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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Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Shen, Grace L
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Tufts University
United States
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Seddon, Johanna M; Ferrara, Daniela (2017) Rare Genetic Variants in Age-Related Macular Degeneration. JAMA Ophthalmol 135:1045-1046
Seddon, Johanna M (2017) Macular Degeneration Epidemiology: Nature-Nurture, Lifestyle Factors, Genetic Risk, and Gene-Environment Interactions - The Weisenfeld Award Lecture. Invest Ophthalmol Vis Sci 58:6513-6528
Merle, Bénédicte M J; Silver, Rachel E; Rosner, Bernard et al. (2017) Associations Between Vitamin D Intake and Progression to Incident Advanced Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 58:4569-4578
Ferrara, Daniela; Silver, Rachel E; Louzada, Ricardo N et al. (2017) Optical Coherence Tomography Features Preceding the Onset of Advanced Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 58:3519-3529
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
Lane, Mark; Ferrara, Daniela; Louzada, Ricardo Noguera et al. (2016) Diagnosis and Follow-Up of Nonexudative Choroidal Neovascularization With Multiple Optical Coherence Tomography Angiography Devices: A Case Report. Ophthalmic Surg Lasers Imaging Retina 47:778-81
Seddon, Johanna M; McLeod, D Scott; Bhutto, Imran A et al. (2016) Histopathological Insights Into Choroidal Vascular Loss in Clinically Documented Cases of Age-Related Macular Degeneration. JAMA Ophthalmol 134:1272-1280
Yu, Yi; Wagner, Erin K; Souied, Eric H et al. (2016) Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†. Hum Mol Genet 25:5276-5285
Merle, Bénédicte M J; Silver, Rachel E; Rosner, Bernard et al. (2016) Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study. Am J Clin Nutr 103:1135-44
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 163:154-166.e8

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