PURPOSE To find genetic contributions to glaucoma in African Americans. DESIGN Cross-sectional, case-control study. PARTICIPANTS One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. METHODS MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). MAIN OUTCOME MEASURES Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946). RESULTS Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively. CONCLUSIONS A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

中文翻译：

---

非洲人后裔原发性开角型青光眼的遗传结构：非洲人后裔和青光眼评估研究 III。

目的 寻找非裔美国人青光眼的遗传因素。设计横断面病例对照研究。参与者 1875 名原发性开角型青光眼 (POAG) 患者和 1709 名对照者，他们自认是非洲人后裔 (AD)，来自非洲人后裔和青光眼评估研究 (ADAGES) III 和维克森林大学药品。方法 将 MegaChip 基因型归因于千个基因组数据。通过线性混合模型校正相关性和群体分层来测试单核苷酸多态性 (SNP) 与 POAG 和高级 POAG 的关联。遗传风险评分通过接受者操作特征曲线（ROC-AUC）进行测试。主要观察指标 原发性开角型青光眼定义为视野缺损，无其他非眼部疾病 (n = 1875)。高级 POAG 的定义是基于年龄的视野平均偏差 (n = 946)。结果 1828.1922 个 SNP 满足 r2 > 0.7 的插补质量和次要等位基因频率 > 0.005。观察到晚期 POAG 与新基因座 EN04 的关联（rs185815146 β，0.36；标准误差，0.065；P < 3×10-8）。对于 POAG，在 9p21 欧洲血统 (ED) POAG 信号 (rs79721419；P < 6.5×10-5) 处观察到 AD 信号，独立于先前观察到的 9p21 ED 信号 (rs2383204；P < 2.3×10-5)。分析。观察到与 FNDC3B 中的 POAG 相关（rs111698934；P < 3.9×10-5），而不是与先前报道的 ED SNP 连锁不平衡（LD）。先前确定的与 AD 患者 POAG 相关的其他基因座有：8q22、AFAP1 和 TMC01。候选基因中包含 11 个 SNP 的未加权遗传风险评分的 AUC 为 0.62。通过使用带有交叉验证的惩罚矩阵分解来研究另外两个风险评分；确定了 50 个和 400 个 SNP 的风险评分，ROC 分别为 AUC = 0.74 和 AUC = 0.94。结论 在 AD 患者中，EN04 基因座可能与晚期 POAG 存在新的关联。除了这一发现之外，这项针对 AD POAG 患者的全基因组关联研究通过识别先前基因座 (9p21) 中的新信号，以及由于平均 LD (FNDC3B) 较短而推进区域的精细作图，对 POAG 遗传学做出了贡献。尽管未经证实和临床试验没有用处，但遗传风险评分的使用表明，这些数据中仍然存在大量 AD 特异性遗传信息。