We will build upon the established and recently identified genetic loci and environmental and ocular determinants, to incorporate newly discovered loci for age-related macular degeneration (AMD) identified in this proposal for gene-gene, gene-environment, and predictive modeling analyses. We also propose to assess the full spectrum of rare, potentially functional variants, as well as common variants in candidate genes/regions by targeted sequencing. The discovery of causal variants in associated genes will improve the understanding of the underlying mechanisms of AMD development and progression. Knowledge of causal variants will lead to more accurate definitions and classification systems for AMD. We will expand our unique databases to accomplish the scientific aims of the study and to facilitate expanded collaborative efforts with other investigators. We will also conduct functional studies to define the mechanisms associated with the genetic variants. As a result of this effort, we anticipate that additional new pathogenic genetic pathways will be identified for this increasing cause of blindness. These potential discoveries will lead to novel therapeutic and preventive measures for preserving vision, and will reduce the burden of marked visual loss due to the advanced forms of AMD.

Public Health Relevance

We will expand knowledge about the genetic architecture of age-related macular degeneration (AMD) by identifying new genetic loci as well as how behaviors and modifiable factors increase or decrease genetic susceptibility. Discovery of new genetic markers which are pathogenic and have a strong influence on AMD will lead to new treatments. Experimental studies will identify the mechanisms related to the newly discovered genetic variants.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011309-18
Application #
8728240
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Shen, Grace L
Project Start
1996-03-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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Shah, Anjali R; Williams, Steven; Baumal, Caroline R et al. (2016) Predictors of Response to Intravitreal Anti-Vascular Endothelial Growth Factor Treatment of Age-Related Macular Degeneration. Am J Ophthalmol 163:154-66.e8
Wagner, Erin K; Raychaudhuri, Soumya; Villalonga, Mercedes B et al. (2016) Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci Rep 6:31531
Triebwasser, Michael P; Roberson, Elisha D O; Yu, Yi et al. (2015) Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 56:6873-8
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Seddon, Johanna M; Silver, Rachel E; Kwong, Manlik et al. (2015) Risk Prediction for Progression of Macular Degeneration: 10 Common and Rare Genetic Variants, Demographic, Environmental, and Macular Covariates. Invest Ophthalmol Vis Sci 56:2192-202
Merle, Bénédicte M J; Silver, Rachel E; Rosner, Bernard et al. (2015) Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. Am J Clin Nutr 102:1196-206
Yu, Yi; Triebwasser, Michael P; Wong, Edwin K S et al. (2014) Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration. Hum Mol Genet 23:5283-93
Seddon, Johanna M; Reynolds, Robyn; Yu, Yi et al. (2014) Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration. PLoS One 9:e87047

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