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 #
5R01EY013315-09
Application #
7797374
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
2010-04-01
Budget End
2011-03-31
Support Year
9
Fiscal Year
2010
Total Cost
$491,386
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
Liu, Yutao; Allingham, R Rand (2017) Major review: Molecular genetics of primary open-angle glaucoma. Exp Eye Res 160:62-84
Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas et al. (2016) A Common Variant in MIR182 Is Associated With Primary Open-Angle Glaucoma in the NEIGHBORHOOD Consortium. Invest Ophthalmol Vis Sci 57:3974-81
Pasquale, Louis R (2016) Vascular and autonomic dysregulation in primary open-angle glaucoma. Curr Opin Ophthalmol 27:94-101
(2016) Erratum. Invest Ophthalmol Vis Sci 57:4528
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
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
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
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
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

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