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Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

Publication ,  Journal Article
Carnes, MU; Liu, YP; Allingham, RR; Whigham, BT; Havens, S; Garrett, ME; Qiao, C; NEIGHBORHOOD Consortium Investigators, ; Katsanis, N; Oh, EC ...
Published in: PLoS Genet
2014

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2014

Volume

10

Issue

5

Start / End Page

e1004372

Location

United States

Related Subject Headings

  • Trans-Activators
  • Optic Nerve
  • Intraocular Pressure
  • Humans
  • Homeodomain Proteins
  • Glaucoma, Open-Angle
  • Genome-Wide Association Study
  • Female
  • Eye
  • Developmental Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Carnes, M. U., Liu, Y. P., Allingham, R. R., Whigham, B. T., Havens, S., Garrett, M. E., … Hauser, M. A. (2014). Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet, 10(5), e1004372. https://doi.org/10.1371/journal.pgen.1004372
Carnes, Megan Ulmer, Yangfan P. Liu, R Rand Allingham, Benjamin T. Whigham, Shane Havens, Melanie E. Garrett, Chunyan Qiao, et al. “Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.PLoS Genet 10, no. 5 (2014): e1004372. https://doi.org/10.1371/journal.pgen.1004372.
Carnes MU, Liu YP, Allingham RR, Whigham BT, Havens S, Garrett ME, et al. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 2014;10(5):e1004372.
Carnes, Megan Ulmer, et al. “Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.PLoS Genet, vol. 10, no. 5, 2014, p. e1004372. Pubmed, doi:10.1371/journal.pgen.1004372.
Carnes MU, Liu YP, Allingham RR, Whigham BT, Havens S, Garrett ME, Qiao C, NEIGHBORHOOD Consortium Investigators, Katsanis N, Wiggs JL, Pasquale LR, Ashley-Koch A, Oh EC, Hauser MA. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 2014;10(5):e1004372.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

2014

Volume

10

Issue

5

Start / End Page

e1004372

Location

United States

Related Subject Headings

  • Trans-Activators
  • Optic Nerve
  • Intraocular Pressure
  • Humans
  • Homeodomain Proteins
  • Glaucoma, Open-Angle
  • Genome-Wide Association Study
  • Female
  • Eye
  • Developmental Biology