Functional assessment of a convergent gene network underlying allergic diseases and IgE.

Abstract

The relationships between allergic diseases (AD) and IgE levels are complex. We sought to identify genes associated with AD and IgE having close proximity in the interactome and to elucidate the associated biological mechanisms. We integrated a comprehensive interactome with data from genome-wide (GWAS) and epigenome-wide (EWAS) association studies of AD and IgE levels, respectively. We used the SigMod algorithm to identify gene modules enriched in AD- and IgE-associated signals. We performed a connectivity analysis of these two modules to characterize direct cross-trait connections. Finally, we conducted an in-depth functional analysis of the directly-connected AD and IgE genes. We identified gene modules that were significantly associated with AD and IgE, respectively (P < 10^-5). The connectivity analysis revealed that 139 AD- and IgE-associated genes had direct cross-trait connections in the interactome. Combinations of these genes were enriched (false discovery rate < 0.05) in pathways notably involved in type 2 and non-type 2 immune responses. These results were corroborated by cell-specific enrichment of gene expression. Of the 139 genes, 55% (77 genes) had not previously been associated with AD and/or IgE. These genes are implicated in biological processes including host defense against pathogens, ubiquitination, gene expression regulation, inflammation, and neuroimmune interactions. The 139 genes are enriched in drug targets (P = 7.7 × 10^-7). This study sheds light on the biological mechanisms influenced by AD and IgE genes that are directly linked in the interactome. It emphasizes the role of IgE in both allergic and antiviral responses. This study also identifies new genes for further investigation.