Valeria Lo Faro1,2, Jacoline B Ten Brink2, Harold Snieder3, Nomdo M Jansonius1, Arthur A Bergen4,5,6. 1. Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. 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. 3. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 4. 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. aabergen@amsterdamumc.nl. 5. Department of Ophthalmology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands. aabergen@amsterdamumc.nl. 6. Netherlands Institute for Neuroscience (NIN-KNAW), Amsterdam, The Netherlands. aabergen@amsterdamumc.nl.
Abstract
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
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