Understanding the clinical impact of cumulative genetic risk to glaucoma

原发性开角型青光眼(POAG)是最常见的青光眼亚型，是一种典型的 具有很强的多基因成分的复杂疾病。这项提议与美国国立卫生研究院的路线图保持一致， 利用POAG长达十年的基因发现努力，进入精确医学方法， 促进青光眼早期诊断，同时概述预防青光眼相关失明的策略。在这 研究中，我们提出了三个具体目标。1)我们将组装所有为POAG发现的常见基因变体 在过去的十年中，在4项独立研究中加入了一个多祖先小组，以测试他们是否可以预测青光眼 人口(英国生物库，一项嵌入在人口中的健康专业病例对照研究 样本和来自2个医院生物库的患者(总样本量：约600,286例中超过12,000例POAG病例 科目)。2)以医院为基础的生物信息库提供了一个贡献基于精确的医学知识的机会 关于青光眼。我们将邀请来自两个医院生物库的800名患者，这些患者分别患有低度和高度青光眼 用于系统临床评估的多基因风险评分(Prs)。这种详细的表型-基因相关性 将提供对青光眼的独特见解，并将展示此类生物库的效用，以识别 以前未确诊的疾病，青光眼领域中未得到满足的需求。3)而青光眼患者 可能是青光眼的最强预测因素，我们预计相当数量的受试者有高眼压 RPS不会显示青光眼疾病；相反，一些RPS低的受试者会患上青光眼。 我们将探索MYOC Q368X等遗传变异和独特的环境因素(饮食 蔬菜来源的硝酸盐摄入量、女性雌激素暴露时间和牙齿健康状况)修改 在我们的4个研究人群中，我们的精神分裂症与青光眼的关系。通过制定和应用多个 对于一组不同种族的受试者，这项建议将突出 青光眼遗传信息量面板作为筛查工具。这项提议将推进以下主要目标 将POAG提升为精准医学学科地位。最后，它将识别特定的疾病 可在作出诊断前实施的预防策略。

Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is a prototypical common complex disease with a strong polygenetic component. This proposal is aligned with the NIH roadmap, leveraging the decade-long effort of gene discovery for POAG into precision medicine approaches that facilitate an early glaucoma diagnosis while outlining strategies to prevent glaucoma-related blindness. In this study, we propose 3 specific aims. 1) We will assemble all of the common gene variants discovered for POAG over the past decade into a multi-ancestry panel to test whether they predict glaucoma in 4 independent study populations (the UK Biobank, a health professional case-control study embedded in a population based sample, and patients from 2 hospital-based biobanks (total sample size: over 12,000 POAG cases in ~600,286 subjects). 2) Hospital-based biobanks offer an opportunity to contributed precision based medical knowledge about glaucoma. We will invite 800 patients from two hospital-based biobanks with low and high glaucoma polygenetic risk score (PRS) for systematic clinical evaluation. This detailed phenotype-genotype correlation will provide unique insights into glaucoma and will demonstrate the utility of such biobanks to identify previously undiagnosed disease, an unmet need in the field of glaucoma. 3) While a glaucoma PRS is probably the strongest predictor of glaucoma, we anticipate that a considerable number of subjects with high PRS will not demonstrate glaucomatous disease; conversely, some subjects with low PRS will have glaucoma. We will explore whether genetic variants such as MYOC Q368X and unique environmental factors (dietary nitrate intake from vegetable sources, estrogen exposure duration in women and dental health status) modify the relation between our PRS and glaucoma in our 4 study populations. By formulating and applying a multi- ancestral glaucoma PRS to an ethnically-diverse group of subjects, this proposal will highlight the role of a glaucoma genetic informativity panel as a screening tool. This proposal will advance the major objective of promoting POAG to the status of a precision-based medicine discipline. Finally, it will identify specific disease prevention strategies that could be implemented before a diagnosis is made.