The underlying hypothesis of this proposal is that identifiable genetic influences play a critical role in the pathophysiology of primary open angle glaucoma (POAG). Furthermore, we believe that the best approach toward identification of the underlying genes is a coordinated attack on this complex disorder utilizing multiple genetic and genomic avenues of investigation, a process that has come to be known as genomic convergence. The major objective of this proposal is to identify the gene that contributes to the development of an early adult onset form of POAG on chromosome 15 (mean family age at diagnosis =45.3 years). We have identified a new genetic locus for POAG on chromosome 15q11-13 through the use of statistical genetic methods suited to the investigation of complex inherited disorders and utilizing a large strictly ascertained database of multiplex POAG families. Using, a novel approach for phenotypic subsetting (ordered subset analysis [OSA]) we have shown that the phenotypic subset of families with an early adult onset form of POAG in the 4th and 5th decades of life (approximately 20% of families within the complete dataset) accounts for the majority of the chromosome 15 linkage information. Our preliminary data suggest that this new locus is a common Mendelian form of POAG. The critical element of this proposal is to apply genomic convergence, or the application of multiple scientific lines of genomic investigation, to determine the genetic contribution of disease. The primary goals of this proposal are threefold: 1) to reduce the minimal candidate interval (MCI) by expanding the size of our early-onset POAG multiplex family dataset and by establishing an association data set of early onset POAG families in conjunction with state of the art molecular and genetic analysis of these data. 2) to create a focused and enriched pool of candidate genes through the use of microarray techniques on human POAG tissue specimens while incorporating the use of existing SAGE/EST libraries; and 3) to analyze candidate genes by sequencing coding regions and conducting association analysis using SNP's. In this manner, we will integrate our family resources, statistical, and molecular expertise to identify the primary genes in POAG. This proposal offers a powerful approach to determine the genetic identity of a major cause of POAG. Determining the molecular underpinnings of POAG will provide enormous benefits in the search for new diagnostic and treatment approaches to this disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Chin, Hemin R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
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
Wallace, Dana J; Chau, Felix Y; Santiago-Turla, Cecilia et al. (2014) Osteogenesis imperfecta and primary open angle glaucoma: genotypic analysis of a new phenotypic association. Mol Vis 20:1174-81
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

Showing the most recent 10 out of 42 publications