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.
Highlights
Glaucoma is the leading cause of irreversible blindness worldwide [1]
In the discovery phase of our study, we performed genome-wide DNA copy number variant analysis in 92 Primary Open Angle Glaucoma (POAG) cases genotyped on the Illumina HumanHap610 BeadChip
The copy number variants (CNVs) frequencies in our POAG patients were compared to publicly available controls genotyped on the Illumina HumanCNV370 BeadChip
Summary
Glaucoma is the leading cause of irreversible blindness worldwide [1]. As a heterogeneous group of disorders, glaucoma is a pathologic condition characterized by progressive loss of retinal ganglion cells with corresponding loss of the visual field. Well recognized risk factors for the development of POAG include elevated intraocular pressure (IOP), increasing age, African ancestry, and family history of glaucoma [3,4]. Genomewide association studies have been used to identify genetic risk factors for POAG or glaucoma-related ocular phenotypes [13,14,15,16,17,18,19]. These genes and regions include caveolin 1 and 2 (CAV1/2), transmembrane and coiled-coil domains 1 (TMCO1), SIX homeobox 1 (SIX1), and cyclin-dependent kinase inhibitor 2B (CDKN2B) [13,19,20]
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