title: Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.
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.
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Tufts University School of Medicine, 800 WashingtonStreet, No. 450, Boston, MA 02111, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Tushar R
authors.initials: TR
authors.lastname: Bhangale
authors.forename: Jesen
authors.initials: J
authors.lastname: Fagerness
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Eric H
authors.initials: EH
authors.lastname: Souied
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Merriam
authors.forename: Gabriëlle H S
authors.initials: GH
authors.lastname: Buitendijk
authors.forename: Robyn
authors.initials: R
authors.lastname: Reynolds
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chin
authors.forename: Lucia
authors.initials: L
authors.lastname: Sobrin
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Lee
authors.forename: Nicolas
authors.initials: N
authors.lastname: Leveziel
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Betsy
authors.initials: B
authors.lastname: Campochiaro
authors.forename: Peter
authors.initials: P
authors.lastname: Campochiaro
authors.forename: R Theodore
authors.initials: RT
authors.lastname: Smith
authors.forename: Gaetano R
authors.initials: GR
authors.lastname: Barile
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.forename: Ruth
authors.initials: R
authors.lastname: Hogg
authors.forename: Usha
authors.initials: U
authors.lastname: Chakravarthy
authors.forename: Luba D
authors.initials: LD
authors.lastname: Robman
authors.forename: Omar
authors.initials: O
authors.lastname: Gustafsson
authors.forename: Haraldur
authors.initials: H
authors.lastname: Sigurdsson
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Vingerling
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Rando
authors.initials: R
authors.lastname: Allikmets
authors.forename: Milam A
authors.initials: MA
authors.lastname: Brantley
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D024121:Collagen Type X / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D024121:Collagen Type X; D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases; C092830:FRK protein, human