Fig. 1

Study flow. Peripheral blood mononuclear cell (PBMC) and nasal transcriptome profiles from 341 participants with and without asthma were generated and studied to characterize systemic and airway responses in asthma. Using PBMC transcriptome data from the discovery set, we first identified differentially expressed genes (DEGs) associated with asthma (yellow box). Genes that were also associated with asthma with the same direct of effect in the independent test set were deemed validated “PBMC asthma genes.” Weighted gene coexpression network analysis and enrichment testing were then performed to identify co-expression modules enriched for PBMC asthma genes (PBMC asthma modules). Next, probabilistic causal (Bayesian) networks were built separately for the discovery set and test set. Key driver analysis was performed on each network using PBMC asthma module members as targets. Key drivers identified in both the discovery and test sets were deemed “PBMC key drivers.” The same series of analyses was performed with the nasal transcriptome data generated in parallel from participants to identify nasal asthma genes, nasal asthma modules, and nasal key drivers (green box). To characterize relationships between the PBMC key drivers and nasal key drivers identified, causal mediation analyses were then performed (purple box)