Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size = −0.045 mm, P = 8.17×10−9). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06–1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45×10−9; 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Glaucoma is the second leading cause of blindness globally characterized by progressive loss of retinal ganglion cells (RGCs) and irreversible visual deficiency. As the most common type of glaucoma, primary open angle glaucoma (POAG) is currently an unmet medical need with limited therapy by lowering intraocular pressure (IOP). However, some patients continue to progress even though their IOP are controlled. Although early diagnosis and prompt treatment are crucial in preventing irreversible visual impairment, there are currently no biomarkers for screening POAG. Metabolomics has the advantages of illustrating the final downstream products of the genome and establishing the closest link to the phenotype. So far, there is no study investigating the metabolomic profiles in both aqueous humor and plasma of POAG patients. Therefore, to explore diagnostic biomarkers, unveil underlying pathophysiology and potential therapeutic strategies, a widely targeted metabolomic approach was applied using ultrahigh-resolution mass spectrometry with C18 liquid chromatography to characterize the metabolomic profiles in both aqueous humor and plasma of 28 POAG patients and 25 controls in our study. Partial least squares-discriminant analysis (PLS-DA) was performed to determine differentially expressed metabolites (DEMs) between POAG and age-matched controls. The area under the receiver operating characteristic curve (AUC) was calculated to assess the prediction accuracy of the DEMs. The correlation of DEMs with the clinical parameters was determined by Pearson correlation, and the metabolic pathways were analyzed using MetaboAnalyst 4.0. PLS-DA significantly separated POAG from controls with 22 DEMs in the aqueous humor and 11 DEMs in the plasma. Additionally, univariate ROC analysis and correlation analysis with clinical parameters revealed cyclic AMP (AUC = 0.87), 2-methylbenzoic acid (AUC = 0.75), 3′-sialyllactose (AUC = 0.73) in the aqueous humor and N-lac-phe (AUC = 0.76) in the plasma as potential biomarkers for POAG. Moreover, the metabolic profiles pointed towards the alteration in the purine metabolism pathway. In conclusion, the study identified potential and novel biomarkers for POAG by crosslinking the metabolomic profiles in aqueous humor and plasma and correlating with the clinical parameters. These findings have important clinical implications given that no biomarkers are currently available for glaucoma in the clinic, and the study provided new insights in exploring diagnostic biomarkers and potential therapeutic strategies of POAG by targeting metabolic pathways.

The treatment of phacoemulsification, intraocular lens implantation, and goniosynechialysis is safe and effective for patients with primary angle-closure glaucoma and cataract.