Common Variants in 9p21 and 8q23 are associated with Normal Tension Glaucoma: Results From The NEIGHBOR and GLAUGEN Genome-wide Association Studies

Abstract

Purpose: : To identify genetic risk factors for primary open angle glaucoma overall and for the normal tension and high tension glaucoma subgroups.

Methods: : Genome-wide genotypes were obtained for 1002 primary open angle glaucoma (POAG) cases and 1183 controls from the GLAUGEN study and 2,517 POAG cases and 2,428 controls from the NEIGHBOR study using the Illumina 660W SNP platform. Cases had characteristic visual field defects consistent with glaucomatous optic neuropathy on reliable tests. Elevation of IOP was not a criterion; however, 67% of cases did have elevated IOP (≥22 mmHg) at diagnosis. Controls had normal optic nerves (CDR≤ 0.6), and normal IOP (≤ 21 mmHg). To evaluate SNP association, for each study, we used logistic regression models including DNA source, site, age and eigenvectors as co-variates. After testing for heterogeneity, we completed meta-analyses using METAL for POAG overall as well as for the normal pressure glaucoma (NPG) (defined as highest IOP < 22 mmHg at diagnosis) and high pressure glaucoma (IOP ≥22 mm Hg at diagnosis) subgroups.

Results: : The POAG meta-analysis identified 19 genome-wide significant SNPs: 17 in the CDKN2BAS region on chromosome 9p21 with the most significant SNP being rs2157719 (OR=0.69 [95%CI 0.63-0.75], p = 1.86x10^-18) and two in the SIX1/SIX6 region on chromosome 14q23 (most significant SNP: rs10483727, OR=1.32 [95%CI 1.21-1.43], p= 3.87x10^-11). For the NPG meta-analysis, SNPs in two regions reached genome-wide significance: 13 SNPs in the CDKN2BAS region (most significant SNP was rs2157719, OR = 0.58 [95% CI 0.50-0.67], p=1.17x10^-12) and 3 SNPs on chromosome 8q23 (most significant SNP was rs284489, OR = 0.62 [95% CI 0.53-0.72 ], p=8.88x10^-10). CDKN2BAS regulates expression of CDKN2B, and the 8q23 SNPs influence expression of TSC22 and flank an evolutionarily conserved DNA sequence with predicted regulatory function. Both CDKN2B and TSC22 contribute to TGFbeta signaling. No SNPs reached genome-wide significance in the high pressure group.

Conclusions: : We have identified two genomic regions that are associated with the normal-pressure form of glaucoma. Both regions contain regulatory elements predicted to affect expression of genes participating in TGFbeta signaling. The identification of genetic risk factors for optic nerve disease in glaucoma may lead to novel neuroprotective therapies for this common blinding disease.

Keywords: genetics • gene mapping • optic nerve