# Mediation of Polygenic Asthma Risk Through Gene Expression

## TL;DR

The study explores how genetic risk scores for asthma relate to asthma in African-ancestry populations and finds that this relationship is partly explained by immune markers and gene expression patterns.

## Contribution

The study validates asthma polygenic risk scores in African-ancestry populations and identifies biological pathways mediating their effects.

## Key findings

- The best-performing PRS was derived from a large African-ancestry sample and showed a 10.4% increase in AUC.
- The PRS effect on asthma was mediated by IgE levels, allergen-specific IgE, and eosinophils.
- Gene expression modules related to T2 inflammation, wound healing, and medication response partially mediated the PRS-asthma relationship.

## Abstract

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.

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.

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).

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.

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. 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 pathophysiology components of asthma like airway wound healing and asthma medication response. △AUC, change in the area under the ROC curve (AUC); CAAPA, Consortium on Asthma among African‐Ancestry Populations in the Americas; GWAS, genome‐wide association studies; IgE, immunoglobulin E; PRS, polygenic risk score; T2, type 2.