PAGE-G: Precision Approach combining Genes and Environment in Glaucoma

PAGE-G：青光眼基因与环境相结合的精准方法

• 批准号: 10797646
• 负责人: Sally Liu Baxter
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797646
• 关键词: Address; Affect; African; African ancestry; Age of Onset; All of Us Research Program; Automobile Driving; Binding; Biomedical Research; Blindness; Characteristics; Chromatin; Chronic Disease; Clinical; Clinical Data; Complex; Data; Databases; Disease; Disease Management; Doctor of Philosophy; Early Diagnosis; Early treatment; Elements; Enhancers; Environment; Environmental Risk Factor; European; Evaluation Studies; Event; Eye; Eye diseases; Functional disorder; Gene Combinations; Genetic; Genetic Risk; Genetic Variation; Genomics; Glaucoma; Healthcare; Heritability; Human; Individual; Knowledge; Literature; Maps; Measures; Medical; Meta-Analysis; Modeling; Nucleic Acid Regulatory Sequences; Optic Nerve; Participant; Performance; Persons; Phenotype; Population; Population Heterogeneity; Process; Publishing; Regulation; Regulatory Element; Research Personnel; Resources; Risk; Risk Estimate; Risk Factors; Role; Testing; Tissues; Training; United Kingdom; United States National Institutes of Health; Untranslated RNA; Variant; Veterans; Work; annotation system; biobank; cell type; cohort; comorbidity; disorder risk; diverse data; functional genomics; gene environment interaction; genetic information; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic data; health care availability; health care service utilization; high risk; improved; innovation; insight; personalized approach; polygenic risk score; precision medicine; programs; progression risk; risk stratification; risk variant; social; social determinants; social factors; social health determinants; statistics; tool; transcription factor; whole genome

PROJECT SUMMARY/ABSTRACT Glaucoma is the world’s leading cause of irreversible blindness and is projected to affect >110 million people by 2040. Risk stratification is important in order to identify individuals at high risk of glaucoma, since early detection and treatment can help decrease the risk of irreversible vision loss. Because glaucoma has a high level of heritability, polygenic risk scores (PRS) have been developed to examine risk stratification based on genetic variants. However, because genome-wide association studies have most commonly been performed in European descent populations, PRS may not generalize well to non-European descent populations. This is a major issue for glaucoma given that non-European descent populations carry a disproportionate burden of glaucoma, including earlier age of onset, faster disease progression, and higher risk of vision loss. The All of Us Research Program offers an opportunity to further improve PRS models for glaucoma and enhance a precision medicine approach for this complex condition. First, the recent release of whole genome sequencing data on the All of Us Researcher Workbench provides additional genomic data from a diverse cohort of participants to add to the growing literature of genomic studies in glaucoma. We plan to develop a wide array of PRS models that will be trained and tested on data from All of Us (Aim 1). Further, we will leverage an innovative tool that annotates variants according to their regulatory activity in disease-specific cell types (in this case, eye tissues) to improve the predictive accuracy of trans-ancestry PRS models (i.e., make models trained on one population more widely generalizable to other populations) (Aim 2). Finally, because All of Us includes detailed data regarding environmental factors such as clinical data, healthcare access and utilization, and social determinants of health, it represents a unique opportunity to better understand gene- environment interactions in glaucoma and further refine risk stratification by simultaneously analyzing a multitude of data types (Aim 3). This study aims to improve PRS for glaucoma by enhancing performance via the strategies outlined above. Additionally, these aims may potentially uncover new risk variants and generate new insights regarding their functional importance. These will represent important advancements in precision medicine in glaucoma, particularly for diverse populations who have been traditionally underrepresented in biomedical research yet are most severely affected by this blinding eye disease.

项目摘要/摘要 青光眼是世界上导致不可逆转失明的主要原因，预计将有1.1亿人受到影响 到2040年。风险分层对于识别青光眼高危人群很重要，因为在早期 检测和治疗可以帮助降低不可逆转的视力丧失的风险。因为青光眼有一种很高的 遗传力水平，多基因风险评分(Prs)已被开发来检查风险分层，基于 基因变异。然而，由于全基因组关联研究最常在 对于欧洲裔人口，PR可能不能很好地推广到非欧洲裔人口。这是一个 青光眼的主要问题，因为非欧洲后裔人口背负着不成比例的 青光眼，包括发病年龄更早，疾病进展更快，以及更高的视力丧失风险。 我们所有人的研究计划提供了进一步改进青光眼和青光眼的PRS模型的机会 针对这种复杂的情况，加强精准医疗方法。首先，最近公布的全基因组 我们所有研究人员工作台上的测序数据提供了来自不同物种的额外基因组数据 参与者的队列，以增加青光眼基因组研究的不断增长的文献。我们计划开发一种 将根据我们所有人的数据进行培训和测试的各种PRS模型(目标1)。此外，我们还将 利用一种创新工具，根据变异体在特定疾病细胞中的调节活动对其进行注释 类型(在这种情况下，是眼组织)以提高跨祖先PRS模型的预测精度(即，使 在一个群体上训练的模型可更广泛地推广到其他群体)(目标2)。最后，因为所有人 包括有关环境因素的详细数据，如临床数据、医疗保健获取和 利用，和健康的社会决定因素，它代表着一个独特的机会，更好地了解基因- 青光眼的环境相互作用，并通过同时分析 多种数据类型(目标3)。 这项研究旨在通过上述策略提高青光眼的治疗效果。 此外，这些目标可能会发现新的风险变量，并产生关于其 功能重要性。这些将代表着青光眼精准医学的重要进步， 特别是对于传统上在生物医学研究中代表性不足的不同人群 受这种致盲眼病的影响最为严重。