Exome Array Analysis Identifies Novel Susceptibility Loci for Intraocular Pressure

Intraocular pressure (IOP) is an important physiologic characteristic in maintaining the structure and function of the eye. Elevated IOP is a major risk factor of primary-open angle glaucoma and the only target for current glaucoma therapy. The goal of this study is to identify rare and low frequency variants in regulation of IOP. Using the exome array data, we performed a genome-wide association study for IOP in 1,661 unrelated individuals from a population-based cohort, the Beaver Dam Eye Study (BDES). IOP was adjusted for age, sex, systolic blood pressure, IOP treatment and population stratification. We conducted single-variant analysis on 35,091 low frequency and common variants and gene-based analysis on 9,650 gene regions with at least two protein-altering variants. IOP was significantly associated with rs52809447, located in GGA3 at 17q25 (MAF=1.11%, p = 1.3 × 10E-6) and with rs757702, located in OGDH at 17p14-p13 (MAF = 1.60%, p = 1.5 × 10E-6). Two novel loci, the HAP1 (huntingtin-associated protein 1) at 17q21 (p = 1.1 × 10E-6) and TNR (tenascin R) at 1q24 (p = 3.0 × 10E-6) reached genome-wide significance in gene-based analysis. The inhibitory role of TNR gene in retinal ganglion cell survival and axonal regeneration suggests a potential involvement in the glaucomatous progression. The implications of GGA3, OGDH and HAP1 with Alzheimer’s disease and IOP, lend support to the shared pathways of neurodegeneration in the brain and in the eye