GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease

Yutao Liu, Jason Gibson, Joshua Wheeler, Lydia Coulter Kwee, Cecile M. Santiago-Turla, Stephen K. Akafo, Paul R. Lichter, Douglas E. Gaasterland, Sayoko E. Moroi, Pratap Challa, Leon W. Herndon, Christopher A. Girkin, Donald L. Budenz, Julia E. Richards, R. Rand Allingham, Michael A. Hauser

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere27134
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 4 2011

Fingerprint

Galactosylceramidase
glaucoma
gene deletion
Gene Deletion
Genes
Association reactions
Optics
Optic Nerve Diseases
Biomarkers
peripheral nervous system diseases
optics
odds ratio
Odds Ratio
DNA Copy Number Variations
Globoid Cell Leukodystrophy
comparative genomic hybridization
Primary Open Angle Glaucoma
DNA
Testing
Comparative Genomic Hybridization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Liu, Y., Gibson, J., Wheeler, J., Kwee, L. C., Santiago-Turla, C. M., Akafo, S. K., ... 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]. https://doi.org/10.1371/journal.pone.0027134

GALC deletions increase the risk of primary Open-Angle Glaucoma : The role of mendelian variants in complex disease. / Liu, Yutao; Gibson, Jason; Wheeler, Joshua; Kwee, Lydia Coulter; Santiago-Turla, Cecile M.; Akafo, Stephen K.; Lichter, Paul R.; Gaasterland, Douglas E.; Moroi, Sayoko E.; Challa, Pratap; Herndon, Leon W.; Girkin, Christopher A.; Budenz, Donald L.; Richards, Julia E.; Allingham, R. Rand; Hauser, Michael A.

In: PloS one, Vol. 6, No. 11, e27134, 04.11.2011.

Research output: Contribution to journalArticle

Liu, Y, Gibson, J, Wheeler, J, Kwee, LC, Santiago-Turla, CM, Akafo, SK, Lichter, PR, Gaasterland, DE, Moroi, SE, Challa, P, Herndon, LW, Girkin, CA, Budenz, DL, Richards, JE, Allingham, RR & Hauser, MA 2011, 'GALC deletions increase the risk of primary Open-Angle Glaucoma: The role of mendelian variants in complex disease', PloS one, vol. 6, no. 11, e27134. https://doi.org/10.1371/journal.pone.0027134
Liu, Yutao ; Gibson, Jason ; Wheeler, Joshua ; Kwee, Lydia Coulter ; Santiago-Turla, Cecile M. ; Akafo, Stephen K. ; Lichter, Paul R. ; Gaasterland, Douglas E. ; Moroi, Sayoko E. ; Challa, Pratap ; Herndon, Leon W. ; Girkin, Christopher A. ; Budenz, Donald L. ; Richards, Julia E. ; Allingham, R. Rand ; Hauser, Michael A. / GALC deletions increase the risk of primary Open-Angle Glaucoma : The role of mendelian variants in complex disease. In: PloS one. 2011 ; Vol. 6, No. 11.
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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.",
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