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.
Highlights
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly in many countries [1]
We report findings from genome-wide association studies (GWAS) meta-analysis restricted to individuals with early AMD, prior to the development of late, vision-impairing disease
SNPs at the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2)/HTRA1 loci, which were discovered for late AMD, comprised strong and significant risk factors for the development of early AMD as well
Summary
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly in many countries [1]. AMD is characterised by abnormalities in the retinal pigment epithelium (RPE) and the deposition of small extracellular deposits, called drusen, between Bruch’s membrane and the RPE [3]. Large drusen (.125 mm in diameter) with or without fuzzy edges (soft indistinct or distinct drusen) may slowly disappear and be replaced by regions of retinal depigmentation (decreased pigment). Soft drusen involving a large area of the macula are strong indicators of increased risk of progression to late, vision-impairing forms of this disease [4]. Exudative AMD is typified by sub-retinal neovascularisation with sensory retinal and/or RPE detachment, subretinal and/or sub-RPE haemorrhage followed by sub-retinal scarring. GA involves gradual degeneration and disappearance of RPE and photoreceptor cells within the macular area [3]
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