TY - JOUR T1 - Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. JF - PLoS One Y1 - 2013 A1 - Holliday, Elizabeth G A1 - Smith, Albert V A1 - Cornes, Belinda K A1 - Buitendijk, Gabriëlle H S A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Aspelund, Thor A1 - Aung, Tin A1 - Baird, Paul N A1 - Boerwinkle, Eric A1 - Cheng, Ching Yu A1 - van Duijn, Cornelia M A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hewitt, Alex W A1 - Inouye, Michael A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore A1 - Li, Xiaohui A1 - Liew, Gerald A1 - Lumley, Thomas A1 - McElduff, Patrick A1 - McKnight, Barbara A1 - Mitchell, Paul A1 - Psaty, Bruce M A1 - Rochtchina, Elena A1 - Rotter, Jerome I A1 - Scott, Rodney J A1 - Tay, Wanting A1 - Taylor, Kent A1 - Teo, Yik Ying A1 - Uitterlinden, André G A1 - Viswanathan, Ananth A1 - Xie, Sophia A1 - Vingerling, Johannes R A1 - Klaver, Caroline C W A1 - Tai, E Shyong A1 - Siscovick, David A1 - Klein, Ronald A1 - Cotch, Mary Frances A1 - Wong, Tien Y A1 - Attia, John A1 - Wang, Jie Jin KW - Apolipoproteins E KW - Complement Factor H KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Kruppel-Like Transcription Factors KW - Macular Degeneration KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Zinc Finger Protein Gli3 AB -

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.

VL - 8 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract ER -