Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.
Polygenic Risk Score Improves Prediction of Primary Open Angle Glaucoma Onset in the Ocular Hypertension Treatment Study.
复制标题
多基因风险评分可提高高眼压治疗研究中原发性开角型青光眼发病的预测。
DOI：
10.1101/2023.08.15.23294141
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Zebardast,Nazlee
中科院分区：
文献类型：
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作者：
Singh,RishabhK;Zhao,Yan;Elze,Tobias;Fingert,John;Gordon,Mae;Kass,MichaelA;Luo,Yuyang;Pasquale,LouisR;Scheetz,Todd;Segrè,AyelletV;Wiggs,JaneyL;Zebardast,Nazlee
目的：原发性开角型青光眼（Primary open-angle glaucoma，POAG）是一种高度遗传性疾病，有127个已确定的危险基因位点。多基因风险评分（PRS）提供了一个衡量总遗传负担的指标。在这项研究中，我们评估PRS是否改善高眼压患者的危险分层。设计：高眼压治疗研究（OHTS）数据的事后分析。背景、参与者和/或对照：1994年至2020年，在22个研究中心对1636名参与者进行了随访。使用来自最大跨血统POAG荟萃分析的汇总统计量计算了1009名OHTS受试者的PRS，其中权重使用来自英国生物库中488，395名受试者的8，813，496个变体进行训练。方法、干预或检验：生存回归分析，终点为POAG的发展，结合基线协变量，从PRS预测疾病发作。主要结果和测量：结果测量是POAG发作的风险比。一致性指数和时间依赖性AUC用于比较多变量Cox比例风险模型的预测性能。结果：POAG转换者的平均PRS（0.24 ± 0.95）显著高于非转换者（-0.12 ± 1.00）（p < 0.01）。POAG风险随着PRS每增加1.36%，转换范围从最低PRS十分位数的9.5%到最高十分位数的21.8%。低风险和高风险PRS三分位数的比较显示，欧洲和非洲血统的参与者20年POAG风险增加1.8倍（p<0.01）。在随机分配至延迟治疗组的亚组中，PRS十分位数每增加一分，诊断时年龄降低0.52岁（p=0.05）。在早期治疗组中，PRS与POAG诊断时的年龄之间不存在显著的线性关系。与OHTS基线模型（C指数= 0.75）相比，添加PRS作为协变量（C指数= 0.77）后，预测模型显著改善（p<0.01）。PRS高一个标准差，POAG发作的平均风险比为1.25（CI=[1.13，1.44]）。结论：在高眼压患者中，较高的PRS与POAG的风险增加和早期发展相关。早期治疗可以减轻高遗传负担的风险，将临床可检测的疾病延迟长达5.2年。PRS的纳入改善了POAG发病的预测。
Objective or Purpose: Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension. Design: A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data. Setting, Participants, and/or Controls: 1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank. Methods, Interventions, or Testing: Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models. Results: Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (−0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset. Conclusions: Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.