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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease
PLoS ONE, Volume 6, No. 11, Article e27134, Year 2011
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Description
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.
Authors & Co-Authors
Liu, Yutao
United States, Durham
Duke University Medical Center
Gibson, Jason R.
United States, Durham
Duke University Medical Center
Wheeler, Joshua
United States, Durham
Duke University Medical Center
Kwee, Lydia Coulter
United States, Durham
Duke University Medical Center
Santiago-Turla, Cecilia
United States, Durham
Duke Eye Center
Akafo, Stephen K.
Ghana, Accra
University of Ghana
Lichter, Paul R.
United States, Ann Arbor
University of Michigan, Ann Arbor
Gaasterland, Douglas E.
United States, Chevy Chase
Eye Doctors of Washington
Moroi, Sayoko E.
United States, Ann Arbor
University of Michigan, Ann Arbor
Challa, Pratap
United States, Durham
Duke Eye Center
Herndon, Leon W.
United States, Durham
Duke Eye Center
Girkin, Christopher A.
United States, Birmingham
The University of Alabama at Birmingham
Budenz, Donald L.
United States, Miami
Bascom Palmer Eye Institute
Richards, Julia E.
United States, Ann Arbor
University of Michigan, Ann Arbor
Allingham, Robert Rand
United States, Durham
Duke Eye Center
Hauser, Michael Arthur
United States, Durham
Duke University Medical Center
United States, Durham
Duke Eye Center
Statistics
Citations: 40
Authors: 16
Affiliations: 7
Identifiers
Doi:
10.1371/journal.pone.0027134
e-ISSN:
19326203
Research Areas
Disability
Genetics And Genomics
Health System And Policy
Maternal And Child Health
Mental Health
Study Design
Case-Control Study