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Yutao Liu, Jason Gibson, Julia E. Richards, Paul R. Lichter, Douglas E. Gaasterland, Pratap Challa, Leon W. Herndon, Silke Schmidt, R R. Allingham, Michael A. Hauser; Deletions In The GALC Gene Are Associated With Primary Open-angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3304.
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DNA copy number variations (CNV) have been shown to play important roles in human disorders. However, their role in primary open-angle glaucoma (POAG) was not clear. This study is to investigate the role of CNVs in POAG.
We compared the genome-wide frequency of CNVs using high density SNP chip analysis of 71 POAG cases and 561 controls from dbGAP. Several candidate CNVs were subsequently followed up with TaqMan-based realtime PCR analysis in three independent datasets: Caucasian cohort of 1150 cases and 1300 controls, African American cohort of 400 cases and 290 controls, and Ghanaian cohort of 190 cases and 500 controls. High resolution CGH arrays were used to validate and confirm deletions in the GALC gene. Genomic PCR was used to confirm the endpoints of specific GALC deletions.
As shown in table 1, we identified a heterozgyous deletion in the GALC gene using Illumina microarrays (p=0.013). This association was confirmed in our Caucasian POAG dataset (p=0.034) using realtime PCR. When combined with publically available CNV data on 1881 controls, this association was more significant (p = 0.001). The identified CNVs were further validated using CGH arrays, which demonstrated multiple independent GALC deletions, suggesting the complexity of CNVs at this locus. PCR of genomic DNA was used to identify the endpoints of specific GALC deletions. No GALC deletions were found in POAG cases or controls with African ancestry.
Homozygous GALC deletions have previously been reported to cause Krabbe disease with majority of the patients showing optic neuropathy. We have demonstrated that heterozygous GALC deletions are significantly associated with POAG in Caucasians, suggesting a potential role in the etiology of POAG. This is the first report of copy number variations associated with POAG risk.
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