Glaucoma is one of the leading causes of blindness in America, and disproportionately affects African Americans. This grant is focused on finding POAG susceptibility genes in this understudied population. POAG causes blindness through death of the retinal ganglion cells and degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. During the first funding period of this grant, we investigated gene expression in the trabecular meshwork and the retina by generating over 800,000 Serial Analysis of Gene Expression (SAGE) tags. We hypothesize that the genes expressed in these tissues constitute excellent candidates for POAG susceptibility genes. We have just completed linkage analysis in 142 multiplex POAG families using over 5,000 single nucleotide polymorphisms. Analysis of this screen identified one novel linkage peak on Chromosome 3 in African Americans with a non-parametric linkage score greater than 3.0. It also identified a second African American linkage peak on chromosome 2 that replicates a previously identified locus in a Barbados population with a lod score of 3.5. We now propose to follow up these two linkage peaks to identify the causative POAG susceptibility genes. We will use a two-pronged attack to find these genes. First we will use a genomic convergence approach that takes advantage of multiple types of data including linkage, association, expression, and biological pathway analysis. Second, we will use a traditional association mapping approach to characterize these two regions. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this blinding disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013315-10
Application #
8055342
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2000-10-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
10
Fiscal Year
2011
Total Cost
$492,615
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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
Liu, Yutao; Allingham, R Rand (2017) Major review: Molecular genetics of primary open-angle glaucoma. Exp Eye Res 160:62-84
Pasquale, Louis R (2016) Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol 27:94-101
Hauser, Michael A; Aboobakar, Inas F; Liu, Yutao et al. (2015) Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus. Hum Mol Genet 24:6552-63
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
Li, Yi-Ju; Minear, Mollie A; Qin, Xuejun et al. (2014) Mitochondrial polymorphism A10398G and Haplogroup I are associated with Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 55:4577-84
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

Showing the most recent 10 out of 46 publications