Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Departments of Clinical Genetics and Ophthalmology, Amsterdam University Medical Center (AMC), Location AMC K2-217 | AMC-UvA, P.O.Box 22700, 1100 DE, Amsterdam, The Netherlands.
BMC Genomics. 2021 Aug 4;22(1):590. doi: 10.1186/s12864-021-07846-1.
To investigate whether copy number variations (CNVs) are implicated in molecular mechanisms underlying primary open-angle glaucoma (POAG), we used genotype data of POAG individuals and healthy controls from two case-control studies, AGS (n = 278) and GLGS-UGLI (n = 1292). PennCNV, QuantiSNP, and cnvPartition programs were used to detect CNV. Stringent quality controls at both sample and marker levels were applied. The identified CNVs were intersected in CNV region (CNVR). After, we performed burden analysis, CNV-genome-wide association analysis, gene set overrepresentation and pathway analysis. In addition, in human eye tissues we assessed the expression of the genes lying within significant CNVRs.
We reported a statistically significant greater burden of CNVs in POAG cases compared to controls (p-value = 0,007). In common between the two cohorts, CNV-association analysis identified statistically significant CNVRs associated with POAG that span 11 genes (APC, BRCA2, COL3A1, HLA-DRB1, HLA-DRB5, HLA-DRB6, MFSD8, NIPBL, SCN1A, SDHB, and ZDHHC11). Functional annotation and pathway analysis suggested the involvement of cadherin, Wnt signalling, and p53 pathways.
Our data suggest that CNVs may have a role in the susceptibility of POAG and they can reveal more information on the mechanism behind this disease. Additional genetic and functional studies are warranted to ascertain the contribution of CNVs in POAG.
为了研究拷贝数变异（CNVs）是否与原发性开角型青光眼（POAG）的分子机制有关，我们使用了来自两个病例对照研究的 POAG 个体和健康对照的基因型数据，AGS（n=278）和 GLGS-UGLI（n=1292）。使用 PennCNV、QuantiSNP 和 cnvPartition 程序来检测 CNV。在样本和标记物水平都进行了严格的质量控制。鉴定的 CNVs 在 CNV 区域（CNVR）中相交。之后，我们进行了负担分析、CNV-全基因组关联分析、基因集过表达和通路分析。此外，在人眼组织中，我们评估了位于显著 CNVR 内的基因的表达。
我们报告了 POAG 病例与对照组相比，CNVs 的负担有统计学意义上的增加（p 值=0.007）。在两个队列中共同发现，CNV 关联分析确定了与 POAG 相关的具有统计学意义的 CNVR，跨越 11 个基因（APC、BRCA2、COL3A1、HLA-DRB1、HLA-DRB5、HLA-DRB6、MFSD8、NIPBL、SCN1A、SDHB 和 ZDHHC11）。功能注释和通路分析表明，钙黏蛋白、Wnt 信号通路和 p53 通路的参与。
我们的数据表明，CNVs 可能在 POAG 的易感性中起作用，并且它们可以提供更多关于这种疾病背后机制的信息。需要进行额外的遗传和功能研究，以确定 CNVs 在 POAG 中的贡献。
