Plasma Proteogenomics Identifies RGMB as a Candidate for Primary Open-Angle Glaucoma Detected Only in East Asians

PurposeIn East Asians most primary open-angle glaucoma (POAG) occurs at statistically normal intraocular pressure (IOP). We sought plasma proteins linked to POAG through genetic signal not shared with IOP. MethodsWe integrated the BioBank Japan POAG GWAS with a Japanese plasma pQTL resource (Nagahama; SomaScan v4) using SMR/HEIDI and colocalization against POAG and IOP datasets, including a Genomic-SEM-derived non-IOP POAG component, adding a symmetric proteome-wide cross-ancestry colocalization, fine-mapping and multi-signal colocalization of the RGMB region, a formal heterogeneity test, and expression mapping in retina and trabecular meshwork. ResultsOf 679 plasma proteins, four colocalized with POAG in East Asians only, five in Europeans only, none in both. SMR nominated RGMB as a suggestive risk factor (b_SMR = +0.277; HEIDI P > 0.05; PP4 = 0.684; rs1037599); none survived Bonferroni correction. RGMB did not colocalize with European IOP, a European non-IOP POAG component, or European POAG on the same platform, despite a common, directionally consistent pQTL instrument. Multi-signal colocalization reproduced both the East Asian signal and the European null. The per-allele POAG effect differed between ancestries (Cochrans Q P = 0.0036; I{superscript 2} = 88%), the better-powered European data excluding an effect of East Asian magnitude. RGMB and its receptors were expressed in trabecular meshwork cells and unchanged by TGF-{beta}2. ConclusionsThis triangulation nominates the RGMB-neogenin-BMP axis as a POAG candidate detected in East Asians but not Europeans, which does not colocalize with IOP-related traits. The findings are exploratory; ancestry-matched replication and functional validation are required.