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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Shen, Grace L
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Tufts University
United States
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Sobrin, Lucia; Seddon, Johanna M (2014) Nature and nurture- genes and environment- predict onset and progression of macular degeneration. Prog Retin Eye Res 40:1-15
Hutchinson, John N; Raj, Towfique; Fagerness, Jes et al. (2014) Allele-specific methylation occurs at genetic variants associated with complex disease. PLoS One 9:e98464
Hutchinson, John N; Fagerness, Jes; Kirby, Andrew et al. (2014) (Epi)Genetic analyses of age-related macular degeneration: case-control and discordant twin studies. Hum Hered 78:59-72
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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Yu, Yi; Reynolds, Robyn; Rosner, Bernard et al. (2012) Prospective assessment of genetic effects on progression to different stages of age-related macular degeneration using multistate Markov models. Invest Ophthalmol Vis Sci 53:1548-56

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