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

Abstract

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: ). 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.