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Title page for ETD etd-03052015-113543

Type of Document Dissertation
Author Hoffman, Joshua David
Author's Email Address joshua.hoffman@vanderbilt.edu
URN etd-03052015-113543
Title Modeling Macular Degeneration Using Quantitative Phenotypes
Degree PhD
Department Human Genetics
Advisory Committee
Advisor Name Title
Tricia A. Thornton-Wells Committee Chair
Chun Li Committee Member
David C. Samuels Committee Member
Jonathan L. Haines Committee Member
Milam A. Brantley Committee Member
  • AMD
  • genetics
  • Age-Related Macular Degeneration
  • genomics
  • assocation analysis
  • linkage analysis
Date of Defense 2015-03-02
Availability unrestricted
Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the United States (US). Although a multitude of studies have shown that both genetic and environmental factors contribute to the pathogenesis of AMD, little is known on how genetics affects the disease’s rate of progression. We performed a quantitative genetic analysis of drusen progression during the intermediate stage of the disease to understand the role of known AMD genetic variation to this phenotype. Drusen progression was tested against 19 previously identified genetic variants using a cumulative genetic risk score, single variant analyses, and a pathway analysis. We do not observe significant correlation between the 19 variant cumulative genetic risk score and drusen progression (rho = 0.039; p = 0.543). Single marker tests of the remaining 15 variants shows a nominally significant association with rs943080 in VEGFA (p = 0.028). The most highly associated pathway in our pathway analysis is the cell adhesion molecule pathway (p < 0.0001). To understand the contribution of rare-genetic variation to AMD, we performed exome sequencing in five members of a small nuclear Amish family who lack the common risk alleles at the major AMD risk loci. We identified a variant (P503A) in CFH that is not present in dbSNP or 1000Genomes and is associated with AMD in an Ohio and Indiana cohort (p = 9.27x10-13).
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