Shared and distinct genetic variation contributes to risk of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration in East Asians: The GAMA consortium

Abstract

Purpose : Polypoidal choroidal vasculopathy (PCV), developed often in East Asians, have similar and distinct clinical manifestations with typical neovascular age-related macular degeneration (tAMD). As heritable traits, the degree to which genetic variation is shared or unique underlying these two phenotypes is unclear. We aim to examine shared and distinct genetic etiology between PCV and tAMD in East Asians.

Methods : We used SNP-based and gene-based analytic approaches to perform genome-wide SNP data in 1,062 PCV patients and 1,152 tAMD patients versus 5,275 shared non-AMD controls, all of East Asian ancestry recruited from the Genetics of AMD in Asians (GAMA) Consortium. For gene-based analysis, SNPs were annotated to each gene flanking by 20kb. We also applied linkage disequilibrium (LD) score method to estimate genetic correlation between PCV and tAMD using genome-wide SNP data. The diagnosis of neovascular AMD was made based on clinical examinations using dilated fundus photography, fluorescent angiography and optical coherence tomography. Indocyanine green angiography was performed to diagnose PCV.

Results : The genetic correlation based on genome-wide SNP data was high (r = 0.69 ±0.25 s.e, p = 5.0 x 10^-3) between PCV and tAMD. The most genome-wide significant hits for PCV and tAMD converged to functional variants at two well-established regions ARMS2/HTRA1 (A69S; PCV: P = 1.78 x 10^-46; tAMD: P = 4.02 x 10^-80) and CFH (I62V; PCV: P = 2.29 x 10^-26; tAMD: P = 1.56 x 10^-23). A69S mutation was more strongly associated with tAMD than PCV (OR = 1.24 [1.18 -1.30]; P = 4.39 x 10^-4). CFH I62V is an independent signal from the identified Y402H variant in European (r2 < 0.2). Gene-based analysis revealed C2/CFB locus was strongly associated with tAMD (gene-based P =1 x10^-6) but had much weaker association with PCV (gene-based P = 0.0013). Similarly, C6orf223 gene within VEGFA loci (gene-based P =2.40 x10^-5) and HOXB6 gene (gene-based P =4.80 x10^-5) were marginally associated with PCV, but the association was weaker for tAMD (gene-based P = 0.004).

Conclusions : There is shared genetic background between PCV and tAMD but also pinpoint genetic association differences at several regions including ARMS2/HTRA1, VEGFA and HOXB6 loci. We confirmed I62V is the strongest coding variant in CFH gene for both PCV and tAMD in East Asians.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.