Age-related macular degeneration (AMD) is a complex disease in which multiple genetic and environmental components influence the clinical phenotype. The condition is now the major cause of legal blindness in older people in the USA. Understanding the complete genetic epidemiology will enable the development of new therapies and preventive strategies. Several common genetic variants associated with AMD have been identified. We hypothesize that the remaining etiology is explained by a number of individually less common, but functionally significant genetic variants. This project is the beginning of a new and exciting collaboration between the Macular Degeneration Center at the Casey Eye Institute/Oregon Health and Science University and the Department of Genetics to accomplish at the Southwest Foundation for Biomedical Research. Novel AMD-susceptibility genes will be identified by using a powerful joint genome-wide linkage and association strategy in our pre-existing collection of 150 pedigrees enriched for their susceptibility to AMD. We will increase the likelihood of identifying susceptibility-related genetic variation by careful quantification of the phenotype using stored retinal images to identify biological characteristics more closely related to the action of genes. Genes showing the best evidence for each AMD-related phenotype following high-density SNP-array genotyping will be replicated in unrelated AMD cases and controls. Whole Exome Next Generation sequencing will also be undertaken to identify rare or potentially private mutations present in the families. Bayesian QTN and bioinformatics analysis will be used to predict functional variants.

Public Health Relevance

Macular degeneration is a common complex disease that results from the interplay of genes and environmental factors. The objective of this application is to resolve existing and identify novel AMD genetic susceptibility variants using a powerful joint linkage and association strategy in our pre-existing collection of extended pedigrees with the condition. Genotyping will employ SNP-array and Next Generation Whole Exome sequencing techniques.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021532-03
Application #
8541861
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$697,512
Indirect Cost
$129,313
Name
Oregon Health and Science University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Ratnapriya, Rinki; Zhan, Xiaowei; Fariss, Robert N et al. (2014) Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet 23:5827-37
Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew, Emily Y; Clemons, Traci E et al. (2014) Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol 132:142-9
Meyers, Kristin J; Mares, Julie A; Igo Jr, Robert P et al. (2014) Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Invest Ophthalmol Vis Sci 55:587-99
Chew, Emily Y; Klein, Michael L; Clemons, Traci E et al. (2014) No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology 121:2173-80