251. Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module
- Author
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Joerg Menche, Asher Ameli, Amitabh Sharma, Marc Santolini, Per Bakke, Xiaobo Zhou, James D. Crapo, Zhiqiang Jiang, Maksim Kitsak, Terri H. Beaty, Edwin K. Silverman, and Michael H. Cho
- Subjects
Male ,0301 basic medicine ,Network medicine ,Computer science ,Systems biology ,Closeness ,lcsh:Medicine ,Genome-wide association study ,Disease ,Computational biology ,Interactome ,Biological pathway ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,Human interactome ,Affinity chromatography ,Databases, Genetic ,medicine ,Humans ,Leverage (statistics) ,Genetic Predisposition to Disease ,lcsh:Science ,Gene ,Genetic association ,Network module ,COPD ,Multidisciplinary ,GTPase-Activating Proteins ,lcsh:R ,medicine.disease ,030104 developmental biology ,Genetic Loci ,Female ,lcsh:Q ,Genome-Wide Association Study - Abstract
The polygenic nature of complex diseases offers potential opportunities to utilize network-based approaches that leverage the comprehensive set of protein-protein interactions (the human interactome) to identify new genes of interest and relevant biological pathways. However, the incompleteness of the current human interactome prevents it from reaching its full potential to extract network-based knowledge from gene discovery efforts, such as genome-wide association studies, for complex diseases like chronic obstructive pulmonary disease (COPD). Here, we provide a framework that integrates the existing human interactome information with new experimental protein-protein interaction data for FAM13A, one of the most highly associated genetic loci to COPD, to find a more comprehensive disease network module. We identified an initial disease network neighborhood by applying a random-walk method. Next, we developed a network-based closeness approach (CAB) that revealed 9 out of 96 FAM13A interacting partners identified by affinity purification assays were significantly close to the initial network neighborhood. Moreover, compared to a similar method (local radiality), the CAB approach predicts low-degree genes as potential candidates. The candidates identified by the network-based closeness approach were combined with the initial network neighborhood to build a comprehensive disease network module (163 genes) that was enriched with genes differentially expressed between controls and COPD subjects in alveolar macrophages, lung tissue, sputum, blood, and bronchial brushing datasets. Overall, we demonstrate an approach to find disease-related network components using new laboratory data to overcome incompleteness of the current interactome.
- Published
- 2018
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