因此，本研究旨在对 目前 PTSD 遗传学领域研究进行全面的整合分析和进一步的数据挖掘，试图找 出影响 PTSD 最有可信度的基因，识别不同研究之间对结果产生影响的异质性因素，并解释现有遗传学结果背后的生物学机制，最后将结果可视化。

研究一通过构建搜索条目在 PubMed、Web of Science、psycINFO 和 psycARTICLES 数据库中共搜索出 PTSD 遗传学领域 8630 条研究记录，对摘要 初步筛查后纳入 266 篇文献。经统计整理，候选基因关联研究共 214 篇，其中以高加索人群为祖先、以战争为创伤类型、以 DSM-IV 为诊断工具和以年轻人为被试的研究最多；一共报道了 455 个候选基因，对报道次数和报道显著次数统计后发现 SLC6A4、BDNF、FKBP5、COMT、DRD2、CRHR1、SLC6A3、 ADCYAP1R1 和 OXTR 是最有可信度的 PTSD 候选基因。全基因组关联研究共 19 篇，大样本的高质量全基因组关联研究是近几年的研究趋向，但是目前的全基因组关联研究人群只涉及高加索、非洲和拉丁裔人群。

研究二针对候选基因关联研究，对在两篇或两篇以上的研究中报道过的单 核苷酸多态性位点进行元分析，并对至少报道过 1 次显著的候选基因进行基因 差异表达分析和通路富集分析。结果对 SLC6A4，SLC6A3，COMT，FKBP5， OXTR 和 NR3C1 共六个基因进行了元分析，发现只有 SLC6A3 和 FKBP5 与 PTSD 诊断之间存在显著关联。亚组分析显示，SLC6A4 在控制组未经历过创伤暴露以及在战争创伤类型的研究设计中与 PTSD 存在显著关联，在其他情况下 与 PTSD 不相关；SLC6A3 在以年轻人为被试和混合创伤类型的研究中与 PTSD 存在显著关联，在其他情况下无显著结果；FKBP5 在不同祖先、不同年龄阶段被试群体和不同创伤类型的研究中与 PTSD 关联情况不同。差异表达分析显示 PTSD 候选基因集在脑组织中具有特异性的表达模式，在前列腺、睾丸和乳腺组织中呈现显著下调；通路富集分析显示 PTSD 候选基因集参与诸多生物学过程，以神经活性配体与受体之间的相互作用、神经递质受体活性、突触后膜的细胞组分、对乙醇的反应和化学突触中的信号传递过程最为显著。

研究三对全基因组关联研究中的数据进行整合分析，并对达到建议显著阈 值（P<1×10 -5）的基因进行组织特异性差异表达分析和通路富集分析。结果整合分析未发现新的显著基因，差异表达分析和通路富集分析也未发现显著结果。合并候选和全基因组关联基因集，结果发现了四条新的显著通路：儿茶酚胺的摄取过程、维生素 D 对抑郁症中钙信号传导的敏感性、磷酸二酯酶在神经元功能中的作用和 G 蛋白偶联受体信号传导途径的调节。 研究四对整个研究的统计分析结果通过网站进行可视化，将整理的结构化数据表格通过 MySQL 建立关系数据库搭建网站后台，并将关系数据库以及统 计分析结果展示到构建的 PTSD 遗传学网站 PTSDgenetics 中。

综上所述，本研究对 PTSD 遗传学领域研究进行了全面的数据整合与数据挖掘，目前候选基因关联研究是该领域的主要研究方法，在该领域发挥着重要作用并提供了具有重要意义的结果，而大样本的高质量全基因组关联研究是该领域的未来研究趋势。SLC6A3、SLC6A4 和 FKBP5 是最有可信度的 PTSD 候选关联基因，年龄阶段、创伤类型、祖先成分以及控制组是否经历过创伤暴露是影响 PTSD 遗传学研究结果的主要异质性因素，神经递质间的信号传递过程是最可能参与 PTSD 病因学的生物学机制。未来应增加大样本全基因组关联研究，从不同样本特征和不同创伤类型分类研究 PTSD 的遗传学机制，并从多个 层面验证神经递质系统对 PTSD 的影响，为 PTSD 的诊断、预防和临床治疗提供新的见解。

Posttraumatic stress disorder (PTSD) is a clinically observable phenomenon that occurs following significant traumatic events, such as war, natural disasters, or other stressful events. Early twin and family studies indicate that PTSD is influenced by genetic factors. With the development of genotyping and genome sequencing technologies and the reduction in costs, research can now explore the genetic structure of PTSD susceptibility at the molecular level. Genetic variation refers to one or more genetic changes in an individual's DNA sequence, which make some individuals more susceptible to PTSD. Over the past decade, the literature on genetic variation in the field of PTSD has grown annually. However, due to substantial differences between studies in terms of design types, sample demographic variables, trauma types, diagnostic tools, etc., the high heterogeneity among studies, difficulties in reproducing and comparing results, hinder further exploration of the genetic structure of PTSD. Therefore, this study aims to comprehensively integrate current research in the field of PTSD genetics and further explore the data, attempting to identify the most reliable genes influencing PTSD, identify heterogeneity factors affecting results among different studies, and explain the biological mechanisms behind existing genetic results, ultimately visualizing the results.

Study 1 retrieved a total of 8,630 research records in the field of PTSD genetics through constructing search terms in the PubMed, Web of Science, psycINFO, and psycARTICLES databases, and included 266 articles after preliminary screening of abstracts. After statistical compilation, a total of 214 candidate gene association studies were identified, with the most studies conducted on Caucasian populations, with war as the trauma type, DSM-IV as the diagnostic tool, and young people as subjects; a total of 455 candidate genes were reported, and after counting the number of reports and the number of significant reports, SLC6A4, BDNF, FKBP5, COMT, DRD2, CRHR1, SLC6A3, ADCYAP1R1, and OXTR were identified as the most promising candidate genes for PTSD. There were a total of 19 whole-genome association studies, with large-sample, high-quality whole-genome association studies being the trend in recent years, but the populations involved in current whole-genome association studies only include Caucasian, African, and Latino populations.

Study 2 conducted meta-analyses on candidate gene association studies, analyzed tissue-specific differential expression and pathway enrichment of candidate genes reported in two or more studies, and analyzed tissue-specific differential expression and pathway enrichment of at least once significantly reported candidate genes. The results updated the meta-analyses of six genes, SLC6A4, SLC6A3, COMT, FKBP5, OXTR, and NR3C1, and found significant associations only between SLC6A3 and FKBP5 and PTSD diagnosis. Subgroup analysis showed that SLC6A4 was significantly associated with PTSD in control groups without trauma exposure and in studies with war trauma types, but not in other cases; SLC6A3 was significantly associated with PTSD in studies with young people as subjects and mixed trauma types, but not in other age groups or trauma types; FKBP5 showed different associations with PTSD in studies with different ancestries, different age groups of subjects, and different trauma types. Differential expression analysis showed that the PTSD candidate gene set exhibited a specific expression pattern in brain tissues, with significant downregulation in prostate, testis, and breast tissues; pathway enrichment analysis showed that the PTSD candidate gene set is involved in many biological processes, with the most significant being the interaction between neuroactive ligands and receptors, neurotransmitter receptor activity, postsynaptic membrane cellular components, response to ethanol, and chemical synaptic signaling processes.

Study 3 conducted integrated analysis of data from whole-genome association studies and tissue-specific differential expression analysis and pathway enrichment analysis of genes that reached the suggested significance threshold. The integrated analysis did not identify new significant genes, and differential expression analysis and pathway enrichment analysis did not reveal significant results either. Enrichment analysis of merged candidate and whole-genome association gene sets revealed four new pathways: catecholamine uptake, vitamin D sensitive calcium signaling in depression, phosphodiesterases in neuronal function and regulation of G protein coupled receptor signaling pathway.

Study 4 visualized the statistical analysis results of the entire study through a website, established a relational database with structured data through MySQL. The relational database and the statistical analysis results were displayed on the constructed PTSD genetics website, PTSDgenetics.

In summary, this study conducted comprehensive data integration and mining in the field of PTSD genetics. Currently, candidate gene association studies are the primary research method in this field, playing an important role and providing significant results. Large-sample, high-quality whole-genome association studies are the future trend. SLC6A3 and FKBP5 are the most reliable candidate associated genes for PTSD. Age group, trauma type, and ancestral component are the main heterogeneity factors affecting the results of PTSD genetics research, and the signaling process between neurotransmitters is the most likely biological mechanism involved in PTSD etiology. Future studies should increase large-sample wholegenome association studies, study the genetic mechanisms of PTSD from different sample characteristics and different trauma type classifications, and verify the influence of the neurotransmitter system on PTSD from multiple perspectives, providing new insights for the diagnosis, prevention, and clinical treatment of PTSD.