Alex Hewitt1, Stuart MacGregor2, Jue Sheng Ong2, Jiyuan An2, Xikun Han2, Tiger Zhou3, Matthew Law2, Emmanuelle Souzeau3, Kathryn Burdon1, Puya Gharahkhani2, David Mackey4, Jamie Craig3

Purpose: Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide. The aim of this work was to identify novel genes influencing IOP and POAG. Methods: A combined analysis of IOP data from par- ticipants from the UK Biobank (N = 103,914) and previ- ously published data from the International Glaucoma Genetic Consortium (N = 29,578) was performed.
Results: We identified 101 statistically independent genome-wide significant SNPs for IOP, 85 of which had not been previously reported. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, with 53 showing evidence for association after Bonferroni correction (P < 0.05/101). Gene- based tests implicated an additional 22 independent genes for IOP; four were associated with glaucoma following Bonferroni correction (P < 0.05/22), with an additional seven achieving P < 0.05. Pathway analysis revealed a number of previously implicated (extracellular matrix and collagen) and novel (vas- cular development and cell migration) pathways were associated with both IOP and glaucoma. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (OR = 5.6; 95% CI:4.1-7.6) of glaucoma relative to the bottom decile. Within cases, the top decile were diagnosed on aver- age 7 years earlier than the bottom decile. Conclusion: This work sheds new light into the genetic architecture of IOP and glaucoma, both of which are highly heritable. Genetic risk prediction may assist with identifying people at higher risk of POAG.