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Meta-Analysis
. 2011 Sep 15;20(18):3699-709.
doi: 10.1093/hmg/ddr270. Epub 2011 Jun 10.

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

Yi Yu  1 , 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 Campochiaro, Peter 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 Jr, Paul N Baird, Nicholas Katsanis, Unnur Thorsteinsdottir, John P A Ioannidis, Mark J Daly, Robert R Graham, Johanna M Seddon
Affiliations
Meta-Analysis

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

Yi Yu et al. Hum Mol Genet. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Manhattan plot. Log (P) values of association results from the cleaned TMMG data set are plotted for SNPs on each chromosome. SNPs with P < 5 × 10–7 are colored in red and the representative genes for each associated region are labeled.
Figure 2.
Figure 2.
FRK/COL10A1 and VEGFA regions and association with AMD. (A) Observed association in the 500 kb region surrounding the FRK/COL10A1 locus in meta-analysis of TMMG data sets. The representative SNP (rs1999930) for this region with P = 3.1 × 10−7 is shown by a small purple circle. In the combined analysis including all 11 cohorts, this SNP was associated with AMD at P= 1.1 × 10−8 (large purple diamond). (B) Forest plot for rs1999930 association across 11 cohorts. (C) Observed association in the 500 kb region surrounding the VEGFA locus in meta-analysis of TMMG data sets. The represented SNP (rs4711751) for this region of P = 2.2 × 10−5 is shown by a small purple circle. In the combined analysis including all 10 cohorts, this SNP was associated with AMD at P = 8.7 × 10−9 (large purple diamond). (D) Forest plot for rs4711751 association across 10 cohorts.
Figure 3.
Figure 3.
rs934080 in a putative CRX transcription factor-binding site. rs4711751 is in strong LD with rs934080, a variant which resides in a highly evolutionarily conserved region (UCSC genome browser) and disrupts a putative CRX transcription factor-binding site (CAA[T/C]C).
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