Contribution of AMD risk variants to the genetic architecture of choroidal thickness in the Amish

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.