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Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma
Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60–100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.

1553-7390
King, Rebecca
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Struebing, Felix L.
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Allingham, Rand
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Singh, Kuldev
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Sit, Arthur
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Vollrath, Douglas
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Wollstein, Gadi
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Hammond, Christopher J.
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International Glaucoma Genetics Consortium
NEIGHBORHOOD Consortium
King, Rebecca
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Struebing, Felix L.
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Koch, Allison Ashley
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Cooke Bailey, Jessica N.
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Gharahkhani, Puya
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Hammond, Christopher J.
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King, Rebecca, Struebing, Felix L., Li, Ying, Wang, Jiaxing, Koch, Allison Ashley, Cooke Bailey, Jessica N., Gharahkhani, Puya, MacGregor, Stuart, Allingham, Rand, Hauser, Michael, Wiggs, Janey L., Geisert, Eldon E., Allingham, Rand, Brilliant, Murray, Budenz, Don, Bailey, Jessica N.Cooke, Fingert, John, Gaasterland, Douglas, Gaasterland, Teresa, Haines, Jonathan L., Hark, Lisa, Hauser, Michael, Igo, Rob, Kang, Jae Hee, Kraft, Peter, Lee, Richard, Lichter, Paul, Liu, Yutao, Moroi, Syoko, Pasquale, Louis R., Pericak-Vance, Margaret, Realini, Anthony, Rhee, Doug, Richards, Julia R., Ritch, Robert, Schuman, Joel, Scott, William K., Singh, Kuldev, Sit, Arthur, Vollrath, Douglas, Weinreb, Robert N., Wollstein, Gadi, Zack, Don, Aung, Tin, Burdon, Kathryn P., Cheng, Ching Yu, Bailey, Jessica N.Cooke, Craig, Jamie E., Cree, Angela J. and Hammond, Christopher J. , International Glaucoma Genetics Consortium and NEIGHBORHOOD Consortium (2018) Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genetics, 14 (1), [e1007145]. (doi:10.1371/journal.pgen.1007145).

Record type: Article

Abstract

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60–100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.

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Accepted/In Press date: 7 December 2017
e-pub ahead of print date: 25 January 2018
Published date: 25 January 2018

Identifiers

Local EPrints ID: 424198
URI: http://eprints.soton.ac.uk/id/eprint/424198
ISSN: 1553-7390
PURE UUID: 6bdd35d4-4f82-4723-a587-cbff45e68a8a
ORCID for Rebecca King: ORCID iD orcid.org/0000-0003-3953-3413

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Date deposited: 05 Oct 2018 11:34
Last modified: 06 Oct 2020 19:58

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Contributors

Author: Rebecca King ORCID iD
Author: Felix L. Struebing
Author: Ying Li
Author: Jiaxing Wang
Author: Allison Ashley Koch
Author: Jessica N. Cooke Bailey
Author: Puya Gharahkhani
Author: Stuart MacGregor
Author: Rand Allingham
Author: Michael Hauser
Author: Janey L. Wiggs
Author: Eldon E. Geisert
Author: Rand Allingham
Author: Murray Brilliant
Author: Don Budenz
Author: Jessica N.Cooke Bailey
Author: John Fingert
Author: Douglas Gaasterland
Author: Teresa Gaasterland
Author: Jonathan L. Haines
Author: Lisa Hark
Author: Michael Hauser
Author: Rob Igo
Author: Jae Hee Kang
Author: Peter Kraft
Author: Richard Lee
Author: Paul Lichter
Author: Yutao Liu
Author: Syoko Moroi
Author: Louis R. Pasquale
Author: Margaret Pericak-Vance
Author: Anthony Realini
Author: Doug Rhee
Author: Julia R. Richards
Author: Robert Ritch
Author: Joel Schuman
Author: William K. Scott
Author: Kuldev Singh
Author: Arthur Sit
Author: Douglas Vollrath
Author: Robert N. Weinreb
Author: Gadi Wollstein
Author: Don Zack
Author: Tin Aung
Author: Kathryn P. Burdon
Author: Ching Yu Cheng
Author: Jessica N.Cooke Bailey
Author: Jamie E. Craig
Author: Angela J. Cree
Author: Christopher J. Hammond
Corporate Author: International Glaucoma Genetics Consortium
Corporate Author: NEIGHBORHOOD Consortium

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