Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptibility to the disease. The objective of this proposal is to identify POAG susceptibility genes and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will lead to new treatment and diagnostic modalities. Using 103 sibpairs affected by POAG, an initial screen of the human genome has been completed, and sixteen genomic regions demonstrating initially promising linkage results have been identified. The goals of the current proposal are to confirm the initial POAG linkage results with a second set of affected pedigrees, examine candidate genes located in the confirmed regions, and identify genes that confer risk to POAG. To achieve these goals, a second pedigree set of 200 affected sibpairs will be collected and used to confirm the initial linkage results. Follow-up studies will include additional genotyping of new markers located in the regions of interest, and genotyping the initial markers in the second pedigree set. Candidate genes mapped within the confirmed genomic regions will be tested for POAG associations using both linkage analysis and family based association studies using the S-TDT. Genes that show positive associations will be screened for responsible DNA sequence alterations. Specific genetic defects will be correlated with clinical phenotype by investigating familial aggregation of clinical parameters and looking for evidence of gene/gene interactions and how these interactions may influence phenotype. Initial genome screens to identify genes responsible for two POAG risk factors, ocular hypertension (OHT) and pseudoexfoliation (PEX), will be performed.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010886-08
Application #
6476386
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Chin, Hemin R
Project Start
1994-12-01
Project End
2004-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
8
Fiscal Year
2002
Total Cost
$932,771
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
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
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
Pasquale, Louis R (2016) Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol 27:94-101
Bailey, Jessica N Cooke; Loomis, Stephanie J; Kang, Jae H et al. (2016) Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet 48:189-94
Li, Zheng; Allingham, R Rand; Nakano, Masakazu et al. (2015) A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 24:3880-92
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
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
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
Liu, Yutao; Garrett, Melanie E; Yaspan, Brian L et al. (2014) DNA copy number variants of known glaucoma genes in relation to primary open-angle glaucoma. Invest Ophthalmol Vis Sci 55:8251-8
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

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