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

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

Research output: Contribution to journalArticlepeer-review

184 Scopus citations


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 5 1.1 × 10-8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P 5 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 genomewide 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 (US)
Article numberddr270
Pages (from-to)3699-3709
Number of pages11
JournalHuman molecular genetics
Issue number18
StatePublished - Sep 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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