June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Contribution of AMD risk variants to the genetic architecture of choroidal thickness in the Amish
Author Affiliations & Notes
  • Nicole Restrepo
    Epidemiology & Biostatistics , Case Western Reserve University, SHAKER HEIGHTS, Ohio, United States
  • Yeunjoo Song
    Epidemiology & Biostatistics , Case Western Reserve University, SHAKER HEIGHTS, Ohio, United States
  • Renee Laux
    Epidemiology & Biostatistics , Case Western Reserve University, SHAKER HEIGHTS, Ohio, United States
  • Larry Deon Adams
    Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Denise Fuzzell
    Epidemiology & Biostatistics , Case Western Reserve University, SHAKER HEIGHTS, Ohio, United States
  • Laura J Caywood
    Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Violet Horst
    Ophthalmology and Genetics, University of Pennsylvania, Philadelphia , Pennsylvania, United States
  • Tine MacKay
    Ophthalmology and Genetics, University of Pennsylvania, Philadelphia , Pennsylvania, United States
  • Debbie Dana
    Ophthalmology and Genetics, University of Pennsylvania, Philadelphia , Pennsylvania, United States
  • Muneeswar Gupta Nittala
    Doheny Image Reading Center, Doheny Eye Institute , Los Angeles, California, United States
  • Srinivas R Sadda
    Doheny Image Reading Center, Doheny Eye Institute , Los Angeles, California, United States
    Ophthalmology, University of California, Los Angeles, California, United States
  • William K Scott
    Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Dwight Stambolian
    Ophthalmology and Genetics, University of Pennsylvania, Philadelphia , Pennsylvania, United States
  • Margaret A Pericak-Vance
    Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Jonathan L Haines
    Epidemiology & Biostatistics , Case Western Reserve University, SHAKER HEIGHTS, Ohio, United States
  • Footnotes
    Commercial Relationships   Nicole Restrepo, None; Yeunjoo Song, None; Renee Laux, None; Larry Adams, None; Denise Fuzzell, None; Laura Caywood, None; Violet Horst, None; Tine MacKay, None; Debbie Dana, None; Muneeswar Nittala, None; Srinivas Sadda, None; William Scott, None; Dwight Stambolian, None; Margaret Pericak-Vance, None; Jonathan Haines, None
  • Footnotes
    Support  NCI: Computational Genomic Epidemiology of Cancer Fellowship R25T CA094186
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 1835. doi:
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      Nicole Restrepo, Yeunjoo Song, Renee Laux, Larry Deon Adams, Denise Fuzzell, Laura J Caywood, Violet Horst, Tine MacKay, Debbie Dana, Muneeswar Gupta Nittala, Srinivas R Sadda, William K Scott, Dwight Stambolian, Margaret A Pericak-Vance, Jonathan L Haines; Contribution of AMD risk variants to the genetic architecture of choroidal thickness in the Amish. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1835.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To understand the role that genetics plays in risk and progression of AMD. Parsing AMD into quantitative endophenotypes, each with a distinct genetic basis, will improve prediction of risk and increase our understanding of the genetic architecture of AMD. Here we assess the contribution that known AMD risk SNPs contribute to the genetics of choroidal thickness (CT) in an Amish cohort.

Methods : We sampled 579 related individuals from Amish families with early/intermediate AMD cases in Pennsylvania, Ohio, and Indiana. Individuals underwent a health history and ophthalmologic exam including color fundus photography and SD-OCT scans. Individuals were genotyped for 52 known AMD risk-associated SNPs. We performed a genetic association study of individuals from AMD pedigrees ascertained because at least one individual was diagnosed with AMD. CT was treated as both a continuous and a dichotomous trait (thin vs. normal). Tests were performed with R-Package “GWAF” assuming an additive genetic model and a Wald chi-square test for right, left, and mean eye measures. Continuous CT was analyzed under a Generalized Linear Mixed Effects model (GLMM) and dichotomous CT under Generalized Estimating Equations (GEE) model.

Results : Of the SNPs tested, two were consistently identified across statistical algorithms and across models. Rs1142 on chr. 7 is located in the 3’ UTR of the SRSF protein kinase 2 (SRPK2) gene. When considering CT as a dichotomous trait, rs1142 is statistically significant (p < 0.001) across GLMM and GEE regardless of AMD status. Modeling CT as a continuous trait, rs1142 is significant (p =0.005) only after excluding AMD cases from the pedigrees. Rs2230199 is a missense variant in complement component 3 (C3) and is significantly associated with CT as a dichotomous trait under the GEE model and with nominal associations in GLMM (p < 0.05).

Conclusions : The association of a known AMD-risk variant in C3 with CT suggests that the CT endophenotype shares pathophysiology with AMD. Additionally, variants in C3 (i.e., rs2241394) are associated with risk of polypoidal choroidal vasculopathy, which shares characteristics of wet AMD, in the Japanese. The association of C3 rs2230199 in CT of the Amish may highlight a stronger role of C3 in overall choroidal health.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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