Extended Data Fig. 1: Study design.

We applied the multi-trait analysis of GWAS (MTAG) algorithm to datasets of European descent (unless otherwise specified). a, We applied MTAG to four datasets (glaucoma case-control GWAS from the UKBB; GWAS meta-analysis of intraocular pressure (IOP) from the International Glaucoma Genetics Consortium (IGGC) and the UKBB; Vertical cup-disc ratio (VCDR) GWAS data that was either adjusted for vertical disc diameter (VDD) in the UKBB dataset; or not adjusted for VDD in the IGGC). Novel variants identified through this analysis were then confirmed in two independent data sets: an Australasian cohort of advanced glaucoma (ANZRAG) and a consortium of cohorts from the United States (NEIGHBORHOOD). The clinical significance of the PRS derived from the MTAG analysis was validated in independent samples: first, in advanced glaucoma cases (ANZRAG and samples from Southampton/Liverpool in the UK), and second, in a prospectively monitored clinical cohort with early manifest glaucoma (PROGRESSA). b, Prediction in BMES, where we removed the IGGC VCDR and IGGC IOP GWAS from the training datasets, given that they contain BMES data. c, Prediction in the UKBB glaucoma and ICD-10 POAG cases. Here we removed all glaucoma cases and 3,000 controls with IOP/VCDR measurements as well as their relatives from UKBB VCDR/IOP GWAS. We also evaluated the performance of PRS in non-European ancestry (192 cases and 6,841 controls of South Asian ancestry in UKBB). d, Cumulative risk of glaucoma in UKBB. For the analysis of MYOC p.Gln368Ter carriers (n = 965; cases = 72; controls = 893), participants were stratified into tertiles of PRS. We also examined cumulative risk of glaucoma in the general population (that is in MYOC p.Gln368Ter non-carriers, n = 381,196; cases = 7,381; controls = 373,815) stratifying by deciles of the PRS. The discovery and testing datasets were designed to derive the PRS with no sample overlap (Supplementary Note).