Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Genes and Their Functional, Tissue-Dependent and Disease-Related Associations.

Asthma affects more than 300 million people globally and is both under diagnosed and under treated. The most recent and largest genome-wide association study investigating moderate to severe asthma to date was carried out in 2019 and identified 25 independent signals. However, as new and in-depth downstream databases become available, the translational analysis of these signals into target genes and pathways is timely. In this study, unique (U-BIOPRED) and publicly available datasets (HaploReg, Open Target Genetics and GTEx) were investigated for the 25 GWAS signals to identify 37 candidate causal genes. Additional traits associated with these signals were identified through PheWAS using the UK Biobank resource, with asthma and eosinophilic traits amongst the strongest associated. Gene expression omnibus dataset examination identified 13 candidate genes with altered expression profiles in the airways and blood of asthmatic subjects, including and . Gene expression analysis through publicly available datasets highlighted lung tissue cell specific expression, with both and genes showing enriched expression in ciliated cells. Gene enrichment pathway and interaction analysis highlighted the dominance of the gene cluster across many immunological diseases including asthma, type I diabetes, and rheumatoid arthritis. Interaction and prediction analyses found and to be key co-localization partners for other genes, predicted that forms co-expression relationships with 13 other genes, including the gene cluster and that and are co-expressed. Drug interaction analysis revealed that 11 of the candidate genes have an interaction with available therapeutics. This study provides significant insight into these GWAS signals in the context of cell expression, function, and disease relationship with the view of informing future research and drug development efforts for moderate-severe asthma.