Cross-ancestry genome-wide association study for intraocular pressure in 263,134 individuals provides novel insights into glaucoma pathogenesis

Abstract

Purpose : Higher intraocular pressure (IOP) is the cardinal mediating factor for primary open-angle glaucoma (POAG), and lowering IOP is its only proven therapy. The last large-scale genome-wide association study of IOP (IGGC-2018, N=139,555) was restricted to Europeans. We forecast that novel discovery of common IOP-associated variants will increase with larger samples, not plateauing till N=1M. We carried out the largest IOP GWAS to date by including 15 new studies, including non-European cohorts. The full author list is available via Figure 1.

Methods : In addition to IGGC-2018, we included 11 population-based and 4 clinic-based studies. We excluded eyes with previous glaucoma surgery/laser and imputed pre-treatment IOP for eyes using glaucoma drugs by dividing by 0.7. Genotyping, imputation and linear regression association of allege dosage with mean IOP of both eyes were carried out locally by each study. We carried out a fixed-effects meta-analysis of contributing study results.

Results : We included 263,134 participants across cohorts of European, Asian, African and Latino ancestry. We identified 206 genomic regions significantly associated with IOP, half of which were not previously reported for IOP/POAG. The most significant novel locus was in ADAMTS17 (rs72755233; P=2.6x10^-19), a missense polymorphism (Thr490Ile) previously linked to Weil-Marchesani syndrome and cardiac malformations in humans, and a known cause of glaucoma in canines. Association was also significant for rs2393730 in ARID5B (P=3.3x10^-18). Novel genes implicated by our analyses are involved in cardiac and circulatory system development and were significantly enriched for expression in fibroblasts, particularly trabecular meshwork beam cells. Our results explain 13% of IOP variance in UK Biobank, up from 9% in IGGC-2018. A polygenic Cox regression model including variants associated with POAG and cup-disc ratio as well as IOP was strongly associated with age at glaucoma diagnosis in UK Biobank (Hazard Ratio=1.05 per risk score centile; P=4.3x10^-189).

Conclusions : Compared to IGGC-2018, a doubling of sample size has doubled the loci discovered for IOP. These results provide novel insights into IOP regulation and glaucoma risk, and can underpin accurate prediction models for glaucoma onset.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Figure 1: Please scan for full author list