Glaucoma is a leading cause of irreversible blindness and has a substantial impact on the quality of life of millions of Americans. Primary open angle glaucoma (POAG) is the most common form of glaucoma and has a strong genetic component. POAG is regarded as a group of disorders and is clinically characterized by several quantitative traits (QTs), such as visual field loss, optic nerve cupping and thin central corneal thickness (CCT). Intraocular pressure (IOP) is another important QT that is often used to assess the risk of developing glaucoma. The pathogenesis of glaucoma is not well understood. The heterogeneity of POAG has challenged the efforts of its genetic investigations. Recently, researchers have begun to use the quantitative features associated with glaucoma to facilitate the search for glaucoma disease-causing genes. Glaucoma disproportionately affects Mexican Americans (MAs). While MAs are the largest and fast growing minority group in the US, genetic studies in MAs have lagged behind. The goal of this study is to identify genetic determinants responsible for POAG in the understudied MAs. We have finished a complete ophthalmologic examination for glaucoma and ocular hypertension and obtained DNA on 5,338 participants in the Los Angeles Latino Eye Study (LALES). We will use a genome-wide association study (GWAS) to identify genetic factors related to components of the glaucoma phenotype in MAs.
Our specific aims are: to genotype the 5,338 participants using the Illumina OmniExpress and newly developed HumanExome BeadChips and impute genotypes based on the 1000 Genomes Project reference panels;to carry out a series of GWAS analyses to identify genetic loci associated with the quantitative features of POAG, e.g. cup-to-disc ratio, CCT and IOP;to identify and test significant pathways influencing the glaucoma phenotype;and to carry out fine mapping and replicate findings among different ethnic groups. This study will initiate the discovery of glaucoma variants and pathways that are common and unique to MAs. Furthermore, the knowledge derived from this study will extend our understanding of glaucoma and may potentially suggest new detection and therapeutic avenues for this blinding disease.

Public Health Relevance

Glaucoma disproportionately affects Mexican Americans, the most populous minority population in the US. However, the genetic factors contributing to this increased susceptibility are poorly understood. This study will have significant public health benefits by identifying variants, genes and pathways associated with glaucoma, thereby potentially leading to early detection and effective treatment of this blinding disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY022651-01
Application #
8345500
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Chin, Hemin R
Project Start
2012-09-30
Project End
2017-06-30
Budget Start
2012-09-30
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
University of Southern California
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Fan, Bao Jian; Chen, Xueli; Sondhi, Nisha et al. (2018) Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus. Invest Ophthalmol Vis Sci 59:2495-2502
Nannini, Drew R; Kim, Heejin; Fan, Fangda et al. (2018) Genetic Risk Score Is Associated with Vertical Cup-to-Disc Ratio and Improves Prediction of Primary Open-Angle Glaucoma in Latinos. Ophthalmology 125:815-821
Kang, Kai B; Lawrence, Brian D; Gao, X Raymond et al. (2017) Micro- and Nanoscale Topographies on Silk Regulate Gene Expression of Human Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 58:6388-6398
Nannini, Drew R; Torres, Mina; Chen, Yii-Der I et al. (2017) A Genome-Wide Association Study of Vertical Cup-Disc Ratio in a Latino Population. Invest Ophthalmol Vis Sci 58:87-95
Fini, M Elizabeth; Schwartz, Stephen G; Gao, Xiaoyi et al. (2017) Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine. Prog Retin Eye Res 56:58-83
Nannini, Drew; Torres, Mina; Chen, Yii-Der I et al. (2016) Reply. Ophthalmology 123:e31-2
Gao, Xiaoyi; Nannini, Drew R; Corrao, Kristen et al. (2016) Genome-wide association study identifies WNT7B as a novel locus for central corneal thickness in Latinos. Hum Mol Genet 25:5035-5045
Nannini, Drew; Torres, Mina; Chen, Yii-Der I et al. (2016) African Ancestry Is Associated with Higher Intraocular Pressure in Latinos. Ophthalmology 123:102-8
Jeong, Shinwu; Patel, Nitin; Edlund, Christopher K et al. (2015) Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. Invest Ophthalmol Vis Sci 56:2737-48

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