GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.
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; howeve...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3208571?pdf=render |
| _version_ | 1811284403403358208 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yutao Liu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T02:28:07Z |
| format | Article |
| id | doaj.art-132b754901af4ad7bab0456d12f55515 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T02:28:07Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-132b754901af4ad7bab0456d12f555152022-12-22T03:06:41ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01611e2713410.1371/journal.pone.0027134GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease.Yutao LiuJason GibsonJoshua WheelerLydia Coulter KweeCecile M Santiago-TurlaStephen K AkafoPaul R LichterDouglas E GaasterlandSayoko E MoroiPratap ChallaLeon W HerndonChristopher A GirkinDonald L BudenzJulia E RichardsR Rand AllinghamMichael A HauserDNA 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.http://europepmc.org/articles/PMC3208571?pdf=render |
| spellingShingle | 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 GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. PLoS ONE |
| title | GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. |
| title_full | GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. |
| title_fullStr | GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. |
| title_full_unstemmed | GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. |
| title_short | GALC deletions increase the risk of primary open-angle glaucoma: the role of Mendelian variants in complex disease. |
| title_sort | galc deletions increase the risk of primary open angle glaucoma the role of mendelian variants in complex disease |
| url | http://europepmc.org/articles/PMC3208571?pdf=render |
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