CDKN2BAS Genotype - Glaucoma Phenotype Correlations In The GLAUGEN Study And The NEIGHBOR Consortium

Abstract

Purpose: : We assessed whether 10 CDKN2BAS region single nucleotide polymorphisms (SNPs) are associated with phenotypic features of primary open-angle glaucoma (POAG).

Methods: : We conducted a POAG case-only analysis of 976 cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the NEI Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W quad array. We evaluated 10 SNPs in the CDKN2BAS region associated with POAG at the genome wide significant level (p<5E-08) in NEIGHBOR and confirmed in GLAUGEN. The POAG phenotypic outcomes included age at disease onset, intraocular pressure (IOP) at diagnosis, cup-disc ratio (CDR), Mean Deviation and Pattern Standard Deviation (PSD) on Humphrey visual field (VF) tests, pattern of VF loss on initial testing (peripheral, paracentral, superior, inferior). We used linear regression models for continuous phenotypes and logistic regression models for categorical phenotypes after adjusting for appropriate covariates in GLAUGEN and NEIGHBOR separately, and then pooled results with meta-analytical techniques.

Results: : For rs2157719, the top CDKN2BAS SNP associated with POAG in a meta-analysis of the GLAUGEN-NEIGHBOR genome-wide association studies (OR=0.69; p=1.86 E-18), each risk allele [G] was associated with a 0.6 mmHg higher IOP at diagnosis (95% CI: 0.3-0.8 mmHg; p=0.001) in pooled analysis. The dose of risk alleles for all other CDKN2BAS SNPs that were inversely associated with POAG risk also showed similar positive associations with IOP that was significant after correcting for multiple comparisons. We also found an inverse relation between dose of risk allele of rs2157719 (and for the other CDKN2BAS SNPs as well) and the chance of CDR greater than 0.6 or CDR asymmetry ≥0.2 (OR=0.72; 95% CI: 0.58-0.89; p=0.0023); associations remained after controlling for PSD or an ATOH7 SNP associated with disc size. No CDKN2BAS SNPs were consistently associated with any other glaucoma phenotype evaluated.

Conclusions: : This case-only analysis suggests that POAG patients with the protective CDKN2BAS alleles will tend to present with higher damaging IOP and smaller CDR. We did not find consistent associations between these SNPs and any other POAG feature we assessed.

Keywords: genetics • clinical (human) or epidemiologic studies: biostatistics/epidemiology methodology