TY - JOUR
T1 - Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma
AU - King, Rebecca
AU - Struebing, Felix L.
AU - Li, Ying
AU - Wang, Jiaxing
AU - Koch, Allison Ashley
AU - Bailey, Jessica N.Cooke
AU - Gharahkhani, Puya
AU - International Glaucoma Genetics Consortium
AU - NEIGHBORHOOD Consortium
AU - MacGregor, Stuart
AU - Allingham, R. Rand
AU - Hauser, Michael A.
AU - Wiggs, Janey L.
AU - Geisert, Eldon E.
AU - Brilliant, Murray
AU - Budenz, Don
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 - Pasquale, Louis R.
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 - Craig, Jamie E.
AU - Cree, Angela J.
AU - Hammond, Christopher J.
AU - Hewitt, Alex W.
AU - Höhn, René
AU - Hysi, Pirro
AU - Gonzalez, Adriana I.Iglesias
AU - Jonas, Jost
AU - Khawaja, Anthony
AU - Khor, Chiea Cheun
AU - Klaver, Caroline C.W.
AU - Pasutto, Francesca
AU - Mackey, David
AU - Mitchell, Paul
AU - Mishra, Aniket
AU - Pang, Calvin
AU - Springelkamp, Henriette
AU - Thorleifsson, Gudmar
AU - Thorsteinsdottir, Unnur
AU - van Duijn, Cornelia M.
AU - Viswanathan, Ananth
AU - Vitart, Veronique
AU - Wojciechowski, Robert
AU - Wong, Tien
AU - Young, Terrri L.
AU - Zeller, Tanja
PY - 2018/1/25
Y1 - 2018/1/25
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.
KW - Cornea
KW - Glaucoma
KW - Retinal ganglion cells
KW - Ophthamology
KW - Mammalian Genomics
UR - http://www.scopus.com/inward/record.url?scp=85041686338&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1007145
DO - 10.1371/journal.pgen.1007145
M3 - Article
C2 - 29370175
AN - SCOPUS:85041686338
SN - 1553-7390
VL - 14
JO - PloS Genetics
JF - PloS Genetics
IS - 1
M1 - e1007145
ER -