Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis

Abstract

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

Figure 1. Regional association results for chromosome 7 SNPs in the GLI-Kruppel family member GLI3 gene.

The index, associated SNP is named and shown as a purple diamond (rs2049622: P = 8.9×10⁻⁶); remaining SNPs are colored according to the strength of LD (r²) with the index SNP (see figure legend). Pairwise LD and local recombination rates were calculated using HapMap CEU population data (Phase 2, release #22), with annotated genes mapped according to NCBI Build 36 sequence position.

Figure 2. Regional association results for chromosome 11 SNPs in the tyrosinase precursor (TYR) gene.

The index, associated SNP is named and shown as a purple diamond (rs621313: P = 3.5×10⁻⁶).

Figure 3. Regional association results for chromosome 19 SNPs in the PVRL2/APOE/TOMM40 gene cluster.

The index, associated SNP is named and shown as a purple diamond (rs2075650: P = 1.1×10⁻⁶).