Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) related progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from POAG is a condition of public health significance worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary open-angle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBOR/GLAUGEN meta-analysis, have identified POAG-related genes. However, to comprehensively define the POAG complex genetic architecture large datasets with well-defined phenotypes are required. To achieve the sample size necessary for POAG gene discovery we formed the NEIGHBORHOOD consortium (NEIGHBOR Heritable Overall Operational Database) that includes harmonized genotype and phenotype data for 3,873 cases and 33,642 controls. During the prior funding period we have 1) developed infrastructure for the NEIGHBORHOOD consortium; 2) conducted analyses using the NEIGHBORHOOD data including: GWAS for POAG and the normal-tension subgroup (NTG), gene-phenotype studies, endophenotype genetic association studies, pathway analyses and functional assessment of rare coding variants in associated genes. The immediate goals of this competing renewal are: 1) Add new datasets that contribute cases and controls with clinical features of particular relevance and interest; 2) perform genetic analyses to identify new genes/genomic regions contributing to POAG and related subgroups and also to assess gene- gene interactions and molecular pathway contributions; 3) Explore gene-phenotype relationships for novel genes discovered through recent GWAS; and 4) continue to support the consortium resources and logistics. Additionally, this proposal will provide resources supporting studies investigating gene-environment interactions and molecular studies defining disease mechanisms relevant to POAG and NTG. Ultimately this information will form the basis of novel, and ideally neuro-protective, therapies.

Public Health Relevance

Primary open angle glaucoma (POAG) causes permanent loss of vision and is a condition of public health significance worldwide, affecting millions of people. The etiology of POAG is poorly understood and effective means of primary prevention and curative therapies are not available. In this proposal, our collaborative consortium will complete genetic studies to identify risk factors for POAG with the ultimate goals of developing effective screening and prevention strategies and novel therapies targeted to the molecular events responsible for the disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZEY1)
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Agarwal, Neeraj
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Massachusetts Eye and Ear Infirmary
United States
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Struebing, Felix L; King, Rebecca; Li, Ying et al. (2018) Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse. Exp Eye Res 169:61-67
Gharahkhani, Puya; Burdon, Kathryn P; Cooke Bailey, Jessica N et al. (2018) Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma. Sci Rep 8:3124
Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H et al. (2018) Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Invest Ophthalmol Vis Sci 59:629-636
Iglesias, Adriana I; Mishra, Aniket; Vitart, Veronique et al. (2018) Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nat Commun 9:1864
Fan, Bao Jian; Chen, Xueli; Sondhi, Nisha et al. (2018) Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus. Invest Ophthalmol Vis Sci 59:2495-2502
Shiga, Yukihiro; Akiyama, Masato; Nishiguchi, Koji M et al. (2018) Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. Hum Mol Genet 27:1486-1496
Khawaja, Anthony P; Cooke Bailey, Jessica N; Wareham, Nicholas J et al. (2018) Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma. Nat Genet 50:778-782
King, Rebecca; Struebing, Felix L; Li, Ying et al. (2018) Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genet 14:e1007145
Taniguchi, Elise V; Paschalis, Eleftherios I; Li, Dejiao et al. (2017) Thin minimal rim width at Bruch's membrane opening is associated with glaucomatous paracentral visual field loss. Clin Ophthalmol 11:2157-2167
Wang, Tiange; Huang, Tao; Kang, Jae H et al. (2017) Habitual coffee consumption and genetic predisposition to obesity: gene-diet interaction analyses in three US prospective studies. BMC Med 15:97

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