Multivariate GWAS Analysis Reveals a Common Genetic Factor Linking Dry Eye Disease to Gastrointestinal Comorbidities
4 affiliations
- 1Department of Ophthalmology, Zigong First People's Hospital, Zigong, Sichuan, People's Republic of China
- 2Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China
- 3Department of Pathology, Deyang People's Hospital, Deyang, Sichuan, People's Republic of China
- 4Department of Ophthalmology, Jinan Third People's Hospital, Jinan, Shandong, People's Republic of China
Abstract
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.
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BibTeX
@article{li2026multivariate,
title = {{Multivariate GWAS Analysis Reveals a Common Genetic Factor Linking Dry Eye Disease to Gastrointestinal Comorbidities}},
author = {Gangyi Li and Jie Lin and Shuai Tang and Yuke Wang},
journal = {Translational Vision Science \& Technology},
year = {2026},
month = oct,
doi = {10.1167/tvst.15.10.32},
url = {https://doi.org/10.1167/tvst.15.10.32},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Multivariate GWAS Analysis Reveals a Common Genetic Factor Linking Dry Eye Disease to Gastrointestinal Comorbidities
AU - Gangyi Li
AU - Jie Lin
AU - Shuai Tang
AU - Yuke Wang
PY - 2026
DA - 2026/10/22
JO - Translational Vision Science & Technology
DO - 10.1167/tvst.15.10.32
UR - https://doi.org/10.1167/tvst.15.10.32
AB - 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.
SN - 2164-2591
ER -