The Genetic Architecture of Diabetic Retinopathy

糖尿病视网膜病变的遗传结构

• 批准号: 10605816
• 负责人: Joseph H Breeyear
• 金额: $ 3.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605816
• 关键词: Address; Adult; Blindness; Blood-Retinal Barrier; Chronic Disease; Clinical Management; Cohort Studies; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Dyslipidemias; Electronic Medical Records and Genomics Network; Environment; Etiology; Eye; Gene Expression; Genes; Genetic; Genome; Genotype; Heart; Homeostasis; Hypertension; Individual; Insulin; Insulin Resistance; Kidney; Knowledge; Linkage Disequilibrium; Literature; Logistic Regressions; Meta-Analysis; Methods; Microvascular Dysfunction; Modeling; Monitor; National Eye Institute; Organ; Outcome; Participant; Patients; Performance; Phenotype; Predisposition; Prevalence; Public Health; Regression Analysis; Reporting; Resources; Retina; Risk; Risk Factors; Sample Size; Severities; Structure; System; Testing; Tissues; Training; Type 2 diabetic; Veterans; Work; clinical decision-making; clinical risk; diabetic; genetic architecture; genetic risk factor; genetic variant; genome wide association study; glucose metabolism; glycemic control; high body mass index; high risk; improved; multi-ethnic; neovascularization; polygenic risk score; predictive modeling; prevent; programs; racial population; screening; statistics; trait; transcriptome

The Genetic Architecture of Diabetic Retinopathy Project Summary/Abstract Diabetic retinopathy (DR) is the leading cause of vision loss and preventable blindness in adults, afflicting an estimated 93 million individuals worldwide. As the global prevalence of diabetes mellitus (DM) rises, the global prevalence of diabetic retinopathy will also rise. The eye is highly susceptible to damage from DM due to the delicate structures and intricate control of homeostasis in the ocular environment. DR has long been recognized as a microvascular disease triggered by the breakdown of the blood-retinal barrier and neovascularization in the retina. The course of diabetic disease and severity of sequelae vary substantially between cases, and the cause for this variability is not explained well by known risk factors. Several genome- wide association studies (GWAS) of DR have been completed, and while a modest number of significant loci have been reported only a single locus has been significantly associated with DR after a replication. These studies were conducted in collaborative consortia of cohort studies and the largest study to date included 22,279 cases and 23,977 diabetic controls. We will leverage the previous studies in combination with resources from the Million Veteran Program (MVP), BioVU, and the eMERGE Network (an estimated 77,518 cases, 133,295 type II diabetic controls) to test the hypothesis that common genetic variants are associated with DR in the largest multi-ethnic GWAS to date. AIM 1. We will combine evidence for association from logistic regression analysis of DR-SNP relationships across the resources described above using inverse variance-weighted fixed effects meta-analyses, both within and across racial groups. The majority of previous studies focused on detecting SNP-phenotype associations and did not evaluate regulatory genetic effects or polygenic and causal effects for DR. AIM 2. We will use the summary statistics from the meta-analysis and the Gene-Tissue Expression Project in an analysis using S-PrediXcan to evaluate associations between DR and genetically predicted gene expression. Additionally, we will identify genetically predicted gene effects that are not due to linkage disequilibrium contamination through the use of a colocalization analysis. Colocalization methods are under constant development, and we will monitor the literature for best practices. AIM 3. We will develop a genome-informed predictive model, combining a diabetic retinopathy polygenic risk score (PRS), DR PheWAS results, and current clinical risk factors for DR. We will develop a DR PRS utilizing the summary statistics of the MVP GWAS and Pollack et al., followed by training in BioVU. A PheWAS analysis incorporating the DR PRS can elucidate previously unknown association between DR associated loci and other disease traits. We will combine the PRS, PheWAS results, and current clinical risk factors into the genome informed predictive model that will be validated in the eMERGE Network. The outlined study will significantly increase the sample size of previous studies of DR, evaluate regulatory effects on DR, and develop predictive models that may have utility in clinical decision making of DR patients.

糖尿病视网膜病变的遗传结构 项目总结/摘要 糖尿病视网膜病变（DR）是成人视力丧失和可预防失明的主要原因， 估计全球有9300万人。随着全球糖尿病（DM）患病率的上升， 糖尿病视网膜病变的患病率也将上升。眼睛是非常容易受到损害的DM由于 眼部环境中的精细结构和复杂的稳态控制。DR长期以来 被认为是一种由血视网膜屏障破坏引发的微血管疾病， 视网膜的新生血管形成。糖尿病的病程和后遗症的严重程度差别很大 这种变异性的原因不能用已知的风险因素很好地解释。几个基因组- DR的广泛关联研究（GWAS）已经完成，虽然有少量的重要位点 据报道，只有一个基因座与复制后的DR显著相关。这些 研究是在队列研究协作联盟中进行的，其中包括迄今为止最大的研究 22，279例病例和23，977例糖尿病对照。我们将利用以前的研究， 来自百万退伍军人计划（MVP），BioVU和eMERGE网络的资源（估计为77，518 例，133，295例II型糖尿病对照），以检验常见遗传变异与 迄今为止最大的多种族GWAS中的DR。AIM 1.我们将结合联合收割机的证据 使用反向回归分析对上述资源中的DR-SNP关系进行逻辑回归分析 方差加权固定效应荟萃分析，包括种族内和种族间。大多数以前的 研究集中于检测SNP-表型关联，没有评估调控遗传效应， DR. AIM 2的多基因和因果效应。我们将使用荟萃分析的汇总统计数据和 使用S-PrediXcan分析中的基因-组织表达项目，以评估DR与 基因预测的基因表达。此外，我们将确定遗传预测的基因效应， 而不是由于连锁不平衡污染通过使用共定位分析。共定位 我们正在不断制定各种方法，并将监测文献中的最佳做法。AIM 3.我们将 开发基因组信息预测模型，结合糖尿病视网膜病变多基因风险评分（PRS）、DR PheWAS结果和DR的当前临床风险因素。我们将利用总结制定DR PRS MVP GWAS和Pollack等人的统计数据，然后在BioVU接受培训PheWAS分析， DR PRS可以阐明DR相关基因座与其他疾病之间先前未知关联 性状我们将联合收割机将PRS、PheWAS结果和当前临床风险因素结合到基因组中， 将在eMERGE网络中验证的预测模型。这项研究将大大增加 先前DR研究的样本量，评估对DR的监管效果，并开发预测模型 这可能在DR患者的临床决策中具有实用性。