A Deep Phenotype Association Study (DeePAS) in AREDS2 reveals specific phenotype associations with AMD-related genetic variants

Abstract

Purpose : Age-related macular degeneration (AMD) is a multifactorial disease with a highly variable phenotypic presentation. Recently, a Genome-Wide Association Study identified 52 single nucleotide polymorphisms (SNPs) that showed an association with AMD. These genetic variants may represent different pathways involved in AMD pathogenesis and contribute to the variability of the phenotype. We performed a Deep Phenotype Association Study (DeePAS) in Age-Related Eye Disease Study 2 (AREDS2) to identify variants that are related to specific AMD and non-AMD phenotypes.

Methods : Genotyping information of the 52 GWAS SNPs was available for 1826 AREDS2 participants. AREDS2 participants have had detailed phenotyping for AMD characteristics and have been assessed for phenotypes related to other retinal disease, cataract, cardiovascular disease, neurological disease, cognitive function, gastro-intestinal and endocrine disease, nutrient serum levels and other. In total, we distinguished 138 phenotypes. The DeePAS was performed by correlating the 52 SNPs with all available phenotypes. Associations that reached Bonferroni-corrected significance were replicated in AREDS.

Results : The DeePAS revealed that the SNP rs3750846 in the ARMS2/HTRA1 locus was significantly associated with subretinal hemorrhage related to neovascular AMD (OR 1.57 (1.33-1.86), p=8.16*10^-8). This association remained significant after conditioning on participants who had neovascular AMD, showing that it was indeed subretinal hemorrhage driving the association and not neovascular AMD itself. Two SNPs in the CFH locus, rs10922109 and rs570618, were associated with drusen area in the ETDRS grid (p=1.54*10^-12 and p=3.41*10^-9 respectively) and center subfield (p=6.38*10^-11 and p=3.46*10^-8 respectively). These associations were significantly replicated in AREDS.

Conclusions : This DeePAS showed that AMD-related SNPs may be associated with specific phenotypes. A SNP in ARMS2/HTRA1 was significantly associated with subretinal hemorrhage and two SNPs in CFH were associated with drusen area, possibly revealing underlying pathophysiological pathways.

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

 

Manhattan plot of Deep Phenotype Association Study in AREDS2