Primary open angle glaucoma (POAG) is a significant cause of blindness 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. While POAG has a significant heritability, recent genome-wide association studies using moderate sample sizes have only identified a few POAG-related genes with modest effect sizes. These results suggest that large datasets with well-defined phenotypes are needed to fully delineate the genetic architecture of POAG. This proposal will efficiently use existing datasets to create a large sample useful for investigation o genetic determinants of POAG, with a primary focus of identifying genes contributing to the POAG-related quantitative endophenotype, cup-to-disc ratio (CDR). Emerging data suggests that CDR, even when subjectively ascertained, is an important outcome providing valuable insights into the pathogenesis of POAG. Previously we formed two collaborative consortia contributing 3,517 POAG cases and 3,631 controls for GWA studies, the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) and the GLAUGEN study (Glaucoma Genetics). The immediate goals of this proposal are: 1) expand the NEIGHBOR and GLAUGEN consortia to create the NEIGHBORHOOD (NEIGHBOR Heritable Overall Operational Database) consortium and database, which will include harmonized genotype and phenotype data for a total of 4,652 POAG cases, 16,909 subjects with CDR and 42,486 controls~ and, 2) use this enhanced dataset to perform meta-analyses to identify novel genes influencing CDR, as well as genes that contribute to POAG. Additionally, this proposal will form the basis of future studies of other POAG related traits and gene-gene and gene-environment interactions for CDR and POAG.

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 develop an operational database housing phenotype and genotype information for over 4600 POAG cases, 16,000 individuals with data for the heritable POAG endophenotype cup-to-disc ratio (CDR), and 42,000 controls that can be used to identify risk factors for POAG with the ultimate goal of elucidating the molecular pathogenesis of POAG making it possible to implement effective screening and prevention strategies and to develop novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022305-03
Application #
8728250
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Agarwal, Neeraj
Project Start
2012-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$394,460
Indirect Cost
$94,353
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Loomis, Stephanie J; Kang, Jae H; Weinreb, Robert N et al. (2014) Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss. Ophthalmology 121:508-16
Carnes, Megan Ulmer; Liu, Yangfan P; Allingham, R Rand et al. (2014) Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet 10:e1004372
Ozel, A Bilge; Moroi, Sayoko E; Reed, David M et al. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133:41-57
Kang, J H; Loomis, S J; Yaspan, B L et al. (2014) Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma. Eye (Lond) 28:662-71
Bailey, Jessica N Cooke; Yaspan, Brian L; Pasquale, Louis R et al. (2014) Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Hum Genet 133:1319-30
Springelkamp, Henriët; Höhn, René; Mishra, Aniket et al. (2014) Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process. Nat Commun 5:4883
Gharahkhani, Puya; Burdon, Kathryn P; Fogarty, Rhys et al. (2014) Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet 46:1120-5
Lu, Yi; Vitart, Veronique; Burdon, Kathryn P et al. (2013) Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet 45:155-63
Cooke Bailey, Jessica N; Sobrin, Lucia; Pericak-Vance, Margaret A et al. (2013) Advances in the genomics of common eye diseases. Hum Mol Genet 22:R59-65