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Title: | GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease | Authors: | Liu Y. Gibson J. Wheeler J. Kwee L.C. Santiago-Turla C.M. Akafo S.K. Lichter P.R. Gaasterland D.E. Moroi S.E. Challa P. Herndon L.W. Girkin C.A. Budenz D.L. Richards J.E. Allingham R.R. Hauser M.A. |
Keywords: | aldehyde dehydrogenase 1 family member A2 cell protein ciliary rootlet coiled coil rootlletin protein eyes absent 1 homolog 1 protein galactosylceramidase RAS p21 protein activator 4 unclassified drug galactosylceramidase adult article comparative genomic hybridization controlled study copy number variation enzyme activity galactosylceramidase gene gene gene deletion gene function gene loss gene replication genetic association genetic risk genotype heterozygosity loss human open angle glaucoma real time polymerase chain reaction risk assessment single nucleotide polymorphism validation process genetic predisposition genetics open angle glaucoma Comparative Genomic Hybridization Galactosylceramidase Gene Deletion Genetic Predisposition to Disease Glaucoma, Open-Angle Humans Real-Time Polymerase Chain Reaction |
Issue Date: | 2011 | Citation: | Liu Y., Gibson J., Wheeler J., Kwee L.C., Santiago-Turla C.M., Akafo S.K., Lichter P.R., Gaasterland D.E., Moroi S.E., Challa P., Herndon L.W., Girkin C.A., Budenz D.L., Richards J.E., Allingham R.R., Hauser M.A. (2011). GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease. PLoS ONE 6 (11) : e27134. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0027134 | Rights: | Attribution 4.0 International | Abstract: | DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI -1.1-12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG. © 2011 Liu et al. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/162025 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0027134 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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