Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma.

Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, the leading cause of irreversible blindness worldwide. IOP is also the only modifiable risk factor for glaucoma. Previous genome-wide association studies have established the contribution of common genetic variants to IOP. The role of rare variants for IOP was unknown. Using whole exome sequencing data from 110,260 participants in the UK Biobank (UKB), we conducted the largest exome-wide association study of IOP to date. In addition to confirming known IOP genes, we identified 40 novel rare-variant genes for IOP, such as BOD1L1, ACAD10 and HLA-B, demonstrating the power of including and aggregating rare variants in gene discovery. About half of these IOP genes are also associated with glaucoma phenotypes in UKB and the FinnGen cohort. Six of these genes, i.e. ADRB1, PTPRB, RPL26, RPL10A, EGLN2, and MTOR, are drug targets that are either established for clinical treatment or in clinical trials. Furthermore, we constructed a rare-variant polygenic risk score and showed its significant association with glaucoma in independent participants (n = 312,825). We demonstrated the value of rare variants to enhance our understanding of the biological mechanisms regulating IOP and uncovered potential therapeutic targets for glaucoma.