Importance Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

中文翻译：

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遗传变异与非洲血统个体中原发性开角型青光眼的关联

重要性 与欧洲或亚洲血统相比，非洲血统人群的原发性开角型青光眼患病率增加，临床严重程度更高。尽管如此，非洲血统的个体在致盲疾病的基因组研究中仍未得到充分研究。目的 对非洲血统人群进行全基因组关联研究 (GWAS)，并评估原发性开角型青光眼相关位点的潜在发病机制。设计、设置和参与者 一个 2 阶段 GWAS，其发现数据集包含 2320 名原发性开角型青光眼患者和 2121 名无原发性开角型青光眼的对照个体。验证阶段包括另外 6937 名受影响的个人和 14917 名未受影响的个人，使用多中心临床和基于人群的参与者招募方法。研究参与者是从 2003 年到 2018 年从加纳、尼日利亚、南非、美国、坦桑尼亚、英国、喀麦隆、沙特阿拉伯、巴西、刚果民主共和国、摩洛哥、秘鲁和马里招募的。角型青光眼具有开放的虹膜角膜角，并显示有视野缺损的青光眼性视神经病变。升高的眼内压不包括在病例定义中。对照个体没有升高的眼压和青光眼的迹象。暴露与原发性开角型青光眼相关的遗传变异。主要结果和措施 原发性开角型青光眼的存在。全基因组显着性被定义为 P < 5 × 10-8 在发现阶段以及在组合发现和验证数据的荟萃分析中。结果 共有 2320 名原发性开角型青光眼患者（平均 [四分位距] 年龄，64.6 [56-74] 岁；1055 [45.5%] 名女性）和 2121 名无原发性开角型青光眼（平均 [四分位距]） 63.4 [55-71] 岁；1025 [48.3%] 名女性）被包括在发现 GWAS 中。GWAS 发现荟萃分析表明淀粉样蛋白-βA4 前体蛋白结合家族 B 成员 2（APBB2；染色体 4，rs59892895T>C）的变异与原发性开角型青光眼（比值比 [OR]，1.32 [95%] CI，1.20-1.46]；P = 2 × 10-8）。该关联在对另外 6937 名受影响个体和 14917 名未受影响个体的分析中得到验证（OR，1.15 [95% CI，1.09-1.21]; P < .001）。当所有数据都包含在荟萃分析中时，rs59892895*C 风险等位基因的每个副本都与原发性开角型青光眼的风险增加相关（OR，1.19 [95% CI，1.14-1.25]；P = 4 × 10- 13)。rs59892895*C 风险等位基因仅在非洲血统人群中以可观的频率存在。相比之下，rs59892895*C 风险等位基因在欧洲或亚洲血统的个体中的频率低于 0.1%。结论和相关性在这项全基因组关联研究中，APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。当所有数据都包含在荟萃分析中时，rs59892895*C 风险等位基因的每个副本都与原发性开角型青光眼的风险增加相关（OR，1.19 [95% CI，1.14-1.25]；P = 4 × 10- 13)。rs59892895*C 风险等位基因仅在非洲血统人群中以可观的频率存在。相比之下，rs59892895*C 风险等位基因在欧洲或亚洲血统的个体中的频率低于 0.1%。结论和相关性在这项全基因组关联研究中，APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。当所有数据都包含在荟萃分析中时，rs59892895*C 风险等位基因的每个副本都与原发性开角型青光眼的风险增加相关（OR，1.19 [95% CI，1.14-1.25]；P = 4 × 10- 13)。rs59892895*C 风险等位基因仅在非洲血统人群中以可观的频率存在。相比之下，rs59892895*C 风险等位基因在欧洲或亚洲血统的个体中的频率低于 0.1%。结论和相关性在这项全基因组关联研究中，APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。rs59892895*C 风险等位基因仅在非洲血统人群中以可观的频率存在。相比之下，rs59892895*C 风险等位基因在欧洲或亚洲血统的个体中的频率低于 0.1%。结论和相关性在这项全基因组关联研究中，APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。rs59892895*C 风险等位基因仅在非洲血统人群中以可观的频率存在。相比之下，rs59892895*C 风险等位基因在欧洲或亚洲血统的个体中的频率低于 0.1%。结论和相关性在这项全基因组关联研究中，APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。APBB2 基因座的变异显示出与原发性开角型青光眼的不同血统关联。如果在其他人群中得到验证，这一发现可能会对风险评估和治疗策略产生影响。