Although there are numerous genetic variants associated with age-related degeneration (AMD), a meaningful fraction of missing heritability has yet to be exlained. Many studies have focused on identifying the common variants contributing to this disease in the general population.
One aim of this project is to discover rare, highly penetrant genetic variants contributing to familial forms of AMD. The AMD Registry and Biorepository is a large cohort with unique characteristics that include standardized clinical phenotype data and longitudinal prospective data. Some families from this cohort have multiple members with advanced AMD that cannot be explained by known AMD-associated genetic variants and will be sequenced using next-generation sequencing to discover novel variants. Variants found to perfectly segregate with the disease in these families will be assessed for association with AMD in an independent case-control cohort. To discover additional genetic variants contributing to the missing heritability, a second aim is to assess known and novel genetic variants for their role in progression of AMD over time, particularly the effect each variant has on the initiation of the disease and the transition to early, intermediate, and advanced stages. To further the understanding of AMD as a complex trait, quantitative and semi-quantitative intermediate sub-phenotypes will be assessed for association with these genetic variants. Results from this study will fill gaps in our knowledge about the genetics of AMD. We will use these discoveries to develop improved predictive models for AMD progression, and our results may lead to more accurate diagnoses and better therapeutic targets. The ultimate goal is to prevent or slow the progression of AMD and reduce the burden of visual loss due to this disease.

Public Health Relevance

To expand the knowledge of the genetic architecture of age-related macular degeneration (AMD), we aim to identify novel rare variants contributing to familial AMD and assess the relationship of all known variants to date (including any novel variants identified in this project) with progression to advanced disease as well as with intermediate sub-phenotypes. These discoveries will help to fill gaps in our knowledge and will provide novel insights into the genetic mechanisms and risk factors contributing to AMD pathogenesis and progression over time. Results will enhance predictive modeling and may lead to the development of new therapeutic strategies to prevent the burden of visual loss related to this disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY011309-19A1
Application #
9177095
Study Section
Special Emphasis Panel (ZEY1-VSN (02))
Program Officer
Shen, Grace L
Project Start
1996-03-01
Project End
2017-09-29
Budget Start
2016-09-30
Budget End
2017-09-29
Support Year
19
Fiscal Year
2016
Total Cost
$437,500
Indirect Cost
$187,500
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
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
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
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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