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

TitleInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.
Publication TypeJournal Article
Year of Publication2013
AuthorsHolliday, EG, Smith, AV, Cornes, BK, Buitendijk, GHS, Jensen, RA, Sim, X, Aspelund, T, Aung, T, Baird, PN, Boerwinkle, E, Cheng, CYu, van Duijn, CM, Eiriksdottir, G, Gudnason, V, Harris, T, Hewitt, AW, Inouye, M, Jonasson, F, Klein, BEK, Launer, L, Li, X, Liew, G, Lumley, T, McElduff, P, McKnight, B, Mitchell, P, Psaty, BM, Rochtchina, E, Rotter, JI, Scott, RJ, Tay, W, Taylor, K, Teo, YYing, Uitterlinden, AG, Viswanathan, A, Xie, S, Vingerling, JR, Klaver, CCW, Tai, SE, Siscovick, D, Klein, R, Cotch, MFrances, Wong, TY, Attia, J, Wang, JJin
Corporate/Institutional AuthorsWellcome Trust Case Control Consortium 2,
JournalPLoS One
Volume8
Issue1
Paginatione53830
Date Published2013
ISSN1932-6203
KeywordsApolipoproteins E, Complement Factor H, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Kruppel-Like Transcription Factors, Macular Degeneration, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Zinc Finger Protein Gli3
Abstract<p>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.</p>
DOI10.1371/journal.pone.0053830
Alternate JournalPLoS ONE
PubMed ID23326517
PubMed Central IDPMC3543264
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N01 HC085086 / HC / NHLBI NIH HHS / United States
ZIA EY000401-09 / / Intramural NIH HHS / United States
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ZIA EY000401-11 / / Intramural NIH HHS / United States
ZIA EY000426-10 / / Intramural NIH HHS / United States
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AG-15928 / AG / NIA NIH HHS / United States
085475/08/Z / / Wellcome Trust / United Kingdom
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090532 / / Wellcome Trust / United Kingdom
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085475/B/08/Z / / Wellcome Trust / United Kingdom
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