Large-Scale Proteome-Wide Mendelian Randomization Identifies Novel Proteins for Glaucoma and Related Traits  

作　　者：Ziyu Zhu Shaopeng Yang Hubert Yuenhei Lao Xiaoying Zhong Huangdong Li Riqian Liu Wenyong Huang Wei Wang 朱梓瑜;杨少鹏;Hubert Yuenhei Lao;钟晓莹;李黄东;刘日乾;黄文勇;王伟(State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangdong Provincial Clinical Research Center for Ocular Diseases,Guangzhou,China;+4 Medical Doctor Program.Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing,China;Hainan Eye Hospital and Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Haikou,China)

机构地区：[1]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science,Guangdong Provincial Clinical Research Center for Ocular Diseases,Guangzhou,China [2]+4 Medical Doctor Program.Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing,China [3]Hainan Eye Hospital and Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Haikou,China

出　　处：《Eye Science》2024年第2期93-114,共22页眼科学报（英文版）

基　　金：supported by the Hainan Province Clinical Medical Center,the National Natural Science Foundation of China(82171084,82371086).

摘　　要：Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.POAG data were sourced from the largest FinnGen study,comprising 8,530 DR cases and 391,275 European controls.A two-sample MR analysis,supplemented by bidirectional MR,Bayesian co-localization analysis,and phenotype scanning,was conducted to examine the causal relationships between plasma proteins and POAG.The analysis was validated by identifying associations between plasma proteins and POAG-related traits,including intraocular pressure(IOP),retinal nerve fibre layer(RNFL),and ganglion cell and inner plexiform layer(GCIPL).By searching druggable gene lists,the ChEMBL database,and the ClinicalTrials.gov database,the druggability and clinical development activity of the identified proteins were systematically evaluated.Results:Eighteen proteins were identified with significant associations with POAG risk after multiple comparison adjustments.The ORs per standard deviation increase in protein levels ranged from 0.39(95%CI:0.24–0.62;P=7.70×10^(-5))for phospholipase C gamma 1(PLCG1)to 1.29(95%CI:1.16–1.44;P=6.72×10^(-6))for nidogen-1(NID1).Bidirectional MR indicated that reverse causality did not interfere with the results of the main MR analyses.Five proteins exhibited strong co-localization evidence(PH4≥0.8):protein sel-1 homolog 1(SEL1L),tyrosine-protein kinase receptor UFO(AXL),nidogen-1(NID1)and FAD-linked sulfhydryl oxidase ALR(GFER)were negatively associated with POAG risk,while roundabout homolog 1(ROBO1)showed a positive association.The phenotype scanning did not reveal any confounding factors between pQTLs and POAG.Further,validation analyses identified nine proteins causally related to POAG traits,with five proteins includin

关 键 词：PROTEOME Mendelian Randomization Primary Open-Angle Glaucoma GCIPL Thickness RNFL Thickness Intraocular Pressure 

分 类 号：R775[医药卫生—眼科]