Age-related macular degeneration (AMD) is a highly prevalent, late-onset complex disorder caused by a combination of interacting genetic and environmental factors. Recent studies have identified several Mendelian loci, most notably those encoding proteins of the complement system, which are highly associated with the development of AMD. These loci currently explain between 50-70% of the disease, thus other causal factors most certainly participate in the disease development. Indeed, multiple lines of evidence suggest a role for various environmental factors in AMD. It has been proposed, for example, that diet, smoking, and photochemical damage increase oxidative stress, thereby contributing to development of AMD. These environmental factors act through non-Mendelian genetic mechanisms, including epigenetic regulation of gene expression and damage to mitochondrial DNA (mtDNA), which have been documented in various late-onset complex traits. None of these disease mechanisms has been comprehensively studied in AMD. The major goal of this proposal is to test the hypothesis that the non-Mendelian genetic mechanisms such as copy number variation of genes, epigenetic regulation of gene expression and somatic variation in mtDNA play a significant role in AMD. To investigate this hypothesis, we will utilize a unique repository comprised of 4,000 extensively characterized (both clinically and genetically) human donor eyes and advanced methods of genetic analyses to address the following specific aims: 1) refinement of our knowledge relating to AMD endo- phenotypes and genotype/phenotype correlation by enhanced phenotyping of AMD cases using advanced image analysis;2) determination of specific genes/loci where copy number variation is associated with AMD;3) assessment of epigenetic regulation of gene expression in the development of AMD and;4) assessment of the role of acquired, somatic variation in mtDNA in susceptibility to AMD. The discovery of additional genetic and """"""""environmental"""""""" causes of AMD will contribute important new information pertaining to disease etiology, and will reveal potential new surrogate biomarkers and diagnostic tests. More importantly, the proposed project will likely provide for new pharmacological targets for the treatment of this extremely prevalent and devastating disorder.

Public Health Relevance

AMD is the most prevalent cause of vision loss in the elderly, affecting millions of Americans representing a major public health problem with currently limited treatment options that are palliative in nature. Several major Mendelian genetic loci associated with AMD (explaining roughly 50% of the disorder) have been identified, however, less is known about the other half possibly consisting of environmental and non-Mendelian components. Identification of copy number variation of genes, their methylation/expression status and variation in mitochondrial DNA and the resulting pathophysiological effects will contribute new information pertaining to disease etiology, will reveal potential surrogate biomarkers and diagnostic tests, and will suggest pharmacological targets for the treatment of this extremely prevalent and devastating disorder.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Shen, Grace L
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Cantsilieris, Stuart; Nelson, Bradley J; Huddleston, John et al. (2018) Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family. Proc Natl Acad Sci U S A 115:E4433-E4442
Fritsche, Lars G; Igl, Wilmar; Bailey, Jessica N Cooke et al. (2016) A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet 48:134-43
Piekutowska-Abramczuk, Dorota; Kocy?a-Karczmarewicz, Beata; Ma?kowska, Maja et al. (2016) No Evidence for Association of SCO2 Heterozygosity with High-Grade Myopia or Other Diseases with Possible Mitochondrial Dysfunction. JIMD Rep 27:63-8
Grassmann, Felix; Friedrich, Ulrike; Fauser, Sascha et al. (2015) A Candidate Gene Association Study Identifies DAPL1 as a Female-Specific Susceptibility Locus for Age-Related Macular Degeneration (AMD). Neuromolecular Med 17:111-20
Duncker, Tobias; Marsiglia, Marcela; Lee, Winston et al. (2014) Correlations among near-infrared and short-wavelength autofluorescence and spectral-domain optical coherence tomography in recessive Stargardt disease. Invest Ophthalmol Vis Sci 55:8134-43
Garg, Aakriti; Wapner, Ronald J; Ananth, Cande V et al. (2014) Choroidal and retinal thickening in severe preeclampsia. Invest Ophthalmol Vis Sci 55:5723-9
Schubert, Carl; Pryds, Anders; Zeng, Shemin et al. (2014) Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy. Hum Mutat 35:859-67
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
Fritsche, Lars G; Chen, Wei; Schu, Matthew et al. (2013) Seven new loci associated with age-related macular degeneration. Nat Genet 45:433-9, 439e1-2
Burke, Tomas R; Yzer, Suzanne; Zernant, Jana et al. (2013) Abnormality in the external limiting membrane in early Stargardt disease. Ophthalmic Genet 34:75-7

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