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Jamie E Craig, Kathryn P Burdon, Tiger Zhou, Owen M. Siggs, Alex W Hewitt, David A Mackey, Puya Gharahkhani, Gabriel Cuellar, Stuart MacGregor; Genome-wide approach to detecting copy number variation in open angle glaucoma blindness utilizing the Australian and New Zealand Registry of Advanced Glaucoma. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2550. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The pathogenesis of open angle glaucoma (OAG) is poorly understood. There is a strong genetic basis, with a small component explained by rare variants of large effect size detected by sequencing, and a larger component due to common variants of small effect size detected by GWAS. Both methods miss copy number variation (CNV) unless specifically targeted. CNV has been implicated in developmental glaucoma (PITX2, FOXC1) and normal tension glaucoma (TBK1). This study aimed to investigate CNVs in OAG using a genome wide approach.
1109 cases with advanced OAG met entry criteria (advanced field loss with VA worse than 20/200, or severe global or fixation involving field loss) and passed QC. Developmental glaucoma was excluded. Cases were compared to 2100 unexamined controls. Samples were genotyped on the Illumina OmniExpress or 1M array platform and calling of CNVs was determined using comparative fluorescence intensities at adjacent SNPs (as implemented in PennCNV software). A CNV was likely to be called if at least 3 contiguous SNPs showed a consistent call for either duplication or deletion. Association analysis used Fishers exact test.
We validated CNV calling by using an internal control for CNV in the TBK1 gene. 3 cases in this dataset were known to carry duplications proven by real time PCR. All cases were detected by our calling strategy (verus nil in controls, p<0.05). At chromosome 1p36.13, three independent CNVs close to EPHA2 (implicated in cataract) were found in 14 cases vs 2 controls (p=2x10-5, OR 13.2). CNVs directly involving single genes on chromosome 7q22, 6q14, and 20q13 were found in 7 (p=10-4), 6 (p=10-3) and 5 (p=10-3) cases respectively, versus nil controls. No CNVs in cases were detected in MYOC, SIX1/6, OPTN, CYP1B1, PITX2 or FOXC1. A single CNV in NTF4 was identified in one case but also in one control.
We examined the contribution of CNVs to OAG using a population based approach. CNVs in genes previously implicated in glaucoma are not a common mechanism of disease. We have confirmed the role of TBK1 duplication as a rare cause of NTG. Many genes had similar signals to TBK1. We have defined several candidate genes requiring further follow-up to determine whether they are causally implicated in OAG.
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