Cipriani, V and Leung, HT and Plagnol, V and Bunce, C and Khan, JC and Shahid, H and Moore, AT and Harding, SP and Bishop, PN and Hayward, C and Campbell, S and Armbrecht, AM and Dhillon, B and Deary, IJ and Campbell, H and Dunlop, M and Dominiczak, AF and Mann, SS and Jenkins, SA and Webster, AR and Bird, AC and Lathrop, M and Zelenika, D and Souied, EH and Sahel, JA and Léveillard, T and French AMD Investigators, and Cree, AJ and Gibson, J and Ennis, S and Lotery, AJ and Wright, AF and Clayton, DG and Yates, JR (2012) Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3. Hum Mol Genet , 21 (18) 4138 - 4150. 10.1093/hmg/dds225.
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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 C2-CFB 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.
|Title:||Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.|
|Additional information:||PMCID: PMC3428154|
|Keywords:||Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 6, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Immunophilins, Linear Models, Logistic Models, Macular Degeneration, Male, Odds Ratio, Polymorphism, Single Nucleotide, Principal Component Analysis, Proto-Oncogene Proteins, Receptors, Notch, Sequence Analysis, DNA, Tenascin|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute|
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