Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. Compelling evidence supports the hypothesis that specific genes influence susceptiblity to the disease. We have previously completed a genome wide screen and follow-up studies that have identified two POAG candidate loci with high likelihood of containing POAG susceptibility genes on chromosomes 14 and 15. The major objective of this proposal is to identify the POAG susceptibility gene(s) located within the defined genetic region on chromosome 14 and determine the relationships between specific genetic defects and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. To accomplish this overall goal, the size of the minimal genetic interval on chromosome 14 will be reduced by performing linkage analyses on new multiplex families affected with POAG, as well as identifying areas of linkage disequillibrium within the minimal genetic interval using family-based SNP association studies. Known genes and novel gene fragments within the refined minimal genetic interval will be identified using the annotated human genome sequence and will be prioritized for screening using function and expression information from a variety of sources. Identified DNA sequence variants will be examined for biological significance by case/control analyses using a large cohort of POAG cases and age-matched controls. Haplotypes associated with candidate genes will be analyzed using a case/control approach to identify potential regulatory changes that could be missed by sequencing alone. 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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY015872-01
Application #
6812952
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Chin, Hemin R
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$475,812
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
Khawaja, Anthony P; Cooke Bailey, Jessica N; Kang, Jae Hee et al. (2016) Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses. Invest Ophthalmol Vis Sci 57:5046-5052
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
Fan, Bao J; Pasquale, Louis R; Kang, Jae H et al. (2015) Association of clusterin (CLU) variants and exfoliation syndrome: An analysis in two Caucasian studies and a meta-analysis. Exp Eye Res 139:115-22
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
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
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

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