W177 - Meta-analysis of Genome-wide Association Studies of Asthma Exacerbation

Abstract Text: Asthma exacerbations are a major cause of asthma-related morbidity and mortality. Pathogenesis of asthma involves a complex interaction between genetic and environmental factors. Genetic factors for susceptibility may differ from those associated with progression and severity, suggesting the presence of genetic factors specific to exacerbations. Genome-wide association studies (GWAS) have identified ~200 loci associated with asthma susceptibility, but few studies have investigated genetics of underlying exacerbations. Here, we present a large-scale GWAS of asthma exacerbations using a meta-analysis framework including FinnGen and UK Biobank. Individuals with asthma and at least one exacerbation were compared to those with asthma but no history of exacerbation. Exacerbations were defined based on physician or hospital records, prescriptions for oral corticosteroids and antibiotics. UK Biobank included 11,798 exacerbators and 30,543 non-exacerbators, while FinnGen included 8,469 exacerbators and 38,518 non-exacerbators. Individual GWAS was performed using REGENIE adjusted for age, sex, ancestry and relatedness. Meta-analysis was conducted using fixed-effect inverse variance-weighted method implemented in METAL. We identified 23 independent signals, four of which reached genome-wide significance (p < 5x10-8). Potential causal genes for asthma exacerbations were prioritized using a combination of statistical approaches. Inflammatory pathways activated in response to infectious agents are implicated, which can cause acute lung injuries and subsequently contribute to exacerbations in asthma patients. Validation of these findings in independent cohorts and across diverse ancestries, coupled with functional investigations, will be essential to elucidate their mechanisms of action and potentially inform target discovery and therapeutic development.