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Sayoko Moroi, Ayse Ozel, David Reed, Kari Branham, Michael Hauser, Louis Pasquale, Janey Wiggs, Julia Richards, Jun Li, NEIGHBOR Consortium; Genome-wide Association Study and Meta-Analysis of Intraocular Pressure in Primary Open-Angle Glaucoma Cases and Controls in the NEIGHBOR, GLAUGEN and AMD-MMAP Studies. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4497. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Intraocular pressure (IOP), a major risk for glaucoma, is influenced by both genetic and environmental factors. We performed a genome-wide association study (GWAS) to discover common genetic variants associated with IOP.
We assessed the association between single nucleotide polymorphisms (SNPs) and IOP from primary open-angle glaucoma (POAG) cases and controls in more than 6,000 subjects of European ancestry, who are part of the NEIGHBOR (NEI Glaucoma Human genetics collaBORation) consortium, the GLAUGEN (Glaucoma Genes and Environment) study, and the University of Michigan subset of AMD-MMAP MI (Age-related Macular Degeneration-Michigan, Mayo, AREDS and Philadelphia) studies. There were 466,573 SNPs shared across studies. When there were IOP values for both eyes, the maximum IOP was used. The association between IOP and genotypes was tested with a linear regression additive model adjusted for age, gender, and principal component (PC) scores. Treated IOPs were adjusted by dividing by 0.7, an approach confirmed in a subset of patients with pre- and post-treatment IOP values. We also performed a candidate gene association analyses for IOP using the following previously reported IOP related and glaucoma genes: TMCO1, CDKN2B-AS1, GAS7 and CAV1/CAV2.
This dataset included 1,931 cases and 2,199 controls from NEIGHBOR, 820 cases and 343 controls from GLAUGEN, and 128 cases and 870 controls from the Michigan cohort of AMD-MMAP. While no signal achieved genome-wide significance in individual studies, a meta-analysis identified that IOP was associated with TMCO1 (rs7518099-G, p = 6.5E-8). Focused analyses of TMCO1, CDKN2B-AS1, GAS7, and CAV1/CAV2 revealed association signals that are consistent across the three studies and replicated the previously reported association in both effect size and direction. In the NEIGHBOR dataset, the association at TMCO1 was stronger in males than in females; and the effects at CDKN2B-AS1 and CAV-1/CAV2 were stronger in the younger subjects.
Our meta-analysis identified significant association between IOP and TMCO1. In addition, the previously reported genes of CDKN2B-AS1, GAS7, and CAV1/CAV2 revealed association signals consistent in both effect size and direction with previous reports. Our results add to the GWAS evidence that these genes are involved in IOP regulation.
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