Journal article
Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma
PLoS genetics, Vol.10(5), pp.e1004372-e1004372
2014
DOI: 10.1371/journal.pgen.1004372
PMCID: PMC4038608
PMID: 24875647
Abstract
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
Details
- Title: Subtitle
- Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma
- Creators
- Megan Ulmer Carnes - The Center for Human Genetics, Duke University, Durham, North Carolina, United States of AmericaYangfan P Liu - Duke UniversityR Rand Allingham - Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of AmericaBenjamin T Whigham - Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of AmericaShane Havens - Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of AmericaMelanie E Garrett - The Center for Human Genetics, Duke University, Durham, North Carolina, United States of AmericaChunyan Qiao - Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Beijing Tongren Hospital, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical University, Beijing, ChinaNicholas Katsanis - The Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, United States of AmericaJaney L Wiggs - Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of AmericaLouis R Pasquale - Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of AmericaAllison Ashley-Koch - The Center for Human Genetics, Duke University, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of AmericaEdwin C Oh - The Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Neurology, Duke University Medical Center, Durham, North Carolina, United States of AmericaMichael A Hauser - The Center for Human Genetics, Duke University, Durham, North Carolina, United States of America; Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of AmericaNEIGHBORHOOD Consortium Investigators
- Contributors
- John Fingert (Contributor) - University of Iowa, Ophthalmology and Visual Sciences
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.10(5), pp.e1004372-e1004372
- DOI
- 10.1371/journal.pgen.1004372
- PMID
- 24875647
- PMCID
- PMC4038608
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- United States
- Grant note
- EY015872 / NEI NIH HHS\r\nR01 EY015473 / NEI NIH HHS\r\nEY015473 / NEI NIH HHS\r\nR01EY013315 / NEI NIH HHS\r\nP30 EY014104 / NEI NIH HHS\r\nR01EY015543 / NEI NIH HHS\r\nR01EY019126 / NEI NIH HHS\r\nEY022305 / NEI NIH HHS\r\nU01 HG004728 / NHGRI NIH HHS\r\nP30 EY005722 / NEI NIH HHS\r\nUO1 HG004728 / NHGRI NIH HHS\r\nR01 EY022305 / NEI NIH HHS
- Language
- English
- Date published
- 2014
- Academic Unit
- Ophthalmology and Visual Sciences
- Record Identifier
- 9983980058202771
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