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Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.


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 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.

SUBMITTER: Cipriani V 

PROVIDER: S-EPMC3428154 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.

Cipriani Valentina V   Leung Hin-Tak HT   Plagnol Vincent V   Bunce Catey C   Khan Jane C JC   Shahid Humma H   Moore Anthony T AT   Harding Simon P SP   Bishop Paul N PN   Hayward Caroline C   Campbell Susan S   Armbrecht Ana Maria AM   Dhillon Baljean B   Deary Ian J IJ   Campbell Harry H   Dunlop Malcolm M   Dominiczak Anna F AF   Mann Samantha S SS   Jenkins Sharon A SA   Webster Andrew R AR   Bird Alan C AC   Lathrop Mark M   Zelenika Diana D   Souied Eric H EH   Sahel José-Alain JA   Léveillard Thierry T   Cree Angela J AJ   Gibson Jane J   Ennis Sarah S   Lotery Andrew J AJ   Wright Alan F AF   Clayton David G DG   Yates John R W JR  

Human molecular genetics 20120613 18


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 ser  ...[more]

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