New insights into genetic comorbidity mechanisms: type 2 diabetes and primary open-angle glaucoma.

IF 2 Q2 OPHTHALMOLOGY

BMJ Open Ophthalmology Pub Date : 2025-07-16 DOI:10.1136/bmjophth-2025-002219

Yixu Wang, Ye Tian, Yumeng Quan, Shuyan Zhou, Yufei Dang, Xiaoxia Zhang, Cheng Pei

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引用次数: 0

Abstract

Aims: To investigate the shared genetic mechanisms between type 2 diabetes (T2D) and primary open-angle glaucoma (POAG). Using large-scale genome-wide association study (GWAS) data, we performed single nucleotide polymorphism (SNP) level analysis to detect pleiotropic variants and loci, paired eQTL mapping analysis and gene-level analysis to identify candidate pleiotropic genes. In addition, Mendelian randomisation (MR) analysis was performed to assess causal associations.

Materials and methods: We used POAG GWAS data from Finngen (9565 cases and 430 250 controls) and T2D GWAS data from 55 555 European ancestry samples. We used Linkage Disequilibrium SCore (LDSC) regression to assess the genetic association between T2D and POAG and further used PLeiotropic Analysis under the COmposite null hypothesis (PLACO) to identify shared genetic variants between paired traits. Finally, we further used MR analysis to explore the causal association between T2D and POAG at the genetic level.

Results: The LDSC results and MR analysis revealed that the T2D effect was significantly higher than that of the POAG (OR=1.09, 95% CI 1.03 to 1.14, p=1.50×10^-3). The PLACO property analysis determined that the T2D sum POAG shared 178 individual SNPs, separate localisation of 79 individual causes. The five most popular choices are based on the effectiveness of CCND2, SVEP1, ST6GAL1, TCF7L2 and HMGA2. expression quantitative trait loci mapping further revealed 36 genes with regulatory roles in optic nerve-related brain tissues. Functional enrichment analyses indicated that these pleiotropic genes are involved in neurodevelopmental, neuroprotective and metabolic pathways, with tissue-specific enrichment observed in neural, pancreatic, adipose and retinal tissues. It is possible to present the main comorbid mechanisms of T2D and POAG.

Conclusions: Our study provides new insights into the aetiology and pathogenesis of T2D and POAG at the genetic level.

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遗传共病机制的新见解：2型糖尿病和原发性开角型青光眼。

目的：探讨2型糖尿病（T2D）与原发性开角型青光眼（POAG）的共同遗传机制。利用大规模全基因组关联研究（GWAS）数据，我们进行了单核苷酸多态性（SNP）水平分析以检测多效性变异和位点，配对eQTL定位分析和基因水平分析以确定候选多效性基因。此外，还进行了孟德尔随机化（MR）分析以评估因果关系。材料和方法：我们使用来自Finngen的POAG GWAS数据（9565例和430250例对照）和来自55555份欧洲血统样本的T2D GWAS数据。我们使用连锁不平衡评分（LDSC）回归来评估T2D和POAG之间的遗传关联，并进一步使用复合零假设（PLACO）下的多效性分析（PLeiotropic Analysis）来确定配对性状之间的共享遗传变异。最后，我们进一步使用MR分析在遗传水平上探索T2D和POAG之间的因果关系。结果：LDSC结果和MR分析显示，T2D效应显著高于POAG （OR=1.09, 95% CI 1.03 ~ 1.14, p=1.50×10-3）。PLACO特性分析确定T2D和POAG共有178个snp， 79个个体原因的单独定位。最受欢迎的五个选择是基于CCND2、SVEP1、ST6GAL1、TCF7L2和HMGA2的有效性。表达数量性状位点定位进一步揭示了视神经相关脑组织中36个具有调控作用的基因。功能富集分析表明，这些多效性基因参与神经发育、神经保护和代谢途径，并在神经、胰腺、脂肪和视网膜组织中观察到组织特异性富集。有可能提出T2D和POAG的主要合并症机制。结论：本研究为T2D和POAG的病因和发病机制在遗传水平上提供了新的认识。

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