Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Yi Yu, Tushar R Bhangale, Jesen A Fagerness, Stephan Ripke, Gudmar Thorleifsson, Perciliz L Tan, Eric H Souied, Andrea J Richardson, Joanna E Merriam, Gabrielle Buitendijk, Robyn Reynolds, Soumya Raychaudhuri, Kimberly A Chin, Lucia Sobrin, Evangelos Evangelou, Phil Hyoun Lee, Aaron Yuntai Lee, Nicolas Leveziel, Donald Jeffrey Zack, Betsy Ann CampochiaroPeter Anthony Campochiaro, Roland Theodore Smith, Gaetano R Barile, Robyn Heather Guymer, Ruth Esther Hogg, Usha Chakravarthy, Liubov Robman, Omar Gustafsson, Haraldur Sigurdsson, Ward A Ortmann, Timothy W Behrens, Kari Stefansson, Andre G Uitterlinden, Cornelia M van Duijn, Johannes R Vingerling, Caroline Klaver, Rando L Allikmets, Milam A Brantley, Paul N Baird, Nicholas Katsanis, Unnur Thorsteinsdottir, John P A Ioannidis, Mark J Daly, Roberts Graham, Johanna M Seddon

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213 Citations (Scopus)


Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 ? 10-8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 ? 10-9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
Original languageEnglish
Pages (from-to)3699 - 3709
Number of pages11
JournalHuman Molecular Genetics
Issue number18
Publication statusPublished - 2011

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