QIMR Berghofer Medical Research Institute, Brisbane, Australia.
School of Medicine, University of Queensland, St Lucia, Brisbane, Australia.
JAMA Ophthalmol. 2021 Feb 1;139(2):224-231. doi: 10.1001/jamaophthalmol.2020.5404.
Glaucoma is the world's leading cause of irreversible blindness. Primary open-angle glaucoma (POAG) is typically asymptomatic early in the disease process, and unfortunately, many are diagnosed too late to prevent vision loss.
Genome-wide association studies, which evaluate the association between genetic variants and phenotype across the genome, have mapped many genes for POAG. As well as uncovering new biology, genetic information can be combined into a polygenic risk score (PRS), which aggregates an individual's disease risk over many genetic variants. In this nonsystematic review, performed from June 21, 2019, to October 1, 2020, we address a series of questions to explain the challenges and opportunities in translating genetic discoveries in POAG. We summarize what is known about POAG genetics and how its endophenotypes, such as intraocular pressure or cup-disc ratio, can help with prediction. We discuss the sample sizes available and how increases in the future may have an effect on the utility of prediction approaches. We explore particular scenarios, such as the use of PRS in risk stratification, and applications for individuals who are particularly high risk for POAG as a result of them carrying both a high penetrance mutation and an unfavorable PRS. Finally, we discuss the issue of equity in applying these tests and the prospects for prediction for people from various ancestry groups. The cost-effectiveness evaluation of glaucoma PRS in direct-to-consumer genetic testing and across different ancestry groups is warranted in future research.
Advances in glaucoma genetics have opened the door for risk stratification based on genetic risk predictions. The PRS approach has shown good promise in predicting who will be at highest risk of POAG, which could improve outcomes if these predictions can be acted on to result in improved clinical outcomes.
青光眼是全球导致不可逆性失明的首要原因。原发性开角型青光眼（POAG）在疾病早期通常没有症状，不幸的是，许多人被诊断出疾病时已经太晚，无法防止视力丧失。
全基因组关联研究（评估整个基因组中遗传变异与表型之间的关联）已经确定了许多 POAG 相关基因。除了揭示新的生物学机制外，遗传信息还可以组合成多基因风险评分（PRS），该评分聚合了个体在许多遗传变异上的疾病风险。在本次非系统性综述中，我们从 2019 年 6 月 21 日至 2020 年 10 月 1 日，针对一系列问题进行了探讨，旨在解释将 POAG 的遗传发现转化为临床实践所面临的挑战和机遇。我们总结了 POAG 遗传学的已知内容，以及其内表型（如眼压或杯盘比）如何有助于预测。我们讨论了现有的样本量大小，以及未来的增加如何影响预测方法的实用性。我们还探讨了特定情况，如 PRS 在风险分层中的应用，以及对于那些由于携带高外显率突变和不利的 PRS 而特别高风险发生 POAG 的个体的应用。最后，我们讨论了在不同的祖先群体中应用这些测试的公平性问题，以及对不同种族群体进行预测的前景。在未来的研究中，有必要对直接面向消费者的基因检测和不同的祖先群体中的青光眼 PRS 进行成本效益评估。
青光眼遗传学的进展为基于遗传风险预测的风险分层打开了大门。PRS 方法在预测谁将面临最高 POAG 风险方面显示出了良好的前景，如果这些预测可以付诸行动，以改善临床结局，那么这将改善结果。
