{"doi":"10.1111/all.70101","title":"Mediation of Polygenic Asthma Risk Through Gene Expression","abstract":"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.","journal":"Allergy","year":2025,"id":537447,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.7874,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":940697,"name":"Brooke Szczesny","orcid":null,"position":1,"is_corresponding":false},{"id":400684,"name":"Kanika Kanchan","orcid":"0009-0003-4993-8841","position":2,"is_corresponding":false},{"id":1423702,"name":"Erika Esquinca","orcid":null,"position":3,"is_corresponding":false},{"id":24851,"name":"Meher Preethi Boorgula","orcid":null,"position":4,"is_corresponding":false},{"id":18447,"name":"Sameer Chavan","orcid":"0000-0002-0220-0845","position":5,"is_corresponding":false},{"id":398697,"name":"Monica Campbell","orcid":null,"position":6,"is_corresponding":false},{"id":1060034,"name":"Wendy Lorizio","orcid":null,"position":7,"is_corresponding":false},{"id":255884,"name":"Ayo P. 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