Guo Pan, Chen Shasha, Wang Hao, Wang Yaogang, Wang Ju
School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
School of Public Health, Tianjin Medical University, Tianjin, China.
Front Aging Neurosci. 2022 Jan 20;13:789698. doi: 10.3389/fnagi.2021.789698. eCollection 2021.
During the past years, clinical and epidemiological studies have indicated a close relationship between Alzheimer's disease (AD) and other mental disorders like major depressive disorder (MDD). At the same time, a number of genes genetically associated with AD or MDD have been detected. However, our knowledge on the mechanisms that link the two disorders is still incomplete, and controversies exist. In such a situation, a systematic analysis on these genes could provide clues to understand the molecular features of two disorders and their comorbidity.
In this study, we compiled the genes reported to be associated with AD or MDD by a comprehensive search of human genetic studies and genes curated in disease-related database. Then, we investigated the features of the shared genes between AD and MDD using the functional enrichment analysis. Furthermore, the major biochemical pathways enriched in the AD- or MDD-associated genes were identified, and the cross talks between the pathways were analyzed. In addition, novel candidate genes related to AD and MDD were predicted in the context of human protein-protein interactome.
We obtained 650 AD-associated genes, 447 MDD-associated genes, and 77 shared genes between AD and MDD. The functional analysis revealed that biological processes involved in cognition, neural development, synaptic transmission, and immune-related processes were enriched in the common genes, indicating a complex mechanism underlying the comorbidity of the two diseases. In addition, we conducted the pathway enrichment analysis and found 102 shared pathways between AD and MDD, which involved in neuronal development, endocrine, cell growth, and immune response. By using the pathway cross-talk analysis, we found that these pathways could be roughly clustered into four modules, i.e., the immune response-related module, the neurodevelopmental module, the cancer or cell growth module, and the endocrine module. Furthermore, we obtained 37 novel candidate genes potentially related to AD and MDD with node degrees > 5.0 by mapping the shared genes to human protein-protein interaction network (PPIN). Finally, we found that 37 novel candidate genes are significantly expressed in the brain.
These results indicated shared biological processes and pathways between AD and MDD and provided hints for the comorbidity of AD and MDD.
在过去几年中，临床和流行病学研究表明，阿尔茨海默病（AD）与其他精神障碍如重度抑郁症（MDD）之间存在密切关系。与此同时，已经检测到一些与AD或MDD基因相关的基因。然而，我们对连接这两种疾病的机制的了解仍然不完整，并且存在争议。在这种情况下，对这些基因进行系统分析可以为理解这两种疾病的分子特征及其共病提供线索。
在本研究中，我们通过全面搜索人类遗传学研究和疾病相关数据库中整理的基因，汇编了据报道与AD或MDD相关的基因。然后，我们使用功能富集分析研究了AD和MDD之间共享基因的特征。此外，确定了AD或MDD相关基因中富集的主要生化途径，并分析了这些途径之间的相互作用。此外，在人类蛋白质-蛋白质相互作用组的背景下预测了与AD和MDD相关的新候选基因。
我们获得了650个与AD相关的基因、447个与MDD相关的基因以及AD和MDD之间的77个共享基因。功能分析表明，参与认知、神经发育、突触传递和免疫相关过程的生物学过程在共同基因中富集，这表明两种疾病共病的潜在机制很复杂。此外，我们进行了通路富集分析，发现AD和MDD之间有102个共享通路，这些通路涉及神经元发育、内分泌、细胞生长和免疫反应。通过使用通路相互作用分析，我们发现这些通路大致可分为四个模块，即免疫反应相关模块、神经发育模块、癌症或细胞生长模块和内分泌模块。此外，通过将共享基因映射到人类蛋白质-蛋白质相互作用网络（PPIN），我们获得了37个节点度>5.0的与AD和MDD潜在相关的新候选基因。最后，我们发现37个新候选基因在大脑中显著表达。
这些结果表明AD和MDD之间存在共享的生物学过程和通路，并为AD和MDD的共病提供了线索。
