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

International Glaucoma Genetics Consortium, NEIGHBORHOOD Consortium

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1007145
JournalPLoS Genetics
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2018

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glaucoma
Glaucoma
genomics
risk factor
Quantitative Trait Loci
loci
gene
mice
quantitative trait loci
phenotype
cornea
Cornea
bioinformatics
Single Nucleotide Polymorphism
secondary structure
metadata
risk factors
Retinal Ganglion Cells
eyes
Genome-Wide Association Study

ASJC Scopus subject areas

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

Cite this

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. / International Glaucoma Genetics Consortium; NEIGHBORHOOD Consortium.

In: PLoS Genetics, Vol. 14, No. 1, e1007145, 01.01.2018.

Research output: Contribution to journalArticle

International Glaucoma Genetics Consortium ; NEIGHBORHOOD Consortium. / Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. In: PLoS Genetics. 2018 ; Vol. 14, No. 1.
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title = "Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma",
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.",
author = "{International Glaucoma Genetics Consortium} and {NEIGHBORHOOD Consortium} and Rebecca King and Struebing, {Felix L.} and Ying Li and Jiaxing Wang and Koch, {Allison Ashley} and {Cooke Bailey}, {Jessica N.} and Puya Gharahkhani and Stuart MacGregor and Allingham, {R. Rand} and Hauser, {Michael A.} and Wiggs, {Janey L.} and Geisert, {Eldon E.} and Rand Allingham and Murray Brilliant and Don Budenz and Bailey, {Jessica Cooke} and John Fingert and Douglas Gaasterland and Teresa Gaasterland and Haines, {Jonathan L.} and Lisa Hark and Michael Hauser and Rob Igo and Kang, {Jae Hee} and Peter Kraft and Richard Lee and Paul Lichter and Yutao Liu and Syoko Moroi and Yutao Liu and Margaret Pericak-Vance and Anthony Realini and Doug Rhee and Richards, {Julia R.} and Robert Ritch and Joel Schuman and Scott, {William K.} and Kuldev Singh and Arthur Sit and Douglas Vollrath and Weinreb, {Robert N.} and Gadi Wollstein and Don Zack and Tin Aung and Burdon, {Kathryn P.} and Cheng, {Ching Yu} and Bailey, {Jessica N.Cooke} and Craig, {Jamie E.} and Cree, {Angela J.} and Hammond, {Christopher J.}",
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T1 - Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

AU - International Glaucoma Genetics Consortium

AU - NEIGHBORHOOD Consortium

AU - King, Rebecca

AU - Struebing, Felix L.

AU - Li, Ying

AU - Wang, Jiaxing

AU - Koch, Allison Ashley

AU - Cooke Bailey, Jessica N.

AU - Gharahkhani, Puya

AU - MacGregor, Stuart

AU - Allingham, R. Rand

AU - Hauser, Michael A.

AU - Wiggs, Janey L.

AU - Geisert, Eldon E.

AU - Allingham, Rand

AU - Brilliant, Murray

AU - Budenz, Don

AU - Bailey, Jessica Cooke

AU - Fingert, John

AU - Gaasterland, Douglas

AU - Gaasterland, Teresa

AU - Haines, Jonathan L.

AU - Hark, Lisa

AU - Hauser, Michael

AU - Igo, Rob

AU - Kang, Jae Hee

AU - Kraft, Peter

AU - Lee, Richard

AU - Lichter, Paul

AU - Liu, Yutao

AU - Moroi, Syoko

AU - Liu, Yutao

AU - Pericak-Vance, Margaret

AU - Realini, Anthony

AU - Rhee, Doug

AU - Richards, Julia R.

AU - Ritch, Robert

AU - Schuman, Joel

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur

AU - Vollrath, Douglas

AU - Weinreb, Robert N.

AU - Wollstein, Gadi

AU - Zack, Don

AU - Aung, Tin

AU - Burdon, Kathryn P.

AU - Cheng, Ching Yu

AU - Bailey, Jessica N.Cooke

AU - Craig, Jamie E.

AU - Cree, Angela J.

AU - Hammond, Christopher J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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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