Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module

Amitabh Sharma, Maksim Kitsak, Michael H. Cho, Asher Ameli, Xiaobo Zhou, Zhiqiang Jiang, James D. Crapo, Terri L Beaty, Jörg Menche, Per S. Bakke, Marc Santolini, Edwin K. Silverman

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article number14439
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Chronic Obstructive Pulmonary Disease
Proteins
Genes
Genetic Loci
Gene Regulatory Networks
Genome-Wide Association Study
Alveolar Macrophages
Genetic Association Studies
Sputum
Lung
cellulose acetate-butyrate

ASJC Scopus subject areas

  • General

Cite this

Sharma, A., Kitsak, M., Cho, M. H., Ameli, A., Zhou, X., Jiang, Z., ... Silverman, E. K. (2018). Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. Scientific Reports, 8(1), [14439]. https://doi.org/10.1038/s41598-018-32173-z

Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. / Sharma, Amitabh; Kitsak, Maksim; Cho, Michael H.; Ameli, Asher; Zhou, Xiaobo; Jiang, Zhiqiang; Crapo, James D.; Beaty, Terri L; Menche, Jörg; Bakke, Per S.; Santolini, Marc; Silverman, Edwin K.

In: Scientific Reports, Vol. 8, No. 1, 14439, 01.12.2018.

Research output: Contribution to journalArticle

Sharma, A, Kitsak, M, Cho, MH, Ameli, A, Zhou, X, Jiang, Z, Crapo, JD, Beaty, TL, Menche, J, Bakke, PS, Santolini, M & Silverman, EK 2018, 'Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module', Scientific Reports, vol. 8, no. 1, 14439. https://doi.org/10.1038/s41598-018-32173-z
Sharma, Amitabh ; Kitsak, Maksim ; Cho, Michael H. ; Ameli, Asher ; Zhou, Xiaobo ; Jiang, Zhiqiang ; Crapo, James D. ; Beaty, Terri L ; Menche, Jörg ; Bakke, Per S. ; Santolini, Marc ; Silverman, Edwin K. / Integration of Molecular Interactome and Targeted Interaction Analysis to Identify a COPD Disease Network Module. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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