AbstractBackgroundAsthmatic children who develop obesity have poorer outcomes compared to those that do not, including poorer control, more severe symptoms, and greater resistance to standard treatment. Gene expression networks are powerful statistical tools for characterizing the underpinnings of human disease that leverage the putative co-regulatory relationships of genes to infer biological pathways altered in disease states.ObjectiveThe aim of this study was to characterize the biology of childhood asthma complicated by adult obesity.MethodsWe performed weighted gene co-expression network analysis (WGCNA) of gene expression data in whole blood from 514 adult subjects from the Childhood Asthma Management Program (CAMP). We then performed module preservation and association replication analyses in 418 subjects from two independent asthma cohorts (one pediatric and one adult).ResultsWe identified a multivariate model in which four gene co-expression network modules were associated with incident obesity in CAMP (each P < 0.05). The module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the four obese asthma modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in obese subjects in both replication cohorts (each P < 0.05).ConclusionsOur gene co-expression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of obese asthma.Key MessagesWe hypothesized that individuals with asthma complicated by obesity had distinct blood gene expression signatures.Gene co-expression network analysis implicated several inflammatory biological pathways in one form of obese asthma.Capsule SummaryThis work addresses a knowledge gap about the molecular relationship between asthma and obesity, suggesting that an endotype of obese asthma, known as asthma complicated by obesity, is underpinned by coherent biological mechanisms.AbbreviationsCAMPChildhood Asthma Management ProgramWGCNAweighted gene co-expression network analysisAsthma BRIDGEAsthma BioRepository for Integrative Genomic ExplorationGACRSGenetics of Asthma in Costa Rica StudyCHSSouthern California Children’s Health StudyBMIbody mass indexBICBayes Information CriterionHUGOHuman Genome OrganisationPCprincipal componentGSEAgene set enrichment analysisIL-1interleukin-1Hh signalingHedgehog signaling