Discovering causal genes and comorbidities for asthma

Abstract Asthma is a heterogeneous phenotype that is often associated with other phenotypes. Identifying the genetic mediators that modulate the interaction between asthma and asthma-associated conditions will help inform our understanding of asthma heterogeneity. Here, we used Mendelian randomisation to identify asthma causal genes and their modifier spatial eQTLs within lung and whole blood-specific gene regulatory networks (GRNs), which integrate information on spatial genome organisation with tissue-specific expression quantitative trait loci (eQTL) data. Subsequently, we located the asthma-causal genes in the tissue-specific GRNs to define a putative asthma GRN and identified curated protein interaction partners occurring up to 4 edges (levels) away from the asthma GRN (level 0). We then queried the GWAS Catalog with the spatial eQTLs regulating level 0-4 genes to identify the GWAS traits enriched at each level (hypergeometric test; FDR≤0.05). This identified 113 traits significantly enriched in the regulatory space proximal to asthma, 106 of which had known associations with asthma (e.g., systemic lupus erythematosus and age-related macular degeneration) and seven traits whose association with asthma is yet to be confirmed. Importantly, our analysis identifies the genes and SNPs that modulate the interaction between asthma and asthma-associated traits by identifying the direct and indirect protein interacting partners of asthma causal genes. Finally, we highlight the druggable genes identified in our analysis, thereby providing new drug-repurposing opportunities for asthma.