TransNeT-CGP: A cluster-based comorbid gene prioritization by integrating transcriptomics and network-topological features

Abstract

The local disruptions caused by the genes of one disease can influence the pathways associated with the other diseases resulting in comorbidity. For gene therapies, it is necessary to prioritize the key genes that regulate common biological mechanisms to tackle the issues caused by overlapping diseases. This work proposes a clustering-based computational approach for prioritising the comorbid genes within the overlapping disease modules by analyzing Protein-Protein Interaction networks. For this, a sub-network with gene interactions of the disease pair was extracted from the interactome. The edge weights are assigned by combining the pairwise gene expression correlation and betweenness centrality scores. Further, a weighted graph clustering algorithm is applied and dominant nodes of high-density clusters are ranked based on clustering coefficients and neighborhood connectivity. Case studies based on neurodegenerative diseases such as Amyotrophic Lateral Sclerosis- Spinal Muscular Atrophy (ALS-SMA) pair and cancers such as Ovarian Carcinoma-Invasive Ductal Breast Carcinoma (OC-IDBC) pair were conducted to examine the efficacy of the proposed method. To identify the mechanistic role of top-ranked genes, we used Functional and Pathway enrichment analysis, connectivity analysis with leave-one-out (LOO) method, analysis of associated disease-related protein complexes, and prioritization tools such as TOPPGENE and Heml2.0. From pathway analysis, it was observed that the top 10 genes obtained using the proposed method were associated with 10 pathways in ALS-SMA comorbidity and 15 in the case of OC-IDBC, while that in similar methods like SAPDSB and S2B were 4, 6 respectively for ALS-SMA and 9, 10 respectively for OC-IDBC. In both case studies, 70 % of the disease-specific benchmark protein complexes were linked to top-ranked genes of the proposed method while that of SAPDSB and S2B were 55 % and 60 % respectively. Additionally, it was found that the removal of the top 10 genes disconnect the network into 14 distinct components in the case of ALS-SMA and 9 in the case of OC-IDBC. The experimental results shows that the proposed method can be effectively used for identifying key genes in comorbidity and can offer insights about the intricate molecular relationship driving comorbid diseases.

Keywords: Gene Prioritization Comorbidity Clustering Protein-Protein Interaction Network.