基于生物分子网络分析的精神分裂症功能模块挖掘

Identification of Schizophrenia Functional Modules Based on Biomolecular Network Analysis

精神分裂症(schizophrenia, SCZ)是一种影响人类生命健康和生存质量的复杂性精神疾病,其遗传机制涉及多个生物分子的相互作用。本研究从分子水平挖掘与SCZ相关的功能模块,可为SCZ的基础研究提供新思路。首先,通过蛋白质-蛋白质互作知识引导扩展SCZ风险基因,构建SCZ特异性基因网络;随后,利用Newman分解算法挖掘功能模块,并通过拓扑学分析及泊松分布检验确定每个功能模块的拓扑属性和核心基因;最后,对功能模块进行功能学分析,根据富集到的通路类别评估功能模块之间的相互作用。结果显示,共提取了14个功能模块,均具备无标度网络性质。对所得功能模块进行拓扑学分析,共挖掘出102个核心基因,包括已知与精神分裂症相关的基因(例如EGFR、HAX1、IL1R1、RALGDS等)和尚未有相关报道的基因(例如SVIL、DNAJA1、RABAC1、STX6等)。通过富集分析发现这些功能模块参与多条生物学通路,包括细胞凋亡、ErbB信号通路、细胞周期、磷脂酶D信号通路、PI3K-Akt信号通路等。功能模块分析显示,大部分功能模块不是单独发挥作用的,它们共同影响SCZ的发生发展,具有共享的发病机制。

Schizophrenia(SCZ) is a complex mental illness that affects human health and quality of life. But its pathogenesis is still unclear. It is necessary to elucidate the molecular pathogenesis and identify func-tional modules related to SCZ. Herein, protein-protein interaction knowledge was used as a guide to expand the number of SCZ risk genes into an SCZ-specific gene network. Next, the network was decomposed by us-ing Newman spectral algorithm to obtain functional modules. Then the topological properties and hub genes of each module were identified according to the topological analysis and Poisson distribution test. Enrich-ment analysis of each functional module was performed for evaluating the interactions between the functional modules based on the enriched pathway categories. A total of 14 functional modules were obtained, all of which had scale-free properties. Topological analysis of these modules identified a total of 102 hub genes,most of which(e.g. EGFR, HAX1, IL1 R1, RALGDS, etc.) proved to be associated with SCZ, while the rest(e.g.SVIL, DNAJA1, RABAC1, STX6, etc.) might be novel risk genes. Further bioinformatic functional analysis of KEGG databases revealed that these modules were involved in multiple pathogenic biological pathways(e.g.apoptosis, ErbB signaling pathway, cell cycle, phospholipase D signaling pathway, PI3 K-Akt signaling pathway, etc). Functional modules analysis showed that most of these specific modules did not appear to function in an isolated way;instead, they interacted with each other to influence the occurrence and development of SCZ, having a shared pathogenesis.