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
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

Showing the most recent 10 out of 50 publications