Plasma Proteogenomics Identifies RGMB as a Candidate for Primary Open-Angle Glaucoma Detected Only in East Asians
- 1Ehime university
Abstract
Purpose: In 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. Methods: We 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. Results: Of 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 (Cochran's Q P = 0.0036; I2 = 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-beta2. Conclusions: This 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.
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BibTeX
@misc{okuno2026plasma,
title = {{Plasma Proteogenomics Identifies RGMB as a Candidate for Primary Open-Angle Glaucoma Detected Only in East Asians}},
author = {S. OKUNO and S. MIZOUE and K. NAMIGUCHI and M. YUKAWA and A. SHIRAISHI},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.26366459},
url = {https://www.medrxiv.org/content/10.64898/2026.10.26.26366459v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Plasma Proteogenomics Identifies RGMB as a Candidate for Primary Open-Angle Glaucoma Detected Only in East Asians
AU - S. OKUNO
AU - S. MIZOUE
AU - K. NAMIGUCHI
AU - M. YUKAWA
AU - A. SHIRAISHI
PY - 2026
DA - 2026/10/26
PB - medRxiv
DO - 10.64898/2026.10.26.26366459
UR - https://www.medrxiv.org/content/10.64898/2026.10.26.26366459v1
AB - Purpose: In 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. Methods: We 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. Results: Of 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 (Cochran's Q P = 0.0036; I2 = 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-beta2. Conclusions: This 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.
ER -