title: GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.
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.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, United States of America. yutao.liu@duke.edu
authors.forename: Yutao
authors.initials: Y
authors.lastname: Liu
authors.forename: Jason
authors.initials: J
authors.lastname: Gibson
authors.forename: Joshua
authors.initials: J
authors.lastname: Wheeler
authors.forename: Lydia Coulter
authors.initials: LC
authors.lastname: Kwee
authors.forename: Cecile M
authors.initials: CM
authors.lastname: Santiago-Turla
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Akafo
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lichter
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Gaasterland
authors.forename: Sayoko E
authors.initials: SE
authors.lastname: Moroi
authors.forename: Pratap
authors.initials: P
authors.lastname: Challa
authors.forename: Leon W
authors.initials: LW
authors.lastname: Herndon
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Girkin
authors.forename: Donald L
authors.initials: DL
authors.lastname: Budenz
authors.forename: Julia E
authors.initials: JE
authors.lastname: Richards
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
mesh_terms: D055028:Comparative Genomic Hybridization; D005698:Galactosylceramidase / Q000235:genetics*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005698:Galactosylceramidase
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