Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia.
OBJECTIVE
To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia.


METHODS
A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n = 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n = 6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis.


RESULTS
Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P = 0.001; β = -5.08 μm/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P = 0.00099; Odds Ratio [OR] = 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; P = 0.018; OR = 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues.


CONCLUSIONS
The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases.
Duke University Center for Human Genetics, Durham, North Carolina 27710, USA.
Megan
M
Ulmer
Jun
J
Li
Brian L
BL
Yaspan
Ayse Bilge
AB
Ozel
Julia E
JE
Richards
Sayoko E
SE
Moroi
Felicia
F
Hawthorne
Donald L
DL
Budenz
David S
DS
Friedman
Douglas
D
Gaasterland
Jonathan
J
Haines
Jae H
JH
Kang
Richard
R
Lee
Paul
P
Lichter
Yutao
Y
Liu
Louis R
LR
Pasquale
Margaret
M
Pericak-Vance
Anthony
A
Realini
Joel S
JS
Schuman
Kuldev
K
Singh
Douglas
D
Vollrath
Robert
R
Weinreb
Gadi
G
Wollstein
Donald J
DJ
Zack
Kang
K
Zhang
Terri
T
Young
R Rand
RR
Allingham
Janey L
JL
Wiggs
Allison
A
Ashley-Koch
Michael A
MA
Hauser
D003315:Cornea / Q000473:pathology*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D015723:Gene Library; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics*; D009929:Organ Size; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D014794:Visual Fields / Q000502:physiology
C575640:CNTNAP4 protein, human; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D012333:RNA, Messenger; C092530:neurotrimin