Multi-omics Mendelian randomization analysis identifies SPATA20 as a cross-omic target in primary open angle glaucoma

To investigate the mitochondrial dysfunction-related genes and their regulatory mechanisms involved in primary open angle glaucoma (POAG), which is characterized by retinal ganglion cell loss.

Multi-omic summary-data-based Mendelian randomization (SMR) integrating methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) were performed for mitochondrial genes with genome-wide association studies (GWAS) of POAG and related traits [intraocular pressure (IOP), macular retinal nerve fiber layer thickness (mRNFL), and macular ganglion cell-inner plexiform layer thickness (mGCIPL)]. Bayesian colocalization was used to support shared causal variants and to define evidence tiers across omics. SPATA20 expression was assessed in a mouse glaucoma model by immunofluorescence and Western blot.

SMR identified 64 mitochondrial genes associated with at least one outcome, including ALDH18A1 for POAG and MRPL55 for mRNFL. eQTL analysis revealed 212 associations, prioritizing MRPL20, SLC25A26, ALAS1, and GLYCTK for POAG, ACAD10 for IOP, ALDH6A1, GRPEL2, and YARS2 for mRNFL, and ALDH6A1, TIMM21, TIMM29, LARS2, and METAP1D for mGCIPL. The pQTL layer implicated 21 proteins, including BOLA1 for POAG. Cross-omic synthesis supported 18 genes by ≥2 omics layers. SPATA20 was supported by all three layers, showed a consistent negative association with mRNFL, and in mice was transiently upregulated in retina, with expression in the ganglion cell layer.

Multi-omic SMR with colocalization highlights mitochondrial genes for POAG and related traits and nominates SPATA20 as a leading cross-omics signal for mRNFL.