title: New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8.
abstract: Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (β = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (β = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (β = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (β = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (β = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (β = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.
authors: MRC Human Genetics Unit, IGMM, Edinburgh, UK. v.vitart@hgu.mrc.ac.uk
authors: Veronique
authors: V
authors: Vitart
authors: Goran
authors: G
authors: Bencić
authors: Caroline
authors: C
authors: Hayward
authors: Jelena
authors: J
authors: Skunca Herman
authors: Jennifer
authors: J
authors: Huffman
authors: Susan
authors: S
authors: Campbell
authors: Kajo
authors: K
authors: Bućan
authors: Pau
authors: P
authors: Navarro
authors: Grgo
authors: G
authors: Gunjaca
authors: Josipa
authors: J
authors: Marin
authors: Lina
authors: L
authors: Zgaga
authors: Ivana
authors: I
authors: Kolcić
authors: Ozren
authors: O
authors: Polasek
authors: Mirna
authors: M
authors: Kirin
authors: Nicholas D
authors: ND
authors: Hastie
authors: James F
authors: JF
authors: Wilson
authors: Igor
authors: I
authors: Rudan
authors: Harry
authors: H
authors: Campbell
authors: Zoran
authors: Z
authors: Vatavuk
authors: Brian
authors: B
authors: Fleck
authors: Alan
authors: A
authors: Wright
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics*; D015331:Cohort Studies; D024062:Collagen Type V / Q000235:genetics*; D019573:Epithelium, Corneal / Q000473:pathology*; D006801:Humans; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; C530725:COL5A1 protein, human; D024062:Collagen Type V; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins