Genome-wide association study of age-related macular degeneration identifies associated variants in the TNXB-FKBPL-NOTCH4 region of chromosome 6p21.3.
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.
Institute of Ophthalmology, University College London, London EC1V 9EL, UK. v.cipriani@ucl.ac.uk
Valentina
V
Cipriani
Hin-Tak
HT
Leung
Vincent
V
Plagnol
Catey
C
Bunce
Jane C
JC
Khan
Humma
H
Shahid
Anthony T
AT
Moore
Simon P
SP
Harding
Paul N
PN
Bishop
Caroline
C
Hayward
Susan
S
Campbell
Ana Maria
AM
Armbrecht
Baljean
B
Dhillon
Ian J
IJ
Deary
Harry
H
Campbell
Malcolm
M
Dunlop
Anna F
AF
Dominiczak
Samantha S
SS
Mann
Sharon A
SA
Jenkins
Andrew R
AR
Webster
Alan C
AC
Bird
Mark
M
Lathrop
Diana
D
Zelenika
Eric H
EH
Souied
José-Alain
JA
Sahel
Thierry
T
Léveillard
Angela J
AJ
Cree
Jane
J
Gibson
Sarah
S
Ennis
Andrew J
AJ
Lotery
Alan F
AF
Wright
David G
DG
Clayton
John R W
JR
Yates
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D020104:Immunophilins / Q000235:genetics*; D016014:Linear Models; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics*; D017422:Sequence Analysis, DNA; D022021:Tacrolimus Binding Proteins; D019063:Tenascin / Q000235:genetics*
C400101:FKBPL protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D019063:Tenascin; C081865:tenascin X; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins