Age Related Maculopathy (ARM) is the leading cause of vision loss in the elderly population in the United States and the Western world and is a major public health issue. Epidemiologic studies have indicated that heredity is a significant risk factor and family studies have further substantiated that ARM could be inherited as a dominant disease with late age of onset and variable expressivity. ARM is not well suited for traditional genetic investigations due to difficulties of clinical ascertainment and the small pedigrees because of its late onset. The evaluation of peripheral fundus for drusen; multiple extramacular drusen (MED) and reticular degeneration of the pigment epithelium (RDPE) has provided improved methods of ascertainment. The Affected Pedigree Member method of genetic analysis of complex inherited traits has successfully determined the linkage of familial Late Onset Alzheimer' s disease and demonstrated the feasibility of studying the genetics of ARM. The development of polymerase chain reaction technique and the closely spaced, polymorphic markers spanning the whole genome will now allow a study of the genetic loci without prior knowledge of candidate gene defects. We propose three specific aims to study the genetics of ARM.
Our first aim i s to collect affected families in two major population centers. The families will be identified then ascertained using the traditional criteria of vision loss, macular drusen and sub retinal neovascularization, and the new criteria of MED and RDPE. We will evaluate the concordance of the clinical features among family members to define a cohort for genetic study.
Our second aim i s to find the optimal sample size for recruitment and number of markers needed for genotyping by computer-simulating ARM inheritance.
Our third aim i s to perform linkage analysis using the Affected Pedigree Member method to identify genetic loci that contribute to ARM susceptibility based on' information obtained with the genotyping of our families. We have already begun by collecting forty five families that suggest autosomal dominant inheritance in thirty- nine pedigrees. The preliminary results of our simulation studies show that it is more powerful to genotype 75 families with markers that are 20 Cm apart than to genotype 150 families at 40 cM distance. To achieve better resolution, the simulation studies show that it is better to genotype another 75 families at 20 cM than to further genotype the original 75 families. This approach illustrates that we can use simulations to select regions for genotyping and analysis with high probability (99%) of success of identifying linkage at reduced cost and effort.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009859-03
Application #
2163581
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1993-09-01
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nusinowitz, S; Wang, Y; Kim, P et al. (2018) Retinal Structure in Pre-Clinical Age-Related Macular Degeneration. Curr Eye Res 43:376-382
Shan, Ying; Tromp, Gerard; Kuivaniemi, Helena et al. (2017) Genetic risk models: Influence of model size on risk estimates and precision. Genet Epidemiol 41:282-296
Lo, Yancy; Kang, Hyun M; Nelson, Matthew R et al. (2015) Comparing variant calling algorithms for target-exon sequencing in a large sample. BMC Bioinformatics 16:75
Bui, Diem K; Jiang, Yingda; Wei, Xin et al. (2015) Genetic ME-a visualization application for merging and editing pedigrees for genetic studies. BMC Res Notes 8:241
Baron, Robert V; Conley, Yvette P; Gorin, Michael B et al. (2015) dbVOR: a database system for importing pedigree, phenotype and genotype data and exporting selected subsets. BMC Bioinformatics 16:91
Gorin, Michael B; Weeks, Daniel E; Baron, Robert V et al. (2014) Endophenotypes for Age-Related Macular Degeneration: Extending Our Reach into the Preclinical Stages of Disease. J Clin Med 3:1335-56
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
Zhan, Xiaowei; Larson, David E; Wang, Chaolong et al. (2013) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 45:1375-9
Gorin, Michael B (2012) Genetic insights into age-related macular degeneration: controversies addressing risk, causality, and therapeutics. Mol Aspects Med 33:467-86
Sofat, Reecha; Casas, Juan P; Webster, Andrew R et al. (2012) Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int J Epidemiol 41:250-62

Showing the most recent 10 out of 33 publications