Importance Refractive error (RE) is the most common form of visual impairment, and myopic RE is associated with an increased risk of primary open-angle glaucoma (POAG). Whether this association represents a causal role of RE in the etiology of POAG remains unknown. Objective To evaluate shared genetic influences and investigate the association of myopic RE with the risk for POAG. Design, Setting, and Participants Observational analyses were used to evaluate the association between mean spherical equivalent (MSE) RE (continuous trait) or myopia (binary trait) and POAG risk in individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. To quantify genetic overlap, genome-wide genetic correlation analyses were performed using genome-wide association studies (GWAS) of MSE RE or myopia and POAG from GERA. Potential causal effects were assessed between MSE RE and POAG using 2-sample Mendelian randomization. Genetic variants associated with MSE RE were derived using GWAS summary statistics from a GWAS of RE conducted in 102 117 UK Biobank participants. For POAG, we used GWAS summary statistics from our previous GWAS (3836 POAG cases and 48 065 controls from GERA). Data analyses occurred between July 2020 and October 2021. Main Outcomes and Measure Our main outcome was POAG risk as odds ratio (OR) caused by per-unit difference in MSE RE (in diopters). Results Our observational analyses included data for 54 755 non-Hispanic White individuals (31 926 [58%] females and 22 829 [42%] males). Among 4047 individuals with POAG, mean (SD) age was 73.64 (9.20) years; mean (SD) age of the 50 708 controls was 65.38 (12.24) years. Individuals with POAG had a lower refractive MSE and were more likely to have myopia or high myopia compared with the control participants (40.2% vs 34.1%, P = 1.31 × 10-11 for myopia; 8.5% vs 6.8%, P = .004 for high myopia). Our genetic correlation analyses demonstrated that POAG was genetically correlated with MSE RE (rg, -0.24; SE, 0.06; P = 3.90 × 10-5), myopia (rg, 0.21; SE, 0.07; P = .004), and high myopia (rg, 0.23; SE, 0.09; P = .01). Genetically assessed refractive MSE was negatively associated with POAG risk (inverse-variance weighted model: OR per diopter more hyperopic MSE = 0.94; 95% CI, 0.89-0.99; P = .01). Conclusions and Relevance These findings demonstrate a shared genetic basis and an association between myopic RE and POAG risk. This may support population POAG risk stratification and screening strategies, based on RE information.

中文翻译：

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近视屈光不正与原发性开角型青光眼之间的关联：2 样本孟德尔随机研究。

重要性 屈光不正 (RE) 是最常见的视力障碍形式，近视 RE 与原发性开角型青光眼 (POAG) 风险增加相关。这种关联是否代表 RE 在 POAG 病因学中的因果作用仍不清楚。目的 评估共同的遗传影响并研究近视 RE 与 POAG 风险的关联。设计、设置和参与者 观察分析用于评估成人健康与衰老遗传流行病学研究 (GERA) 个体的平均球镜等效 (MSE) RE（连续性状）或近视（二元性状）与 POAG 风险之间的关联队列。为了量化遗传重叠，使用 GERA 的 MSE RE 或近视和 POAG 的全基因组关联研究 (GWAS) 进行了全基因组遗传相关性分析。使用 2 样本孟德尔随机化评估 MSE RE 和 POAG 之间的潜在因果效应。与 MSE RE 相关的遗传变异是使用 GWAS 摘要统计数据得出的，该统计数据来自对 102 117 名英国生物银行参与者进行的 RE GWAS。对于 POAG，我们使用了之前 GWAS 的 GWAS 摘要统计数据（来自 GERA 的 3836 个 POAG 病例和 48065 个对照）。数据分析发生在 2020 年 7 月至 2021 年 10 月之间。 主要结果和测量 我们的主要结果是 POAG 风险，即由 MSE RE（屈光度）的单位差异引起的比值比 (OR)。结果 我们的观察分析包括 54 755 名非西班牙裔白人（31 926 [58%] 女性和 22 829 [42%] 男性）的数据。在 4047 名 POAG 患者中，平均 (SD) 年龄为 73.64 (9.20) 岁；50 708 名对照组的平均 (SD) 年龄为 65.38 (12.24) 岁。与对照组参与者相比，患有 POAG 的个体屈光 MSE 较低，并且更有可能患有近视或高度近视（近视为 40.2% vs 34.1%，P = 1.31 × 10-11；8.5% vs 6.8%，P = .004）对于高度近视）。我们的遗传相关分析表明，POAG 与 MSE RE（rg，-0.24；SE，0.06；P = 3.90 × 10-5）、近视（rg，0.21；SE，0.07；P = .004）和高度相关具有遗传相关性。近视（rg，0.23；SE，0.09；P = .01）。遗传评估的屈光 MSE 与 POAG 风险呈负相关（逆方差加权模型：OR 每屈光度越远视 MSE = 0.94；95% CI，0.89-0.99；P = 0.01）。结论和相关性 这些研究结果证明了近视 RE 和 POAG 风险之间存在共同的遗传基础以及相关性。这可能支持基于 RE 信息的人群 POAG 风险分层和筛查策略。