Center for Bioinformatics and Computational Biology, and The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
BMC Med Genomics. 2013;6 Suppl 1(Suppl 1):S17. doi: 10.1186/1755-8794-6-S1-S17. Epub 2013 Jan 23.
Schizophrenia (SCZ) and type 2 diabetes mellitus (T2D) are both complex diseases. Accumulated studies indicate that schizophrenia patients are prone to present the type 2 diabetes symptoms, but the potential mechanisms behind their association remain unknown. Here we explored the pathogenetic association between SCZ and T2D based on pathway analysis and protein-protein interaction.
With sets of prioritized susceptibility genes for SCZ and T2D, we identified significant pathways (with adjusted p-value < 0.05) specific for SCZ or T2D and for both diseases based on pathway enrichment analysis. We also constructed a network to explore the crosstalk among those significant pathways. Our results revealed that some pathways are shared by both SCZ and T2D diseases through a number of susceptibility genes. With 382 unique susceptibility proteins for SCZ and T2D, we further built a protein-protein interaction network by extracting their nearest interacting neighbours. Among 2,104 retrieved proteins, 364 of them were found simultaneously interacted with susceptibility proteins of both SCZ and T2D, and proposed as new candidate risk factors for both diseases. Literature mining supported the potential association of partial new candidate proteins with both SCZ and T2D. Moreover, some proteins were hub proteins with high connectivity and interacted with multiple proteins involved in both diseases, implying their pleiotropic effects for the pathogenic association. Some of these hub proteins are the components of our identified enriched pathways, including calcium signaling, g-secretase mediated ErbB4 signaling, adipocytokine signaling, insulin signaling, AKT signaling and type II diabetes mellitus pathways. Through the integration of multiple lines of information, we proposed that those signaling pathways, which contain susceptibility genes for both diseases, could be the key pathways to bridge SCZ and T2D. AKT could be one of the important shared components and may play a pivotal role to link both of the pathogenetic processes.
Our study is the first network and pathway-based systematic analysis for SCZ and T2D, and provides the general pathway-based view of pathogenetic association between two diseases. Moreover, we identified a set of candidate genes potentially contributing to the linkage between these two diseases. This research offers new insights into the potential mechanisms underlying the co-occurrence of SCZ and T2D, and thus, could facilitate the inference of novel hypotheses for the co-morbidity of the two diseases. Some etiological factors that exert pleiotropic effects shared by the significant pathways of two diseases may have important implications for the diseases and could be therapeutic intervention targets.
精神分裂症（SCZ）和 2 型糖尿病（T2D）都是复杂的疾病。大量研究表明，精神分裂症患者容易出现 2 型糖尿病的症状，但它们之间关联的潜在机制尚不清楚。在这里，我们基于途径分析和蛋白质-蛋白质相互作用来探索 SCZ 和 T2D 之间的发病关联。
通过 SCZ 和 T2D 的优先易感基因集，我们基于途径富集分析，鉴定了针对 SCZ 或 T2D 以及两种疾病的显著途径（调整后的 p 值<0.05）。我们还构建了一个网络来探索这些显著途径之间的相互作用。我们的结果表明，一些途径通过许多易感基因与 SCZ 和 T2D 两种疾病共享。对于 SCZ 和 T2D 的 382 个独特的易感蛋白，我们通过提取其最近的相互作用邻居进一步构建了一个蛋白质-蛋白质相互作用网络。在 2104 个检索到的蛋白质中，有 364 个同时与 SCZ 和 T2D 的易感蛋白相互作用，被提议为两种疾病的新候选风险因素。文献挖掘支持部分新候选蛋白与 SCZ 和 T2D 之间的潜在关联。此外，一些蛋白质是具有高连通性的枢纽蛋白，与涉及两种疾病的多个蛋白质相互作用，暗示它们对发病关联的多效性影响。这些枢纽蛋白中的一些是我们鉴定的富集途径的组成部分，包括钙信号、g 分泌酶介导的 ErbB4 信号、脂肪细胞因子信号、胰岛素信号、AKT 信号和 2 型糖尿病途径。通过整合多条信息，我们提出包含两种疾病易感基因的这些信号途径可能是连接 SCZ 和 T2D 的关键途径。AKT 可能是重要的共享成分之一，可能在连接两种发病过程中发挥关键作用。
我们的研究是 SCZ 和 T2D 的第一个基于网络和途径的系统分析，为两种疾病的发病关联提供了一般的基于途径的观点。此外，我们确定了一组潜在的候选基因，这些候选基因可能有助于连接这两种疾病。这项研究为精神分裂症和 2 型糖尿病共病的潜在机制提供了新的见解，因此，可能有助于为两种疾病的共病提出新的假设。在两种疾病的显著途径中发挥多效性作用的一些病因因素可能对这些疾病具有重要意义，并可能成为治疗干预的靶点。
