GWAS for primary angle-closure glaucoma identifies loci related to ocular biometry and morphology

GWAS of primary angle-closure glaucoma have identified eight loci conferring risk in Asian populations. However, it remains unclear whether the genetic risk factors for the disease are consistent across different populations. Here, we present a discovery GWAS for primary angle-closure glaucoma in Europeans using the UK Biobank. We replicate our findings in six independent European populations and compare these results with results from 14 Asian cohorts. Five genomic regions in the discovery cohort are associated at genome-wide significance, including two loci previously identified in Asian cohorts. We next meta-analyse the discovery and replication cohorts to identify six additional novel loci, all previously associated with refractive error. Mendelian randomisation provides evidence for a causal role of shorter axial length and hypermetropic refractive error on primary angle-closure glaucoma. A polygenic risk score derived from the European ancestry meta-analysis demonstrates significant associations with quantitative ocular traits - including a shallower anterior chamber and higher intraocular pressure - in the independent EPIC-Norfolk cohort. Finally, a multi-ancestry meta-analysis of all 21 European and Asian cohorts identifies 12 further novel loci. This work shows that genetic factors associated with a darker iris and hypermetropia confer risk for primary angle-closure glaucoma.