Whole-genome sequencing study of 674,082 individuals identifies rare variants and genes associated with glaucoma

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. Here, we report the largest whole-genome sequencing study of POAG to date, analyzing 464,778 UK Biobank participants (18,171 cases) and replicating findings in 209,304 All of Us participants (17,167 cases), with additional supporting evidence from FinnGen and the Million Veteran Program. We identified 29 novel genome-wide significant rare-variant associations, including variants in FMO3, FMO4, PRRC2C, and METTL13, while confirming established associations in MYOC and OPTN. Gene-based testing identified significant aggregation of rare variants in six genes, including DDR2, LTBP2, and MTOR. AlphaGenome revealed that many rare noncoding variants exhibit predicted regulatory effects. Expression analyses demonstrated that most identified genes are expressed in glaucoma-relevant ocular tissues. Notably, four identified genes, MTOR, DDR2, LYN, and MAPT, are established drug targets with existing therapeutics for other indications, suggesting potential opportunities for repurposing. Together, these findings advance our understanding of POAG genetic architecture and provide a foundation for therapeutic prioritization. A whole-genome sequencing study of Primary open-angle glaucoma (POAG) identifying 29 novel genome-wide significant rare-variant associations, including variants in FMO3, FMO4, PRRC2C, and METTL13, while confirming established associations in MYOC and OPTN.