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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 using multi-omic analysis. SPATA20 emerges as a significant gene associated with retinal nerve fiber layer thickness in glaucoma.
Area of Science:
- Genetics and Ophthalmology
- Mitochondrial Biology
- Systems Biology
Background:
- Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness characterized by retinal ganglion cell loss.
- Mitochondrial dysfunction is increasingly implicated in the pathogenesis of POAG.
- Understanding the genetic basis and regulatory mechanisms of mitochondrial dysfunction in POAG is crucial for developing effective treatments.
Purpose of the Study:
- To identify mitochondrial dysfunction-related genes involved in POAG.
- To elucidate the regulatory mechanisms underlying these genes.
- To explore the association of these genes with POAG and related ocular traits such as intraocular pressure (IOP) and retinal layer thickness.
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 were analyzed alongside mitochondrial gene data.
- Bayesian colocalization was used to confirm shared causal variants across omics datasets, and SPATA20 expression was validated in a mouse glaucoma model.
Main Results:
- The SMR analysis identified 64 mitochondrial genes associated with POAG or related traits, including ALDH18A1 for POAG and MRPL55 for macular retinal nerve fiber layer (mRNFL) thickness.
- eQTL analysis highlighted MRPL20, SLC25A26, ALAS1, and GLYCTK for POAG; ACAD10 for IOP; and ALDH6A1, GRPEL2, YARS2, TIMM21, TIMM29, LARS2, and METAP1D for related traits.
- SPATA20 was consistently supported across all three omics layers, showing a negative association with mRNFL and upregulation in the ganglion cell layer of mouse retinas.
Conclusions:
- Multi-omic SMR analysis effectively highlights mitochondrial genes implicated in POAG and associated ocular parameters.
- The study nominates SPATA20 as a significant cross-omics signal potentially involved in glaucoma pathogenesis, particularly concerning mRNFL.
- These findings provide valuable genetic insights into mitochondrial dysfunction in POAG and suggest SPATA20 as a potential therapeutic target.
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