Genome-wide Analysis Of Central Corneal Thickness In POAG Cases From The NEIGHBOR Consortium

Abstract

Purpose: : Reduced central corneal thickness (CCT) is associated with increased risk of primary open-angle glaucoma (POAG). Several population-based studies have identified variants associated with normal CCT variation. We have performed a genome-wide association study (GWAS) of CCT in a POAG population to identify novel genetic variants that influence CCT in POAG cases. We then tested these and other previously published CCT associated variants for association with POAG risk.

Methods: : Genotype data were available from the NEIGHBOR and GLAUGEN GWAS studies. 1117 Caucasian individuals, primarily POAG cases, were available for analysis of CCT as a quantitative trait. First, fourteen SNPs from previously published CCT studies were tested for association with CCT in this dataset. Second, we performed a GWAS analyzing CCT as a quantitative trait. Third, 48 SNPs with a p-value < 10^-4 and 14 previously published CCT SNPs, were tested for association with POAG disease risk within the full NEIGHBOR-GLAUGEN dataset, encompassing a total of 3519 POAG cases and 3611 controls.

Results: : First, we replicated association with CCT as a quantitative trait in two of the 14 previously published SNPs: rs12447690, upstream of the ZNF469 gene (p-value=.0013; beta= -4.977 microns), and rs7044529 at the COL5A1 locus (p-value=.0025; beta= -6.587 microns). Second, no SNPs reached genome-wide significance in the NEIGHBOR/GLAUGEN CCT GWAS, most likely due to the small sample size. Third, none of the previously published CCT SNPs were significantly associated with POAG risk. However, several SNPs identified through our CCT GWAS were associated with POAG risk. Two SNPs within the NTM gene on chromosome 11q25 were associated with normal tension POAG (top SNP= rs7481514; p-value=.0007; OR=1.28). Although they were not significant after Bonferroni adjustment, six SNPs in the CNTNAP4 gene showed suggestive association with normal tension POAG (top SNP=rs1428758; p-value=.013; OR=1.20). CNTNAP4 is located within a previously reported keratoconus linkage peak.

Conclusions: : Our results suggest SNPs from CCT loci previously identified in population-based studies are associated with CCT variation but not associated with POAG susceptibility. CCT analysis in POAG cases has identified two separate cell adhesion molecules, NTM and CNTNAP4, both of which are associated with normal tension POAG, suggesting a possible mechanism by which CCT may confer risk in a subset of POAG cases.

Keywords: genetics