Janey Wiggs, Jonathan Haines and colleagues identify three new susceptibility loci for primary open-angle glaucoma. The association signals map near genes implicated in ocular development (FOXC1), neurodegeneration (ATXN2) and mitochondrial function (TXNRD2). Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10−11) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10−10); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10−10). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Purpose: We combined finite element (FE) analysis and dynamic magnetic resonance imaging (MRI) to estimate optic nerve head (ONH) strains during horizontal eye movements, and identified factors influencing such strains. We also compared ONH strains (prelamina, lamina cribrosa, and retrolamina strains) induced by eye movements to those induced by IOP. Methods: The ocular globes and orbits of a healthy subject were visualized during horizontal eye movements (up to 13°), using dynamic MRI. A baseline FE model of one eye was reconstructed in the primary gaze position, including details from the orbital and ONH tissues. Finite element-derived ONH strains induced by eye movements were compared to those resulting from an IOP of 50 mm Hg. Finally, a FE sensitivity study was performed, in which we varied the stiffness of all ONH connective tissues, to understand their influence on ONH strains. Results: Our models predicted that, during horizontal eye movements, the optic nerve pulled the ONH posteriorly. Optic nerve head strains following a lateral eye movement of 13° were large and higher than those resulting from an IOP of 50 mm Hg. These results held true even with variations in connective tissue stiffness. We also found that stiff sclerae reduced lamina cribrosa and prelamina strains during eye movements, but stiff optic nerve sheaths significantly increased those strains. Conclusions: Our models predicted high ONH strains during eye movements, which were aggravated with stiffer optic nerve sheaths. Further studies are needed to explore links between ONH strains induced by eye movements and axonal loss in glaucoma.

The relationship between refractive error and glaucoma has been investigated in several clinical trials and population-based studies.^1-4 Most studies have suggested that moderate to high myopia is associated with increased risk of primary open-angle glaucoma (POAG),^5,6 low-tension glaucoma,^7,8 and ocular hypertension.^9-12 In the Blue Mountains Eye Study in Australia, after adjusting for age, sex, and other risk factors, eyes with moderate myopia were 2 times more likely to have POAG.¹³ In the Barbados Eye Study, a myopic refraction was one of several risk factors for POAG in adult black people.^14,15 The Beaver Dam Eye Study showed that, after taking into account the effects of age, sex, and other risk factors, persons with myopia were 60% more likely to have glaucoma than those with emmetropia.¹⁶ In Asian populations, the relationship of myopia and POAG was reported in the Beijing Eye Study in China (significant relationship with high myopia of less than −6 diopters [D])¹⁷ and the Meiktila Eye Study in Myanmar.¹⁸ However, not all studies have found significant relationships; for example, no association between myopia and POAG was found in the Ocular Hypertension Treatment Study.³

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10⁻³³), we observed one SNP showing significant association to POAG (CDC7–TGFBR3 rs1192415, OR_G-allele = 1.13, P_meta = 1.60 × 10⁻⁸). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.