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Multi-omics Mendelian randomization analysis identifies SPATA20 as a cross-omic target in primary open angle glaucoma
Zhi-Kun Ouyang1, Ling Ge1, Shi-Tong Yu2
1Shanghai Eye Diseases Prevention & Treatment Center/Shanghai Eye Hospital, School of Medicine, Tongji University, National Clinical Research Center for Eye Diseases, Shanghai Engineering Research Center of Precise Diagnosis and Treatment of Eye Diseases, Shanghai 200041, China.
International Journal of Ophthalmology
|July 29, 2026
Summary
This study identifies key mitochondrial genes linked to primary open angle glaucoma (POAG) and related eye conditions. SPATA20 emerges as a significant gene associated with retinal nerve fiber layer thickness in glaucoma.
Area of Science:
- Ophthalmology and Genetics
- Molecular Biology
- Genomics
Background:
- Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness.
- Retinal ganglion cell loss is a hallmark of POAG, but the underlying genetic factors and regulatory mechanisms, particularly involving mitochondrial dysfunction, remain incompletely understood.
- Understanding these mechanisms is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate mitochondrial dysfunction-related genes implicated in POAG.
- To elucidate the regulatory mechanisms governing these genes.
- To identify potential therapeutic targets for POAG and related ophthalmic traits.
Main Methods:
- Multi-omic summary-data-based Mendelian randomization (SMR) was employed, integrating methylation (mQTL), expression (eQTL), and protein (pQTL) quantitative trait loci data.
- Genome-wide association studies (GWAS) for POAG and related traits (intraocular pressure, macular retinal nerve fiber layer thickness, macular ganglion cell-inner plexiform layer thickness) were analyzed.
- Bayesian colocalization and experimental validation in a mouse glaucoma model were used to confirm findings.
Main Results:
- The SMR analysis identified 64 mitochondrial genes associated with POAG or related traits.
- Several genes, including ALDH18A1 (POAG), MRPL55 (mRNFL), MRPL20, SLC25A26, ALAS1, GLYCTK (POAG), and BOLA1 (POAG), were highlighted.
- SPATA20 showed strong cross-omics support and was validated in a mouse model, exhibiting transient upregulation in the retina.
Conclusions:
- Multi-omic SMR combined with colocalization effectively identifies mitochondrial genes relevant to POAG and associated traits.
- SPATA20 is nominated as a significant cross-omics signal for macular retinal nerve fiber layer thickness, a key indicator in glaucoma progression.
- These findings provide novel insights into the genetic architecture of POAG and suggest SPATA20 as a potential therapeutic target.
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