Transcending genome-wide association studies to create useful multi-omic views of glaucoma

Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell loss and functional impairment. It is a clinically heterogeneous disease driven by complex, multilayered molecular mechanisms. High-throughput multi-omic technologies are catalyzing a shift toward integrated multi-omic strategies to define glaucoma trajectory and disentangle its pathophysiology. Genomic, transcriptomic, epigenomic, proteomic, metabolomic, lipidomic, microbiome, and phenomic data can help identify biomarkers, molecular endotypes, and pathways that shape glaucoma susceptibility and progression. In this review, we synthesize the current multi-omic landscape in glaucoma, evaluate the strengths and limitations of each modality, and highlight key challenges in integrative approaches. Lastly, we propose conceptual and methodological frameworks for leveraging multi-omics to define the full spectrum of glaucoma, with a focus on optic nerve integrity, mechanistic insights, and precision medicine, while remaining agnostic to evolving omics technologies.