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


Holliday, EG and Smith, AV and Cornes, BK and Buitendijk, GHS and Jensen, RA and Sim, X and Aspelund, T and Aung, T and Baird, PN and Boerwinkle, E and Cheng, CY and van Duijn, CM and Eiriksdottir, G and Gudnason, V and Harris, T and Hewitt, AW and Inouye, M and Jonasson, F and Klein, BEK and Launer, L and Li, X and Liew, G and Lumley, T and McElduff, P and McKnight, B and Mitchell, P and Psaty, BM and Rochtchina, E and Rotter, J and Scott, RJ and Tay, W and Taylor, K and Teo, YY and Uitterlinden, AG and Viswanathan, A and Xie, S and Vingerling, JR and Klaver, CCW and Tai, ES and Siscovick, D and Klein, R and Cotch, MF and Wong, TY and Attia, J and Wang, JJ, Wellcome Trust Case Control Consortium 2, Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis, PLoS One, 8, (1) Article e53830. ISSN 1932-6203 (2013) [Refereed Article]


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Licensed under Creative Commons Attribution 3.0 Unported (CC BY 3.0)

DOI: doi:10.1371/journal.pone.0053830


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 =1.5נ10-31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3נ10-24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1נ10-6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P =8.9נ10-6) and upstream of GLI2 (rs6721654; P=6.5נ10-6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5נ10-6), 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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:95110
Year Published:2013
Web of Science® Times Cited:188
Deposited By:Medicine
Deposited On:2014-09-24
Last Modified:2014-10-20
Downloads:319 View Download Statistics

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