Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.
Department of Ophthalmology, Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, La Jolla, California.
Ophthalmology. 2019 Jan;126(1):38-48. doi: 10.1016/j.ophtha.2018.10.031. Epub 2018 Oct 21.
To find genetic contributions to glaucoma in African Americans.
Cross-sectional, case-control study.
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.
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).
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).
Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r > 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). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10) 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.
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.
寻找非裔美国人青光眼的遗传贡献。
横断面病例对照研究。
来自非洲裔美国人青光眼评估研究（ADAGES）III 和维克森林医学院的 1875 名原发性开角型青光眼（POAG）患者和 1709 名对照，自我认定为非裔（AD）。
将 MegaChip 基因型外推到千基因组数据。通过线性混合模型测试单核苷酸多态性（SNP）与 POAG 和晚期 POAG 的关联，该模型校正了相关性和群体分层。通过接收者操作特征曲线（ROC-AUC）测试遗传风险评分。
无其他非眼部疾病的视野丧失定义的原发性开角型青光眼（n=1875）。晚期 POAG 定义为基于年龄的视野平均偏差（n=946）。
符合 r>0.7 和次要等位基因频率>0.005 的质量要求的 1828.192 万个 SNPs 进行了关联分析。观察到一个新的 EN04 基因座与晚期 POAG 相关（rs185815146β，0.36；标准误差，0.065；P<3×10）。对于 POAG，在 9p21 欧洲血统（ED）POAG 信号（rs2383204；P<2.3×10）中观察到与先前观察到的 9p21 ED 信号（rs79721419；P<6.5×10）独立的 AD 信号，通过条件分析。FNDC3B（rs111698934；P<3.9×10）与 POAG 相关，与先前报道的 ED SNP 没有连锁不平衡（LD）。在 AD 个体中与 POAG 相关的其他先前确定的基因座包括：8q22、AFAP1 和 TMC01。由候选基因中 11 个 SNP 组成的无权重遗传风险评分观察到 AUC 为 0.62。通过交叉验证的惩罚矩阵分解研究了另外两个风险评分；50 和 400 个 SNP 的风险评分的 AUC 分别为 0.74 和 0.94。
在 AD 个体中，EN04 基因座与晚期 POAG 的新关联被确定。除了这一发现，AD 患者的这项 POAG 全基因组关联研究通过在先前的基因座（9p21）中发现新的信号，以及由于平均 LD 较短（FNDC3B）而推进区域的精细映射，为 POAG 遗传学做出了贡献。尽管没有经过确认和临床试验的验证，遗传风险评分的使用表明，这些数据中仍然存在大量的 AD 特异性遗传信息。
