title: 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.
authors: Centre for Clinical Epidemiology and Biostatistics, and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia. Liz.Holliday@newcastle.edu.au
authors: Elizabeth G
authors: EG
authors: Holliday
authors: Albert V
authors: AV
authors: Smith
authors: Belinda K
authors: BK
authors: Cornes
authors: Gabriëlle H S
authors: GH
authors: Buitendijk
authors: Richard A
authors: RA
authors: Jensen
authors: Xueling
authors: X
authors: Sim
authors: Thor
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authors: Aspelund
authors: Tin
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authors: Aung
authors: Paul N
authors: PN
authors: Baird
authors: Eric
authors: E
authors: Boerwinkle
authors: Ching Yu
authors: CY
authors: Cheng
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Gudny
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authors: Eiriksdottir
authors: Vilmundur
authors: V
authors: Gudnason
authors: Tamara
authors: T
authors: Harris
authors: Alex W
authors: AW
authors: Hewitt
authors: Michael
authors: M
authors: Inouye
authors: Fridbert
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authors: Jonasson
authors: Barbara E K
authors: BE
authors: Klein
authors: Lenore
authors: L
authors: Launer
authors: Xiaohui
authors: X
authors: Li
authors: Gerald
authors: G
authors: Liew
authors: Thomas
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authors: Lumley
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authors: McElduff
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authors: McKnight
authors: Paul
authors: P
authors: Mitchell
authors: Bruce M
authors: BM
authors: Psaty
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authors: Rochtchina
authors: Jerome I
authors: JI
authors: Rotter
authors: Rodney J
authors: RJ
authors: Scott
authors: Wanting
authors: W
authors: Tay
authors: Kent
authors: K
authors: Taylor
authors: Yik Ying
authors: YY
authors: Teo
authors: André G
authors: AG
authors: Uitterlinden
authors: Ananth
authors: A
authors: Viswanathan
authors: Sophia
authors: S
authors: Xie
authors: Johannes R
authors: JR
authors: Vingerling
authors: Caroline C W
authors: CC
authors: Klaver
authors: E Shyong
authors: ES
authors: Tai
authors: David
authors: D
authors: Siscovick
authors: Ronald
authors: R
authors: Klein
authors: Mary Frances
authors: MF
authors: Cotch
authors: Tien Y
authors: TY
authors: Wong
authors: John
authors: J
authors: Attia
authors: Jie Jin
authors: JJ
authors: Wang
mesh_terms: D001057:Apolipoproteins E / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008268:Macular Degeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D000074290:Zinc Finger Protein Gli3
chemical_list: C514392:ARMS2 protein, human; D001057:Apolipoproteins E; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D000074290:Zinc Finger Protein Gli3; D017242:Complement Factor H