Multivariate GWAS Analysis Reveals a Common Genetic Factor Linking Dry Eye Disease to Gastrointestinal Comorbidities

Purpose: Dry eye disease (DED) frequently overlaps clinically with irritable bowel syndrome, gastroesophageal reflux, and peptic ulcer, yet their shared genetic architecture and pathogenic pathways remain elusive. Methods: Univariate genome-wide association studies (GWAS) were conducted for DED and four gastrointestinal diseases. Genomic structural equation modeling defined a shared genetic factor mvDED-GI. FUMA annotated peak variants for subsequent gene-set, tissue, and cell enrichment. Transcriptome-wide association study (TWAS) plus fine-mapping prioritized causal genes, and multi-layer expression-, methylation-, and splicing-quantitative trait locus (QTL) analyses dissected regulatory mechanisms of mvDED-GI. Results: DED exhibited moderate-to-high genetic correlations (rg = 0.52–0.56) with the three gastrointestinal conditions; the four-trait common-factor model achieved ideal fitting indices (comparative fit index [CFI] = 0.995 and standardized root mean square residual [SRMR] = 0.032). Thirteen lead SNPs spanning 11 loci and 450 candidate protein-coding genes were detected. Enrichment highlighted glutamatergic receptor and ion channel pathways preferentially expressed in hippocampus and anterior cingulate cortex. Nine high-confidence genes were validated, with RNF123 and P2RY12 highlighted via brain multi-omics QTL data. Conclusions: Our findings confirm a shared genetic susceptibility connecting DED and common gastrointestinal disorders, predominantly governed by central glutamatergic neurotransmission, central pain modulation, and neuroimmune pathways. Translational Relevance: This multivariate genomic research translates genetic findings into clinical value by defining a shared inherited liability across DED and gastrointestinal comorbidities.