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

(MP). Data Availability. The cryo-EM maps and the refined atomic model of DmSERINC were deposited in the EMDB and wwPDB, respectively, with accession codes EMD-10277 and EMD-10279 and PDB 6SP2. Source data for Figures 4a, 4b, 4c, 4e and for Extended Data Figures 1a, 1c, 1d, 1e, 2b, 3b, 4g-i, 6e-g, are available with the paper online. Author Contributions V.E.P. expressed, purified and characterised DmSERINC, built the atomic model, developed and conducted thermostability assays; V.E.P., P.C., and A.B.-C. prepared and screened cryo-EM grids; A.N. collected all cryo-EM data; V.E.P. and P.C. refined the DmSERINC structure; A.R. and P.C. generated stable cell line for SERINC5 expression, purified and characterised SERINC5 and determined the structure; A.R. conducted thermostability assays on SERINC5 and purified the Fab; P.C. produced mutant SERINC5 constructs; M.P. and C.B. developed and performed assays to measure surface exposure, restriction activity and virion incorporation of SERINC5 variants; W.

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Objective: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. Design: Cross-sectional study. Participants: For the primary analysis, we examined the glaucoma phenotype of 2,154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) including cases recruited from the UK. For replication, we examined an independent cohort of 624 early POAG patients. Methods: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP associated variants and stratified POAG patients into three risk tiers. The lowest and highest quintiles of the score were set as the low and high risk groups respectively and the other quintiles as the intermediate risk group. Main Outcome Measures: Clinical glaucoma phenotype including maximum recorded IOP, age of diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. Results: There was a dose-response relationship between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 (SD 0.62) mmHg than the low genetic risk group (P = 0.006). Compared to the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 (1.0) years (P < 0.001), more family members affected by 0.46 (0.11) members (P < 0.001), and higher rates of incisional surgery (odds ratio 1.5; 95% confidence interval 1.1-2.0; P = 0.007). There was no statistically significant difference in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). Conclusions: The IOP polygenic risk score was positively correlated with maximum IOP, disease severity, need for surgery and number of family members. Genes acting via IOP mediated pathways, when considered in aggregate have clinically important and reproducible implications for glaucoma patients and their close family members.