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.

Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations

“…Previous genome-wide association studies have identified numerous risk-associated variants within 19 susceptibility loci for AMD [6][7][8][9][10] . However, genome-wide association studies focus on common variants (minor allele frequency (MAF) 45%), which are usually located in the intronic regions of the chromosome and do not encode specific functional proteins 11,12 .…”

No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population

“…Rs2075650 within APOE/TOMM40 has been studied for its associations with several age-related disorders and diseases in GWAS, such as cognitive decline 27,28 and Alzheimer's disease (AD), [29][30][31] as well as AMD. 12,13 Apolipoprotein E (ApoE), encoded by the APOE gene, was recognized for its crucial role in lipoprotein transport. An endogenous way of retinal lipid removal may rely on the components of reverse cholesterol transport including ApoE.…”

“…12 Recently, this variant has been identified showing association with early AMD in a GWAS meta-analysis of European population (P ¼ 1.1 Â 10 À6 ), and the signal remained in secondary meta-analysis combining two Singapore-based Asian cohorts (P ¼ 3.2 Â 10 À6 ). 13 However, Guo et al 14 failed to replicate the association between this variant and neovascular AMD, the CNV subtype of advanced AMD in a northern Chinese cohort (P ¼ 0.912), which could be due to the phenotypic discrepancy between AMD subtypes and overall advanced AMD, as well as the genetic discrepancy between different ethnic groups. As no genetic association study of rs2075650 has been performed for overall advanced AMD in Chinese population before, to shed a light on the source of these contradicting results, it is necessary to study the potential impact of rs2075650 on overall advance AMD risk in Chinese population.…”

Effect of supplementing meals with soluble milk proteins on plasma leucine levels in healthy older people: A randomized pilot study

“…The second sample (T0) was performed 20 minutes after the collection of T0', regardless of the time taken by participants to eat the meal. According to randomization, participants then consumed 100 mL of a drink containing either 8.2 g of Prolacta ® (PRO8), 5 g of Prolacta ® (PRO5) or 0 g of Prolacta ® [11] over a maximum of 2 minutes ( Table 2). The consumption of the standardized lunch in addition to the control drink was considered the control meal, providing 27 g of proteins and 2.2 g of leucine.…”