评估包括MYOC变异和普通变异的青光眼遗传风险分层的实用方法：包括MYOC变异的青光眼风险分层。

IF 4.1 1区医学 Q1 OPHTHALMOLOGY

American Journal of Ophthalmology Pub Date : 2025-03-08 DOI:10.1016/j.ajo.2025.03.011

Ngoc-Quynh Le , Weixiong He , Matthew H. Law , Sarah E. Medland , David A. Mackey , Alex W. Hewitt , Puya Gharahkhani , Stuart MacGregor

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引用次数: 0

摘要

目的：MYOC基因的罕见变异与青光眼风险相关，其中p.Gln368Ter是欧洲人最常见的致病变异。基于遗传学的风险分层可能有助于青光眼的早期诊断，但尚不清楚如何最好地将p.Gln368Ter状态与多基因风险评分（PRS）结合起来。本研究旨在探讨利用基因分型阵列数据识别p.Gln368Ter携带者的方法，以及将p.Gln368Ter状态整合到青光眼PRS中的效用。设计：回顾性队列研究方法：我们使用直接基因分型和输入数据确定p.g n368ter携带者。结果在一个具有测序数据的子集中得到证实。在分层分析中，我们将p.Gln368Ter状态和PRS作为两个独立的因素并作为一个总分来评估它们的综合效应。参与者：来自青光眼遗传学（GOG）、QSkin太阳与健康研究（QSkin）和CARTaGENE项目的58,452名参与者，其中6015名具有测序数据。主要结果和指标：直接基因分型与p.Gln368Ter基因代入和测序鉴定的一致性比较。结果：如果没有适当的质量控制，可能会出现大量的误报。然而，在大多数情况下，p.Gln368Ter变异可以通过筛选个体的召唤率和杂合性来准确地进行基因分型。在6015例有测序数据的个体中，直接基因分型与测序结果完全一致。过滤后的直接基因分型结果与输入结果高度一致，在57,468个人中只有16个差异。当不可能进行质量控制时（例如，对个体进行杂合度过滤），我们建议比较基因型和估算结果以确保准确性。将p.Gln368Ter纳入PRS对高危个体的分层有额外的影响，但鉴于该变异的稀有性，并不能改善对一般人群的风险预测。心肌增强的PRS使pgln368ter高风险携带者的比例从QSKIN的32.31%增加到75.38%，CARTaGENE的38.24%增加到79.41%。结论：在严格的质量控制措施下，利用阵列数据可以高精度地进行p.Gln368Ter基因分型。将p.Gln368Ter纳入青光眼PRS可改善携带者的风险分层。

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Evaluating Practical Approaches for Including MYOC Variants Alongside Common Variants for Genetics-Based Risk Stratification for Glaucoma

Objective

Rare variants in the MYOC gene are associated with glaucoma risk, with p.Gln368Ter the most common pathogenic variant in Europeans. Genetics-based risk stratification may aid with early diagnosis for glaucoma but it is unclear how best to combine the p.Gln368Ter status with polygenic risk scores (PRS). Our study aimed to examine approaches for identifying p. Gln368Ter carriers using genotyping array data and the utility of integrating p.Gln368Ter status into glaucoma PRS.

Design

Retrospective cohort study.

Methods

We identified p.Gln368Ter carriers using directly genotyped and imputed data. Results were confirmed in a subset with sequencing data. We evaluated the combined effects of p.Gln368Ter status and PRS in stratified analyses by considering them as two separate factors and as an aggregate score.

Participants

A total of 58,452 participants from the Genetics of Glaucoma, the QSkin Sun and Health Study (QSKIN), and CARTaGENE projects, including 6015 with sequencing data.

Main Outcomes and Measures

The concordance of direct genotyping, compared with imputation and sequencing for p.Gln368Ter identification.

Results

Without appropriate quality control, substantial mis-calling may occur. Nevertheless, the p.Gln368Ter variant could be accurately genotyped in most cases by filtering individuals for call rate and heterozygosity. In 6015 individuals with sequencing data, direct genotyping exhibited perfect concordance with sequencing results. Filtered direct genotyping results showed high agreement with imputed results, with only 16 discrepancies among 57,468 individuals. When quality control is not possible (eg, heterozygosity filtering for an individual), we recommend comparing genotyped and imputed results to ensure accuracy. Incorporating p.Gln368Ter into PRS had additional effects on stratifying high–risk individuals, but did not improve risk prediction for the general population given the variant's rarity. The MYOC-enhanced PRS increased the proportion of p.Gln368Ter carriers classified as high risk from 32.31% to 75.38% in QSKIN and from 38.24% to 79.41% in CARTaGENE.

Conclusions

The p.Gln368Ter variant can be genotyped with high accuracy using array data, provided careful quality control measures are implemented. Incorporating p.Gln368Ter into glaucoma PRS improved risk stratification for carriers.

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来源期刊

American Journal of Ophthalmology 医学-眼科学

CiteScore

9.20

自引率

7.10%

发文量

406

审稿时长

36 days

期刊介绍： The American Journal of Ophthalmology is a peer-reviewed, scientific publication that welcomes the submission of original, previously unpublished manuscripts directed to ophthalmologists and visual science specialists describing clinical investigations, clinical observations, and clinically relevant laboratory investigations. Published monthly since 1884, the full text of the American Journal of Ophthalmology and supplementary material are also presented online at www.AJO.com and on ScienceDirect. The American Journal of Ophthalmology publishes Full-Length Articles, Perspectives, Editorials, Correspondences, Books Reports and Announcements. Brief Reports and Case Reports are no longer published. We recommend submitting Brief Reports and Case Reports to our companion publication, the American Journal of Ophthalmology Case Reports. Manuscripts are accepted with the understanding that they have not been and will not be published elsewhere substantially in any format, and that there are no ethical problems with the content or data collection. Authors may be requested to produce the data upon which the manuscript is based and to answer expeditiously any questions about the manuscript or its authors.