A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma

TLDR

Genetic studies have rapidly identified genes linked to complex diseases, yet the molecular mechanisms by which these genes influence phenotypes remain poorly understood, and the asthma module includes immune pathways shared with other immune‑related diseases. The study aims to identify and validate an asthma disease module within the interactome that is functionally and pathophysiologically relevant. We mapped the asthma disease module as the interactome neighborhood linked to asthma and validated it computationally and experimentally, and used multi‑omics data to pinpoint GAB1 signaling as a novel asthma modulator. The asthma module is enriched for modest GWAS signals and drug‑responsive genes, and our experiments show that glucocorticoid treatment elevates GAB1 while GAB1 knockdown reduces NFkB, revealing a novel GAB1–NFkB regulatory axis in asthma.

Abstract

Recent advances in genetics have spurred rapid progress towards the systematic identification of genes involved in complex diseases. Still, the detailed understanding of the molecular and physiological mechanisms through which these genes affect disease phenotypes remains a major challenge. Here, we identify the asthma disease module, i.e. the local neighborhood of the interactome whose perturbation is associated with asthma, and validate it for functional and pathophysiological relevance, using both computational and experimental approaches. We find that the asthma disease module is enriched with modest GWAS P-values against the background of random variation, and with differentially expressed genes from normal and asthmatic fibroblast cells treated with an asthma-specific drug. The asthma module also contains immune response mechanisms that are shared with other immune-related disease modules. Further, using diverse omics (genomics, gene-expression, drug response) data, we identify the GAB1 signaling pathway as an important novel modulator in asthma. The wiring diagram of the uncovered asthma module suggests a relatively close link between GAB1 and glucocorticoids (GCs), which we experimentally validate, observing an increase in the level of GAB1 after GC treatment in BEAS-2B bronchial epithelial cells. The siRNA knockdown of GAB1 in the BEAS-2B cell line resulted in a decrease in the NFkB level, suggesting a novel regulatory path of the pro-inflammatory factor NFkB by GAB1 in asthma.