Uncovering pleiotropic loci linking keratoconus and allergic diseases through integrative genomic analyses.

Keratoconus (KC) is a progressive corneal disease increasingly linked to immune dysregulation. Epidemiological studies have suggested comorbidity between KC and allergic diseases such as atopic dermatitis (AD), allergic conjunctivitis (AC), allergic rhinitis (AR), and allergic asthma (AA), yet their shared genetic mechanisms remain unclear. To investigate the shared genetic architecture between KC and four common allergic conditions, we integrated genome-wide association study (GWAS) summary statistics using a multi-omics framework. We applied linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) to assess genome-wide genetic correlations. Pleiotropic variants were identified using the PLACO method and functionally annotated with FUMA. Bayesian colocalization and local genetic correlation analyses were conducted to pinpoint shared causal loci. Gene-level associations and pathway enrichment were explored using MAGMA and SMR, and potential regulatory effects were assessed through eQTL mapping and functional databases. All four allergic diseases showed significant positive genetic correlations with KC. PLACO identified 451 pleiotropic SNPs, including 44 independent risk loci. Eight loci showed strong colocalization (PPH4 > 0.8), notably 8q21.13 and 10p14. Functional annotation revealed several variants with regulatory or deleterious potential, such as rs73220641 (KLF5) and rs17686636 (GATA3). MAGMA and SMR prioritized SMAD3, IL18R1, and PCNXL3 as pleiotropic genes, enriched in immune tissues and inflammatory pathways. This multi-omics study uncovers shared genetic loci and immune-related pathways between KC and allergic diseases. The results highlight epithelial barrier dysfunction and immune regulation as converging mechanisms and propose pleiotropic genes as potential therapeutic targets.