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

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.

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.

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.

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.

This multivariate genomic research translates genetic findings into clinical value by defining a shared inherited liability across DED and gastrointestinal comorbidities.