Glaucoma Polygenic Risk Scores Demonstrate Heterogeneous Performance across 2 Large Multiethnic Cohorts

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology. Glaucoma Pub Date : 2026-03-01 Epub Date: 2025-11-24 DOI:10.1016/j.ogla.2025.11.002

Niloufar Bineshfar MD, Liyin Chen PhD, Yan Zhao MS, Kanza Aziz MD, Nazlee Zebardast MD, MPH

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Abstract

Purpose

Glaucoma is a leading cause of irreversible blindness. While polygenic risk scores (PRSs) have shown promise for patient risk stratification, their consistency and reliability across diverse populations remain insufficiently characterized. This study aimed to determine whether published glaucoma PRSs demonstrate consistent population-level performance and individual-level risk assignment in 2 large, multiethnic cohorts.

Design

A cross-sectional study.

Participants

A total of 243 300 individuals (7190 open-angle glaucoma [OAG] cases; 236 110 controls) from the All of Us (AoU) Research Program and 30 306 individuals (1899 cases; 28 407 controls) from the Mass General Brigham (MGB) biobank were included. Participants were aged ≥35 years with available genotype and electronic health record phenotype data.

Methods

We evaluated the performance of 11 published glaucoma PRSs in the Polygenic Score Catalog using logistic regression models. The agreement of PRSs in risk classification was evaluated using Pearson correlation and Jaccard index.

Main Outcome Measures

Associations between cataloged PRSs and OAG and agreement of PRSs in risk classification.

Results

Higher PRSs were all significantly associated with higher odds of OAG; odds ratios (ORs) (per standard deviation) ranged from 1.17 to 1.41 (AoU) and 1.17 to 1.57 (MGB). In AoU, associations were strongest in individuals of European ancestry (ORs 1.22–1.55) and attenuated in African (1.08–1.21) and admixed American (1.09–1.33) ancestries. Despite consistent population-level performance, individual risk concordance across PRSs was low: median Pearson r = 0.42 (interquartile range, 0.35–0.50) and median Jaccard index = 0.16 (interquartile range, 0.13–0.19) for high-risk classification. This discordance persisted across cases, controls, ancestries, and both cohorts.

Conclusions

Our results demonstrate that while PRSs predict glaucoma risk at the cohort level, their instability at the individual level limits stand-alone clinical application. Polygenic risk scores should therefore be considered adjuncts to established glaucoma risk factors. Future work should prioritize developing tools to assess individual PRS reliability and standardizing analytic methods to improve comparability and clinical applicability.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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青光眼多基因风险评分在两个大的多民族队列中显示了不同的表现。

目的：青光眼是不可逆失明的主要原因。虽然多基因风险评分（prs）已显示出患者风险分层的希望，但其在不同人群中的一致性和可靠性仍未充分表征。本研究旨在确定已发表的青光眼PRSs在两个大型多民族队列中是否表现出一致的人群水平表现和个体水平的风险分配。设计：横断面研究。受试者、参与者和/或对照组：来自我们所有人（AoU）研究计划的共有243,300人（7,190例OAG病例，236,110例对照），以及来自麻省总医院（MGB）生物银行的30,306人（1,899例，28,407例对照）。参与者年龄≥35岁，具有可用的基因型和EHR表型数据。方法：我们使用逻辑回归模型评估多基因评分目录中11个已发表的青光眼PRSs的表现。采用Pearson相关和Jaccard指数对PRSs的风险分类一致性进行评价。主要结局和指标：已分类的PRSs与开角型青光眼（OAG）的相关性以及PRSs在风险分类中的一致性。结果：PRSs越高，OAG发生率越高；or（每SD）为1.17 ~ 1.41 (AoU), 1.17 ~ 1.57 （MGB）。在AoU中，欧洲血统个体的相关性最强（or值为1.22 ~ 1.55），非洲血统个体的相关性较弱（or值为1.08 ~ 1.21），美洲混血个体的相关性较弱（or值为1.09 ~ 1.33）。尽管在人群水平上表现一致，但各PRSs的个体风险一致性较低：高风险分类的中位Pearson r = 0.42 (IQR, 0.35-0.50)，中位Jaccard指数= 0.16 （IQR, 0.13-0.19）。这种不一致在病例、对照、祖先和两个队列中持续存在。结论：我们的研究结果表明，虽然PRSs在队列水平上预测青光眼风险，但其在个体水平上的不稳定性限制了单独的临床应用。因此，PRSs应被视为青光眼危险因素的辅助因素。未来的工作应优先开发评估个人PRS可靠性的工具，并标准化分析方法，以提高可比性和临床适用性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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