Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma

Megan Ulmer Carnes, Yangfan P. Liu, R. Rand Allingham, Benjamin T. Whigham, Shane Havens, Melanie E. Garrett, Chunyan Qiao, Nicholas Katsanis, Janey L. Wiggs, Louis R. Pasquale, Allison Ashley-Koch, Edwin C. Oh, Michael A. Hauser, Murray Brilliant, Donald L. Budenz, Hemin R. Chin, Jessica Cooke Bailey, John Fingert, David S. Friedman, Douglas GaasterlandTerry Gaasterland, Jonathan Haines, Michael A. Hauser, Jae H. Kang, Richard K. Lee, Paul R. Lichter, Yutao Liu, Stephanie Loomis, Cathy Essentia McCarty, Sayoko E. Moroi, Louis R. Pasquale, Margaret Pericak-Vance, Anthony Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur Sit, Douglas Vollrath, Robert N. Weinreb, Janey L. Wiggs, Gadi Wollstein, Brian L. Yaspan, Don Zack, Kang Zhang

Research output: Contribution to journalArticle

45 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1004372
JournalPLoS genetics
Volume10
Issue number5
DOIs
StatePublished - May 1 2014

Fingerprint

glaucoma
allele
blindness
Zebrafish
Optic Nerve
Glaucoma
eyes
genotype
genome
optics
Alleles
Odds Ratio
Danio rerio
assay
odds ratio
nerve tissue
Retinal Ganglion Cells
Nucleic Acid Regulatory Sequences
Genome-Wide Association Study
Blindness

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Ulmer Carnes, M., Liu, Y. P., Allingham, R. R., Whigham, B. T., Havens, S., Garrett, M. E., ... Zhang, K. (2014). Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma. PLoS genetics, 10(5), [e1004372]. https://doi.org/10.1371/journal.pgen.1004372

Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma. / Ulmer Carnes, Megan; Liu, Yangfan P.; Allingham, R. Rand; Whigham, Benjamin T.; Havens, Shane; Garrett, Melanie E.; Qiao, Chunyan; Katsanis, Nicholas; Wiggs, Janey L.; Pasquale, Louis R.; Ashley-Koch, Allison; Oh, Edwin C.; Hauser, Michael A.; Brilliant, Murray; Budenz, Donald L.; Chin, Hemin R.; Cooke Bailey, Jessica; Fingert, John; Friedman, David S.; Gaasterland, Douglas; Gaasterland, Terry; Haines, Jonathan; Hauser, Michael A.; Kang, Jae H.; Lee, Richard K.; Lichter, Paul R.; Liu, Yutao; Loomis, Stephanie; McCarty, Cathy Essentia; Moroi, Sayoko E.; Pasquale, Louis R.; Pericak-Vance, Margaret; Realini, Anthony; Richards, Julia E.; Schuman, Joel S.; Scott, William K.; Singh, Kuldev; Sit, Arthur; Vollrath, Douglas; Weinreb, Robert N.; Wiggs, Janey L.; Wollstein, Gadi; Yaspan, Brian L.; Zack, Don; Zhang, Kang.

In: PLoS genetics, Vol. 10, No. 5, e1004372, 01.05.2014.

Research output: Contribution to journalArticle

Ulmer Carnes, M, Liu, YP, Allingham, RR, Whigham, BT, Havens, S, Garrett, ME, Qiao, C, Katsanis, N, Wiggs, JL, Pasquale, LR, Ashley-Koch, A, Oh, EC, Hauser, MA, Brilliant, M, Budenz, DL, Chin, HR, Cooke Bailey, J, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Haines, J, Hauser, MA, Kang, JH, Lee, RK, Lichter, PR, Liu, Y, Loomis, S, McCarty, CE, Moroi, SE, Pasquale, LR, Pericak-Vance, M, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, RN, Wiggs, JL, Wollstein, G, Yaspan, BL, Zack, D & Zhang, K 2014, 'Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma', PLoS genetics, vol. 10, no. 5, e1004372. https://doi.org/10.1371/journal.pgen.1004372
Ulmer Carnes M, 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 genetics. 2014 May 1;10(5). e1004372. https://doi.org/10.1371/journal.pgen.1004372
Ulmer Carnes, Megan ; Liu, Yangfan P. ; Allingham, R. Rand ; Whigham, Benjamin T. ; Havens, Shane ; Garrett, Melanie E. ; Qiao, Chunyan ; Katsanis, Nicholas ; Wiggs, Janey L. ; Pasquale, Louis R. ; Ashley-Koch, Allison ; Oh, Edwin C. ; Hauser, Michael A. ; Brilliant, Murray ; Budenz, Donald L. ; Chin, Hemin R. ; Cooke Bailey, Jessica ; Fingert, John ; Friedman, David S. ; Gaasterland, Douglas ; Gaasterland, Terry ; Haines, Jonathan ; Hauser, Michael A. ; Kang, Jae H. ; Lee, Richard K. ; Lichter, Paul R. ; Liu, Yutao ; Loomis, Stephanie ; McCarty, Cathy Essentia ; Moroi, Sayoko E. ; Pasquale, Louis R. ; Pericak-Vance, Margaret ; Realini, Anthony ; Richards, Julia E. ; Schuman, Joel S. ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur ; Vollrath, Douglas ; Weinreb, Robert N. ; Wiggs, Janey L. ; Wollstein, Gadi ; Yaspan, Brian L. ; Zack, Don ; Zhang, Kang. / Discovery and Functional Annotation of SIX6 Variants in Primary Open-Angle Glaucoma. In: PLoS genetics. 2014 ; Vol. 10, No. 5.
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AU - Garrett, Melanie E.

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AU - Liu, Yutao

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AU - Moroi, Sayoko E.

AU - Pasquale, Louis R.

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AU - Realini, Anthony

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AU - Singh, Kuldev

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