Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXBFKBPLNOTCH4 region of chromosome 6p21.3

French AMD Investigators, Valentina Cipriani*, Hin-Tak Leung, Vincent Plagnol, Catey Bunce, Jane C. Khan, Humma Shahid, Anthony T. Moore, Simon P. Harding, Paul N. Bishop, Caroline Hayward, Susan Campbell, Ana Maria Armbrecht, Baljean Dhillon, Ian J. Deary, Harry Campbell, Malcolm Dunlop, Anna F. Dominiczak, Samantha S. Mann, Sharon A. JenkinsAndrew R. Webster, Alan C. Bird, Mark Lathrop, Diana Zelenika, Eric H. Souied, Jose-Alain Sahel, Thierry Leveillard, Angela J. Cree, Jane Gibson, Sarah Ennis, Andrew J. Lotery, Alan F. Wright, David G. Clayton, John R. W. Yates

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)–HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10−72), CFH (complement factor H) (P =2.3 × 10−47), C2 (complement component 2)–CFB (complement factor B) (P =5.2 × 10−9), C3 (complement component 3) (P =2.2 × 10−3) and CFI (P =3.6 × 10−3) and with more recently reported risk loci at VEGFA (P =1.2 × 10−3) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)–FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10−7, replication P =3.0 × 10−4, combined P =1.3 × 10−9, odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3–1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10−8, replication P =3.8 × 10−5, combined P =2.0 × 10−11, OR = 1.3, 95% CI = 1.2–1.4). These associations remained significant in conditional analyses which included the adjacent C2CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

Original languageEnglish
Pages (from-to)4138-4150
Number of pages13
JournalHuman Molecular Genetics
Volume21
Issue number18
DOIs
Publication statusPublished - 15 Sep 2012

Keywords

  • GENES
  • RISK
  • COMPONENT 2
  • COMPLEMENT FACTOR-H
  • SUSCEPTIBILITY
  • POLYMORPHISM
  • FACTOR-B
  • ANGIOGENESIS
  • TENASCIN-X
  • ENDOTHELIAL GROWTH-FACTOR

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