Mediation of Polygenic Asthma Risk Through Gene Expression

Background Existing asthma polygenic risk scores (PRSs) have minimal validation in African‐ancestry populations, leaving gaps in our understanding of the wide applicability of PRSs. To widen our understanding of the applicability of asthma PRSs, we apply published PRSs in African‐ancestry individuals and quantify the extent to which the PRS‐asthma relationship is mediated by clinical biomarkers and gene‐expression signatures of asthma. Methods We applied 22 PRSs from the PGS Catalog in 673 individuals from the Consortium on Asthma among African‐Ancestry Populations in the Americas (CAAPA) and calculated the percent of the PRS‐asthma relationship that is statistically mediated by clinical and nasal epithelium transcriptomic biomarkers of asthma. Asthma case/control status was defined as ever/never having a doctor's diagnosis of disease. For gene expression mediation analysis, we limited the cases to those with current disease. Results The PRS (PGS001782) created by the Global Biobank Meta‐analysis Initiative ( N = 32,658 individuals of African ancestry) performed the best (ΔAUC = 0.104, AUC = 0.657) adjusted for age, sex, study site, and the first two genetic principal components (PC1‐2). The PRS's effect on asthma was mediated by total IgE (tIgE) (38.8%, p .adj < 0.0002), multi‐allergen ImmunoCAP phadiatop specific IgE (sIgE) (38.7%, p .adj < 0.0002), and eosinophils (7.3%, p .adj = 0.004). Mediation was observed for gene expression modules related to T2 inflammation (21.9%, p .adj < 0.0024), wound healing (11.9%, p .adj = 0.008), and medication response (6.8%, p .adj = 0.049). Conclusion We found the best PRS to be the one derived using the largest sample size and including African‐ancestry individuals. Mediation supports the well‐documented biology of T2 inflammation in asthma as well as pathophysiological components of asthma like wound healing and medication response.