Multi-omics Mendelian randomisation reveals distinct molecular drivers of pathological myopia complications vs simple myopia.

BACKGROUND

Pathological myopia complications are leading causes of irreversible blindness, yet the molecular mechanisms distinguishing them from simple myopia remain poorly understood. We aimed to compare the molecular profiles associated with pathological myopia complications and simple myopia using a multi-omics Mendelian randomisation (MR) framework.

METHODS

Using circulating protein quantitative trait loci data from the INTERVAL study, plasma metabolite genome-wide association study (GWAS) data from the Nightingale Health - UK Biobank initiative and outcome GWAS data for four complication endpoints and myopia from FinnGen R12, together with self-reported myopia from UK Biobank, we performed a two-sample multi-omics MR study. Molecules were classified as complication-specific, myopia-specific, or shared. We performed sensitivity analyses using MR-Egger, weighted median, Steiger directionality, and reverse MR, and assessed classification robustness through threshold-sensitivity and instrument-stratification analyses.

RESULTS

We identified 872 reliable associations (712 protein and 160 metabolite pairs). Complication-specific proteins (n = 387) outnumbered shared ones (n = 55) by seven to one; similarly, 51 metabolites were complication-specific vs. 9 shared. Six lipoprotein lipid ratio-myopia associations survived false discovery rate (FDR) correction (FDR<0.05), all exclusive to simple myopia. Complication-specific proteins were enriched in axon guidance (adjusted P = 2.0 × 10-6), proteoglycan biosynthesis, and cytokine-cytokine receptor interaction pathways. No robust reverse causation was detected. Top complication-specific targets included endothelin-converting enzyme 1 (odds ratio (OR) = 0.796; P = 4.87 × 10-5) for retinal detachment with break, vascular endothelial growth factor receptor 2 (OR = 1.441; P = 4.94 × 10-4) for retinoschisis, and secreted frizzled-related protein 2 (OR = 1.347; P = 1.41 × 10-4).

CONCLUSIONS

Our analysis indicates that molecular drivers of pathological myopia complications are largely distinct from those of simple myopia, with complication-specific targets enriched in neuronal guidance, extracellular matrix metabolism, and inflammatory signalling. These findings may inform therapeutic strategies aimed at preventing the sight-threatening consequences of myopia.