Uncovering pleiotropic loci in allergic rhinitis and leukocyte traits through multi-trait GWAS

Abstract

Allergic rhinitis (AR) is a nasal inflammation triggered by the immune system's response to airborne allergens, with white blood cells playing a crucial role in the development of allergic symptoms. This study aimed to investigate the genetic correlations between AR and various blood traits in European and East Asian populations using linkage disequilibrium score regression (LDSC). By leveraging GWAS summary statistics, we identified significant genetic overlap between AR and eosinophil counts in both populations. Cross-trait analysis revealed 52 pleiotropic loci associated with AR and eosinophil counts in Europeans, while 12 novel loci were discovered in East Asians. Among these, five loci, including IL1RL1 and IL4R, were shared between Europeans and East Asians. Additionally, we identified a novel East Asian-specific locus near the CD28 gene. Differential gene expression analysis further showed that CD28 expression was significantly lower in AR patients compared to healthy controls, suggesting its potential involvement in AR pathogenesis. These findings underscore the utility of multi-trait GWAS in uncovering pleiotropic loci and provide new insights into the genetic architecture of AR, particularly emphasizing population-specific loci like CD28. This research opens avenues for understanding the genetic basis of AR and developing targeted therapies.

Keywords: Allergic rhinitis; Genetic correlation; Genome-wide association study.

Fig. 1

Overall and partitioned genetic correlations between allergic diseases (AR and pollinosis) and hematological traits. (A) Heatmaps of genome-wide genetic correlations between allergic rhinitis and hematological traits in Europeans, and between allergic rhinitis, pollinosis, and hematological traits in East Asians. (B) Heatmaps of partitioned genetic correlations between allergic rhinitis and eosinophil counts in specific genomic regions in Europeans, and between allergic rhinitis, pollinosis, and hematological traits in specific genomic regions in East Asians. The matrix displays the strength of the correlations (indicated by the size of each square), with significant associations marked by an asterisk (p < 0.05). The shade of each square indicates a positive (blue) or negative (red) correlation, with the intensity of the color reflecting the magnitude of the correlation.

Fig. 2

Local genetic correlation between allergic rhinitis and eosinophil counts in European and East Asian populations. (A) The Manhattan plot shows the estimates of local genetic correlation, genetic covariance, and SNP heritability between allergic rhinitis and eosinophil counts in the European population. (B) The Manhattan plot shows the estimates of local genetic correlation, genetic covariance, and SNP heritability between allergic rhinitis and eosinophil counts in the East Asian population. Blue bars represent loci on odd-numbered chromosomes, and red bars represent loci on even-numbered chromosomes, both showing significant local genetic correlation after multiple testing adjustment (p < 0.05/1,703).

Fig. 3

Differential analysis of CD28 expression levels. The violin plot displays the distribution of CD28 expression levels across four groups: AR (green), allergic rhinitis with additional factors (purple), Allergy (orange), and Control (yellow).“ns” indicates no significant difference. Asterisks represent significant differences, with the number of asterisks indicating the level of significance.