创伤后应激障碍与抑郁共病的通路分析和基因多态性分析
文献类型：学位论文
| 作者 | 张静怡 |
| 答辩日期 | 2023-06 |
| 文献子类 | 硕士 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 中国科学院心理研究所 |
| 其他责任者 | 张昆林 |
| 关键词 | PTSD 抑郁 共病基因 生物学通路分析 |
| 学位名称 | 理学硕士 |
| 学位专业 | 应用心理学 |
| 其他题名 | The pathway analysis and gene bolymorbhism analysis of posttraumatic stress disorder and depression comorbidity |
| 中文摘要 | Posttraumatic Stress Disorder (PTSD) is a persistent mental disorder after exposure to a potential traumatic event, which always co-occurring with depression symptom. The comorbidity of PTSD and depression lead to more severe health problems than a single symptom. Compared with the dichotomous diagnosis, the latent profile analysis (LPA) could divide symptom into subgroups, focusing on population heterogeneity, and thus more suitable for comorbid symptoms study. Accordingly, we defined PTSD and depression comorbidity as the coexistence of high levels of symptoms and aimed to explore the genes and biological mechanisms of comorbidity between PTSD and depression. And we also hope to provide some reference for early identification and clinical treatment of comorbidity. Genetic factors are the key of complex mental disorder. And the factors that affect the comorbidity of PTSD and depression should belong to the factors that affect both of them together. To study the comorbidity, besides their respective heredity, more attention should be paid to the genetic correlation of them but few in fact. Most genetic correlation studies used genome-level analysis methods, which could only focus on the overall genetic correlation between diseases, without research on specific genes and mechanisms. However, pathway analysis could identify key genes or proteins of specific pathways which play important role in comorbid symptoms. Besides, gene polymorphism analysis could focus on the impact of a single locus, and gene epistasis could focus on the phenotype effect of genes at one or more loci on genes at another locus. In other words, these methods could focus on the analysis of genes and biological pathways related to both PTSD and depression. Therefore, we finally decided to use pathway analysis and gene polymorphism analysis to reveal the biological mechanism and biological markers of PTSD and depression comorbidity. Firstly, we explored the impact of PTSD and depression susceptibility genes on the comorbidity of PTSD and depression. The ADCYAPIRI gene is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis system for stress, which has been found to affect PTSD through gene-gene interaction effect with the FKBPS gene in our previous study, and has also been proved to correlated with depression by many other studies. Therefore, we used logistic regression to analyze the main, gene-trauma exposure interaction and gene一gene interaction effects of ADCYAPIRI on the impact of comorbidity. Additionally, we only focused on other HPA axis genes, such as FKBPS, CRHRI, and CRHR2 in present study. We found that compared with PTSD-depression combined symptoms, the ADCYAPIRI rs2267735一CRHR2 rs8192496 could significantly negatively affect predominantly PTSD symptoms. We suggested that the ADCYAPI RI一CRHR2 may be a biomarker for the comorbidity of PTSD and depression. Secondly, biological pathways are the ways in which genes and their products in cells realize their functions. The pathway of ADCYAP1Rl gene may also be related to PTSD and depression, which is the mechanism of action of comorbidity. We selected three typical related pathways of ADCYAPIRI gene in the public pathway database MSigDB, including G protein coupled receptors activity pathway, Neurotrophic Tyrosine Receptor Kinases pathways（TRKs) signaling pathway and ADORA2B-mediated anti-inflammatory cytokine production pathway. Then, we used the genome-wide association analysis (GWAS) data of PTSD and MDD in public pathway database PGC. We found that the signaling by NTRKs was significantly associated with both PTSD and MDD. We indicated that the biological mechanism of ADCYAPIRI一CRHR2 effect on the comorbidity might be the activities of NTRKs signaling pathway. Thirdly, the occurrence and development mechanisms of PTSD and depression are complex, involving a huge system of affecting genes and pathways. To explore novel pathways that might also influence the comorbidity of PTSD and depression in whole biological pathways, we used the C2: CP and C5: GO collections in MSigDB suppled by all pathways in PANTHER and BioCyc, as well as the GWAS data of PTSD and MDD in Study 2 for full pathway analysis. We found that the synapse assembly pathway was significantly associated with PTSD and MDD symptoms, which preliminarily showed the existence of a new mechanism of PTSD and depression comorbidity. Finally, we further verified whether the synapse assembly pathway played a role in the comorbidity of PTSD and depression and hoped to find the key part of the pathway. We selected the key genes of synapse assembly pathway,a}T and GABRA2, and used the Chinese trauma population in Study 1 .As for the methods, we used logistic regression to analyze the main, gene-trauma exposure interaction and gene-gene interaction effects ofa}T and GABRA2 for the comorbidity. We found that compared with PTSD-depression combined symptoms, the main effect of GABRA2 significantly negatively affected low-level PTSD-depressed combined symptoms, and the OXT rs2740204-G4BRA2 rs279871 significantly positively affected predominantly PTSD symptoms. Together with Study 3, we suggested the synapse assembly pathway could be considered a physiological mechanism for the comorbidity of PTSD and depression and the GABRA2 anda}T-GABRA2 might be the biomarker of the comorbidity. In summary, the ADCYAPIRI一CRHR2 in our study is a biomarker of PTSD and depression comorbidity, which might play a role through the NTRKs signaling pathway. Moreover, the synapse assembly pathway could also be the mechanism of comorbidity and the GABRA2 anda}T-GABRA2 might also be the biomarker. In the future, a sample with different ancestry and trauma-exposure type, as well as measured by clinical tools, could be used to detect the new biomarkers and mechanism of comorbidity. We hope to provide new insights for early and accurate identification and clinical intervention for the comorbidity of PTSD and depression. |
| 英文摘要 | 创伤后应激障碍(Posttraumatic Stress Disorder, PTSD)是一种因暴露于重大创伤事件而引发的持续存在的常见精神障碍。PTSD常与其他精神障碍出现合并症状，如抑郁。PTSD与抑郁共病会比单个症状更严重地危害个体身心健康。相较于传统的二分诊断法，潜在剖面分析(C latent profile analysis, LPA)方法能将症状表现分为亚组，关注到人群异质性，更适用于定义、研究合并症状。据此，本研究将PTSD与抑郁共病定义为，同时呈现高水平的PTSD和抑郁症状表现。因此，本研究旨在探究PTSD与抑郁共病的易感基因和生物学机制，为共病的早期精准识别、临床治疗干预提供依据。 由于复杂精神疾病的症状表现通常受到遗传因素影响，影响PTSD与抑郁共病的因素应当属于共同影响两者的因素，所以想要研究PTSD与抑郁共病，除了两者各自的遗传性，还更应该关注两者的遗传关联性。但是，目前的遗传关联性研究较少，而且多使用基因组层面的分析方法，只能关注到疾病间的整体关联，没发现具体的基因和机制，较难为共病的精准识别和干预提供依据。 通路分析能够识别与特定实验/病理条件相关的先前已知通路中的关键基因/蛋白质，可以关注特定通路对共病症状的影响;基因多态性分析可以关注单个基因位点对共病症状的影响;基因上位效应可以关注某一或多基因座上的基因对另一基因座上基因的表型影响。换句话说，这些方法能够缩小研究关注层面，聚焦于与PTSD和抑郁均相关的基因和生物学通路进行分析，从而为共病识别干预提供依据。因此，本研究使用通路分析和基因多态性分析，从生物学通路和基因两个层面，揭示PTSD与抑郁共病的生物学机制和生物学标识。 本研究首先探究PTSD、抑郁的易感基因，垂体腺普酸环化酶激活多肤I型受体基因(ADCYAPIRI )，对于PTSD与抑郁共病的影响。ADCYAPI R 1基因参与下丘脑一垂体一肾上腺(hypothalamic-pituitary-adrenal, HPA)轴系统对于应激的调节，已经被我们前期研究发现能够与FK506结合蛋白5基因(FKBPS)共同影响PTSD症状，而且被其他许多研究证明与抑郁症状有较强关联性。因此，我们对于1140名经历过地震的中国成年人，通过自我报告量表和外周血采样测量他们的创伤暴露程度、PTSD症状严重程度、抑郁程度、基因型，使用逻辑回归分析ADCYAPIRI基因主效应、与创伤暴露交互作用、与HPA轴中其他重要基因，包括FKBPS、促肾上腺皮质激素释放激素受体1基因(CRHRI)和促肾上腺皮质激素释放激素受体2基因(CRHR2)的交互作用，对于PTSD与抑郁共病症状的影响。结果发现，相较于PTSD一抑郁联合症状，ADCYAPIRIrs2267735-CRHR2 rs8192496的基因间交互作用能显著负向影响PTSD为主症状。这表明，ADCYAPI R 1-CRHR2交互作用可能是PTSD与抑郁共病的生物标识。 其次，生物学通路是细胞中基因及其产物实现功能的途径，ADCYAPI RI基因所在通路可能同样与PTSD和抑郁有关，是PTSD与抑郁共病的作用机制。所以我们在公共通路数据库一一分子特征数据库(Molecular Signatures Database,MSigDB )中选取ADCYAPI RI基因的三条典型相关通路，G蛋白偶联受体活动通路·神经营养性原肌球蛋白受体激酶C neurotrophic tyrosine receptor kinase,NTRK)信号通路、ADORA2B介导的抗炎细胞因子产生通路，并且使用精神病基因组学联盟公开的全基因组关联分析(genome-wide association analysis,GWAS)数据中的PTSD和重度抑郁症(major depression disorder, MDD)数据，进行通路分析。结果发现，NTRKs信号通路与PTSD和MDD均显著关联，是两者的共享生物学通路。这表明，ADCYAPI RI -CRHR2交互作用影响PTSD与抑郁共病的生物学机制，可能正是NTRKs信号通路的相关活动。 PTSD和抑郁的发生发展机制复杂，涉及的影响基因、通路体系庞大。接下来，为了在全基因组和全部生物学通路范围内，探索还可能影响PTSD与抑郁共病的新通路，我们使用MSigDB中C2: CP和C5: GO的通路集合，补充公共通路数据库PANTHER和BioCyc中的全部通路，以及研究二中PTSD和MDD的GWAS数据，进行全通路分析。结果发现，突触组装通路显著关联于PTSD和MDD症状，初步认为可能是影响PTSD与抑郁共病发生发展的新作用机制。 最后，为了进一步验证突触通路是否对PTSD与抑郁共病起作用，并尝试找出通路中影响共病的主要部分，我们选取突触组装通路中的关键基因催产素基因(OXT)和Y一氨基丁酸受体a-2亚基基因(GABRA2 )，对于研究一的中国创伤人群，使用逻辑回归分析OXT基因、GABRA2基因的主效应、与创伤暴露交互作用，以及两者间交互作用，对PTSD与抑郁共病症状的影响。结果发现，相较于PTSD一抑郁联合症状，GABRA2基因主效应显著负向影响低程度PTSD-抑郁联合症状，OXT rs2740204-GABRA2 rs279871的基因间交互作用显著正向影响PTSD为主症状。这表明，突触组装通路可被视为PTSD与抑郁共病的生物机制，GABRA2基因和OXT-GABRA2基因交互作用可能也是共病的生物标识。 综上所述，本研究表明ADCYAPI R 1基因可能通过与CRHR2基因的交互作用作为PTSD与抑郁共病的遗传基础，是共病的生物标识。NTRKs信号通路可能解释ADCYAPI R 1-CRHR2基因交互作用对共病的作用机制。此外，可能突触组装通路也是共病的生物机制，GABRA2基因和OXT-GABRA2基因交互作用也是共病的遗传基础。这些结果增进了对共病的理解，在临床方面提供了生物标识参考，在预防干预方面指引了靶点。未来可使用不同血统、暴露于不同类型创伤的人群以及测量症状的临床工具，寻找并证实更多PTSD与抑郁共病的生物标识和作用机制，进一步为共病的早期精准识别、临床干预治疗提供新见解。 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/45197]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 推荐引用方式 GB/T 7714 | 张静怡. 创伤后应激障碍与抑郁共病的通路分析和基因多态性分析[D]. 中国科学院心理研究所. 中国科学院大学. 2023. |
入库方式： OAI收割
来源：心理研究所
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