{"title":"通过多性状和多组学整合确定青光眼候选药物靶点的遗传优先级。","authors":"Jianqi Chen, Yangjiani Li, Yingting Zhu, Zhidong Li, Shitong Huang, Wenzhi Huang, Yuyao Ling, Jingying Liang, Yunxia Leng, Yehong Zhuo","doi":"10.1186/s40662-025-00442-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Glaucoma causes permanent blindness. Current treatments have limited effectiveness, necessitating novel therapeutic strategies. We aimed to identify potential drug targets for glaucoma by integrating multi-trait and multi-omic analyses.</p><p><strong>Methods: </strong>We sourced druggable gene expression and protein abundance summary-level data from quantitative trait loci studies, and genetic associations with glaucoma from a large-scale multi-trait analysis. We employed proteome and transcriptome Mendelian randomization (MR) and colocalisation to identify potential therapeutic targets, glaucoma endophenotype MR to explore the potential mechanisms of identified associations, and phenome-wide MR to investigate possible adverse effects of candidate targets.</p><p><strong>Results: </strong>We identified CPXM1 and FLT4 as tier 1; INSR as tier 2; and CPZ and PXDN as tier 3 druggable genes. Genetically predicted higher levels of CPXM1 [odds ratio (OR): 0.86, 95% confidence interval (CI): 0.81-0.91, P<sub>FDR</sub> < 0.001], FLT4 (OR: 0.74, 95% CI: 0.64 - 0.87, P<sub>FDR</sub> = 0.033), INSR (OR: 0.58, 95% CI: 0.43 - 0.78, P<sub>FDR</sub> = 0.042), and CPZ (OR: 0.55, 95% CI: 0.40 - 0.74, P<sub>FDR</sub> = 0.033) were associated with decreased glaucoma risk while those of PXDN (OR: 1.33, 95% CI: 1.15 - 1.54, P<sub>FDR</sub> = 0.033) with increased risk. The associations for CPXM1 (OR: 0.53, 95% CI: 0.39 - 0.73, P < 0.001) and FLT4 (OR: 0.86, 95% CI: 0.78 - 0.95, P = 0.005) were confirmed transcriptome-wide and colocalisation was confirmed for CPXM1 [posterior probability H4 (PPH<sub>4</sub>) = 0.940], FLT4 (PPH<sub>4</sub> = 0.701), and INSR (PPH<sub>4</sub> = 0.706). The protective effects of CPXM1 and CPZ may be attributed to intraocular pressure-lowering activities. The risk associated with PXDN is due to its involvement in glaucomatous neuropathy. No significant adverse effects were identified.</p><p><strong>Conclusions: </strong>This study provides novel insights into glaucoma pathophysiology and promotes pharmaceutical target innovation.</p>","PeriodicalId":12194,"journal":{"name":"Eye and Vision","volume":"12 1","pages":"26"},"PeriodicalIF":4.0000,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243406/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genetic prioritisation of candidate drug targets for glaucoma through multi-trait and multi-omics integration.\",\"authors\":\"Jianqi Chen, Yangjiani Li, Yingting Zhu, Zhidong Li, Shitong Huang, Wenzhi Huang, Yuyao Ling, Jingying Liang, Yunxia Leng, Yehong Zhuo\",\"doi\":\"10.1186/s40662-025-00442-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Glaucoma causes permanent blindness. Current treatments have limited effectiveness, necessitating novel therapeutic strategies. We aimed to identify potential drug targets for glaucoma by integrating multi-trait and multi-omic analyses.</p><p><strong>Methods: </strong>We sourced druggable gene expression and protein abundance summary-level data from quantitative trait loci studies, and genetic associations with glaucoma from a large-scale multi-trait analysis. We employed proteome and transcriptome Mendelian randomization (MR) and colocalisation to identify potential therapeutic targets, glaucoma endophenotype MR to explore the potential mechanisms of identified associations, and phenome-wide MR to investigate possible adverse effects of candidate targets.</p><p><strong>Results: </strong>We identified CPXM1 and FLT4 as tier 1; INSR as tier 2; and CPZ and PXDN as tier 3 druggable genes. Genetically predicted higher levels of CPXM1 [odds ratio (OR): 0.86, 95% confidence interval (CI): 0.81-0.91, P<sub>FDR</sub> < 0.001], FLT4 (OR: 0.74, 95% CI: 0.64 - 0.87, P<sub>FDR</sub> = 0.033), INSR (OR: 0.58, 95% CI: 0.43 - 0.78, P<sub>FDR</sub> = 0.042), and CPZ (OR: 0.55, 95% CI: 0.40 - 0.74, P<sub>FDR</sub> = 0.033) were associated with decreased glaucoma risk while those of PXDN (OR: 1.33, 95% CI: 1.15 - 1.54, P<sub>FDR</sub> = 0.033) with increased risk. The associations for CPXM1 (OR: 0.53, 95% CI: 0.39 - 0.73, P < 0.001) and FLT4 (OR: 0.86, 95% CI: 0.78 - 0.95, P = 0.005) were confirmed transcriptome-wide and colocalisation was confirmed for CPXM1 [posterior probability H4 (PPH<sub>4</sub>) = 0.940], FLT4 (PPH<sub>4</sub> = 0.701), and INSR (PPH<sub>4</sub> = 0.706). The protective effects of CPXM1 and CPZ may be attributed to intraocular pressure-lowering activities. The risk associated with PXDN is due to its involvement in glaucomatous neuropathy. No significant adverse effects were identified.</p><p><strong>Conclusions: </strong>This study provides novel insights into glaucoma pathophysiology and promotes pharmaceutical target innovation.</p>\",\"PeriodicalId\":12194,\"journal\":{\"name\":\"Eye and Vision\",\"volume\":\"12 1\",\"pages\":\"26\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-07-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243406/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Eye and Vision\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40662-025-00442-4\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Eye and Vision","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40662-025-00442-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Genetic prioritisation of candidate drug targets for glaucoma through multi-trait and multi-omics integration.
Background: Glaucoma causes permanent blindness. Current treatments have limited effectiveness, necessitating novel therapeutic strategies. We aimed to identify potential drug targets for glaucoma by integrating multi-trait and multi-omic analyses.
Methods: We sourced druggable gene expression and protein abundance summary-level data from quantitative trait loci studies, and genetic associations with glaucoma from a large-scale multi-trait analysis. We employed proteome and transcriptome Mendelian randomization (MR) and colocalisation to identify potential therapeutic targets, glaucoma endophenotype MR to explore the potential mechanisms of identified associations, and phenome-wide MR to investigate possible adverse effects of candidate targets.
Results: We identified CPXM1 and FLT4 as tier 1; INSR as tier 2; and CPZ and PXDN as tier 3 druggable genes. Genetically predicted higher levels of CPXM1 [odds ratio (OR): 0.86, 95% confidence interval (CI): 0.81-0.91, PFDR < 0.001], FLT4 (OR: 0.74, 95% CI: 0.64 - 0.87, PFDR = 0.033), INSR (OR: 0.58, 95% CI: 0.43 - 0.78, PFDR = 0.042), and CPZ (OR: 0.55, 95% CI: 0.40 - 0.74, PFDR = 0.033) were associated with decreased glaucoma risk while those of PXDN (OR: 1.33, 95% CI: 1.15 - 1.54, PFDR = 0.033) with increased risk. The associations for CPXM1 (OR: 0.53, 95% CI: 0.39 - 0.73, P < 0.001) and FLT4 (OR: 0.86, 95% CI: 0.78 - 0.95, P = 0.005) were confirmed transcriptome-wide and colocalisation was confirmed for CPXM1 [posterior probability H4 (PPH4) = 0.940], FLT4 (PPH4 = 0.701), and INSR (PPH4 = 0.706). The protective effects of CPXM1 and CPZ may be attributed to intraocular pressure-lowering activities. The risk associated with PXDN is due to its involvement in glaucomatous neuropathy. No significant adverse effects were identified.
Conclusions: This study provides novel insights into glaucoma pathophysiology and promotes pharmaceutical target innovation.
期刊介绍：
Eye and Vision is an open access, peer-reviewed journal for ophthalmologists and visual science specialists. It welcomes research articles, reviews, methodologies, commentaries, case reports, perspectives and short reports encompassing all aspects of eye and vision. Topics of interest include but are not limited to: current developments of theoretical, experimental and clinical investigations in ophthalmology, optometry and vision science which focus on novel and high-impact findings on central issues pertaining to biology, pathophysiology and etiology of eye diseases as well as advances in diagnostic techniques, surgical treatment, instrument updates, the latest drug findings, results of clinical trials and research findings. It aims to provide ophthalmologists and visual science specialists with the latest developments in theoretical, experimental and clinical investigations in eye and vision.
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