Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide and their prevalence is rising, largely due to cultural and environmental changes. Genetic investigation is a valuable tool to better understand the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 542,934 European participants and identified 336 novel genetic loci associated with refractive error that explain an additional 4.6% of spherical equivalent heritability, or an improvement by a third over the previous estimates. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may make possible predicting refractive error and the development of personalized myopia prevention strategies in the future.

Glaucoma is the leading cause of irreversible blindness globally.1 Despite its gravity, the disease is frequently undiagnosed in the community.2 Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG).3,4 Here we present a meta-analysis of 139,555 European participants that identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were associated with glaucoma in an independent cohort, 14 of which at a Bonferroni-corrected threshold. Regression-based glaucoma prediction models had an area under Receiving Operator Characteristic curve (AUROC) of 0.76 in USA NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from UK Biobank. Genetic prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

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Purpose: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion celleinner plexiform layer (GCIPL) thicknesses in a large cohort.Design: Cross-sectional study.Participants: We included 42 044 participants in the UK Biobank. The mean age was 56 years. Methods: Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc.Main Outcome Measures: Thicknesses of mRNFL, GCC, and GCIPL.Results: We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: e0.46 mm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61e0.30]; P ¼ 1.1Â10 e8 ), greater social deprivation (most significant for GCIPL: e0.28 mm for most deprived quartile compared with least deprived quartile [95% CI, e0.42 to e0.14]; P ¼ 6.6Â10 e5 ), lower educational attainment (most significant for mRNFL: e0.36 mm for less than O level compared with degree level [95% CI, e0.45 to 0.26]; P ¼ 2.3Â10 e14 ), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: e1.65 mm [95% CI, e1.86 to e1.43]; P ¼ 2.4Â10 e50 ). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (e0.04 mm/mmHg [95% CI, e0.05 to e0.03]; P ¼ 4.0Â10 e10 ) and was not associated significantly with mRNFL (0.00 mm/mmHg [95% CI, e0.01 to 0.01]; P ¼ 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). Conclusions:The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.