A Computational Framework to Identify Cross Association between Complex Disorders by Protein-protein Interaction Network Analysis

Objective: It is a known fact that numerous complex disorders do not happen in isolation indicating the plausible set of shared causes common to several different sicknesses. Hence, analysis of comorbidity can be utilized to explore the association between several disorders. In this study, we have proposed a network-based computational approach, in which genes are organized based on the topological characteristics of the constructed Protein-Protein Interaction Network (PPIN) followed by a network prioritization scheme, to identify distinctive key genes and biological pathways shared among diseases. Methods: The proposed approach is initiated from constructed PPIN of any randomly chosen disease genes in order to infer its associations with other diseases in terms of shared pathways, coexpression, co-occurrence etc. For this, initially, proteins associated to any disease based on random choice were identified. Secondly, PPIN is organized through topological analysis to define hub genes. Finally, using a prioritization algorithm a ranked list of newly predicted multimorbidity-associated proteins is generated. Using Gene Ontology (GO), cellular pathways involved in multimorbidity-associated proteins are mined. Result and Conclusion: The proposed methodology is tested using three disorders, namely Diabetes, Obesity and blood pressure at an atomic level and the results suggest the comorbidity of other complex diseases that have associations with the proteins included in the disease of present study through shared proteins and pathways. For diabetes, we have obtained key genes like GAPDH, TNF, IL6, AKT1, ALB, TP53, IL10, MAPK3, TLR4 and EGF with key pathways like P53 pathway, VEGF signaling pathway, Ras Pathway, Interleukin signaling pathway, Endothelin signaling pathway, Huntington disease etc. Studies on other disorders such as obesity and blood pressure also revealed promising results.

Automated summary

This study proposes a network-based computational approach to identify key genes and biological pathways shared among diseases through analyzing comorbidity. By organizing genes based on protein-protein interaction networks and using a prioritization algorithm, the study reveals potential relationships between complex disorders such as Diabetes, Obesity, and blood pressure.