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 A 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 journalArticle

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 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
Volume20
Issue number18
DOIs
StatePublished - Sep 2011

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Macular Degeneration
Odds Ratio
Genetic Loci
Genome-Wide Association Study
Genetic Predisposition to Disease
Single Nucleotide Polymorphism
Extracellular Matrix
Meta-Analysis
Collagen
Alleles
Genotype
Genome
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Yu, Y., Bhangale, T. R., Fagerness, J., Ripke, S., Thorleifsson, G., Tan, P. L., ... Seddon, J. M. (2011). Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Human Molecular Genetics, 20(18), 3699-3709. [ddr270]. https://doi.org/10.1093/hmg/ddr270

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. / Yu, Yi; Bhangale, Tushar R.; Fagerness, Jesen; Ripke, Stephan; Thorleifsson, Gudmar; Tan, Perciliz L.; Souied, Eric H.; Richardson, Andrea J.; Merriam, Joanna E.; Buitendijk, Gabriëlle H S; Reynolds, Robyn; Raychaudhuri, Soumya; Chin, Kimberly A.; Sobrin, Lucia; Evangelou, Evangelos; Lee, Phil H.; Lee, Aaron Y.; Leveziel, Nicolas; Zack, Donald J; Campochiaro, Betsy; Campochiaro, Peter A; Smith, R. Theodore; Barile, Gaetano R.; Guymer, Robyn H.; Hogg, Ruth; Chakravarthy, Usha; Robman, Luba D.; Gustafsson, Omar; Sigurdsson, Haraldur; Ortmann, Ward; Behrens, Timothy W.; Stefansson, Kari; Uitterlinden, André G.; van Duijn, Cornelia M.; Vingerling, Johannes R.; Klaver, Caroline C W; Allikmets, Rando; Brantley, Milam A.; Baird, Paul N.; Katsanis, Nicholas; Thorsteinsdottir, Unnur; Ioannidis, John P A; Daly, Mark J.; Graham, Robert R.; Seddon, Johanna M.

In: Human Molecular Genetics, Vol. 20, No. 18, ddr270, 09.2011, p. 3699-3709.

Research output: Contribution to journalArticle

Yu, Y, Bhangale, TR, Fagerness, J, Ripke, S, Thorleifsson, G, Tan, PL, Souied, EH, Richardson, AJ, Merriam, JE, Buitendijk, GHS, Reynolds, R, Raychaudhuri, S, Chin, KA, Sobrin, L, Evangelou, E, Lee, PH, Lee, AY, Leveziel, N, Zack, DJ, Campochiaro, B, Campochiaro, PA, Smith, RT, Barile, GR, Guymer, RH, Hogg, R, Chakravarthy, U, Robman, LD, Gustafsson, O, Sigurdsson, H, Ortmann, W, Behrens, TW, Stefansson, K, Uitterlinden, AG, van Duijn, CM, Vingerling, JR, Klaver, CCW, Allikmets, R, Brantley, MA, Baird, PN, Katsanis, N, Thorsteinsdottir, U, Ioannidis, JPA, Daly, MJ, Graham, RR & Seddon, JM 2011, 'Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration', Human Molecular Genetics, vol. 20, no. 18, ddr270, pp. 3699-3709. https://doi.org/10.1093/hmg/ddr270
Yu Y, Bhangale TR, Fagerness J, Ripke S, Thorleifsson G, Tan PL et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Human Molecular Genetics. 2011 Sep;20(18):3699-3709. ddr270. https://doi.org/10.1093/hmg/ddr270
Yu, Yi ; Bhangale, Tushar R. ; Fagerness, Jesen ; Ripke, Stephan ; Thorleifsson, Gudmar ; Tan, Perciliz L. ; Souied, Eric H. ; Richardson, Andrea J. ; Merriam, Joanna E. ; Buitendijk, Gabriëlle H S ; Reynolds, Robyn ; Raychaudhuri, Soumya ; Chin, Kimberly A. ; Sobrin, Lucia ; Evangelou, Evangelos ; Lee, Phil H. ; Lee, Aaron Y. ; Leveziel, Nicolas ; Zack, Donald J ; Campochiaro, Betsy ; Campochiaro, Peter A ; Smith, R. Theodore ; Barile, Gaetano R. ; Guymer, Robyn H. ; Hogg, Ruth ; Chakravarthy, Usha ; Robman, Luba D. ; Gustafsson, Omar ; Sigurdsson, Haraldur ; Ortmann, Ward ; Behrens, Timothy W. ; Stefansson, Kari ; Uitterlinden, André G. ; van Duijn, Cornelia M. ; Vingerling, Johannes R. ; Klaver, Caroline C W ; Allikmets, Rando ; Brantley, Milam A. ; Baird, Paul N. ; Katsanis, Nicholas ; Thorsteinsdottir, Unnur ; Ioannidis, John P A ; Daly, Mark J. ; Graham, Robert R. ; Seddon, Johanna M. / Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 18. pp. 3699-3709.
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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 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.",
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AU - Yu, Yi

AU - Bhangale, Tushar R.

AU - Fagerness, Jesen

AU - Ripke, Stephan

AU - Thorleifsson, Gudmar

AU - Tan, Perciliz L.

AU - Souied, Eric H.

AU - Richardson, Andrea J.

AU - Merriam, Joanna E.

AU - Buitendijk, Gabriëlle H S

AU - Reynolds, Robyn

AU - Raychaudhuri, Soumya

AU - Chin, Kimberly A.

AU - Sobrin, Lucia

AU - Evangelou, Evangelos

AU - Lee, Phil H.

AU - Lee, Aaron Y.

AU - Leveziel, Nicolas

AU - Zack, Donald J

AU - Campochiaro, Betsy

AU - Campochiaro, Peter A

AU - Smith, R. Theodore

AU - Barile, Gaetano R.

AU - Guymer, Robyn H.

AU - Hogg, Ruth

AU - Chakravarthy, Usha

AU - Robman, Luba D.

AU - Gustafsson, Omar

AU - Sigurdsson, Haraldur

AU - Ortmann, Ward

AU - Behrens, Timothy W.

AU - Stefansson, Kari

AU - Uitterlinden, André G.

AU - van Duijn, Cornelia M.

AU - Vingerling, Johannes R.

AU - Klaver, Caroline C W

AU - Allikmets, Rando

AU - Brantley, Milam A.

AU - Baird, Paul N.

AU - Katsanis, Nicholas

AU - Thorsteinsdottir, Unnur

AU - Ioannidis, John P A

AU - Daly, Mark J.

AU - Graham, Robert R.

AU - Seddon, Johanna M.

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