title: A genome-wide association study for corneal curvature identifies the platelet-derived growth factor receptor α gene as a quantitative trait locus for eye size in white Europeans.
abstract: OBJECTIVE
  Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings.
  
  
  METHODS
  White European children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were examined at age about 15.5 years (95% confidence interval=15.45 to 15.48 years). Radius of corneal curvature and axial eye length were measured with an IOLmaster. DNA samples were genotyped with Illumina HumanHap550 arrays and untyped variants imputed using MACH, with CEU individuals from HapMap release 22, Phase II NCBI B36, Single Nucleotide Polymorphism database 126 as the reference panel. Association between corneal curvature and single nucleotide polymorphism (SNP) genotype was tested, genome-wide, using mach2qtl, with sex as a covariate (n=2023; 46.6% male).
  
  
  RESULTS
  The variant exhibiting the strongest evidence for association with corneal curvature (rs6554163; p=2.8×10(-6)) was located in the same linkage disequilibrium block as the previously discovered PDGFRA variants. Meta-analysis of the current and prior findings enhanced the evidence for association (rs17084051, p=4.5×10(-14)). rs6554163 genotype predicted 1.0% of variation in corneal curvature. In addition, these PDGFRA variants were associated with axial eye length, predicting 0.6% of the normal trait variation (p=5.3×10(-4)). Each copy of the minor allele of variants at the locus also increased the risk of corneal astigmatism in this white European cohort (odds ratio [OR]=1.24, 95% confidence interval=1.07-1.45; p=0.006).
  
  
  CONCLUSIONS
  As in Asians, variants at the PDGFRA locus influence corneal curvature (and corneal astigmatism). However, rather than affecting corneal curvature in isolation, this locus influences the size of the eye while maintaining its scaling.
authors: Centre for Myopia Research, School of Optometry, Hong Kong Polytechnic University, Kowloon, Hong Kong. jeremy.guggenheim@polyu.edu.hk
authors: Jeremy A
authors: JA
authors: Guggenheim
authors: George
authors: G
authors: McMahon
authors: John P
authors: JP
authors: Kemp
authors: Saeed
authors: S
authors: Akhtar
authors: Beate
authors: B
authors: St Pourcain
authors: Kate
authors: K
authors: Northstone
authors: Susan M
authors: SM
authors: Ring
authors: David M
authors: DM
authors: Evans
authors: George Davey
authors: GD
authors: Smith
authors: Nicholas J
authors: NJ
authors: Timpson
authors: Cathy
authors: C
authors: Williams
mesh_terms: D000293:Adolescent; D001251:Astigmatism / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D003315:Cornea / Q000033:anatomy & histology* / Q000378:metabolism*; D005060:Europe; D005123:Eye / Q000033:anatomy & histology*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009216:Myopia / Q000235:genetics / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha
references: Invest Ophthalmol Vis Sci. 2005 Sep;46(9):3074-80
references: 16123404
references: Mol Vis. 2011;17:3290-9
references: 22194655
references: Hum Mol Genet. 2011 Jul 15;20(14):2861-8
references: 21505071
references: Invest Ophthalmol Vis Sci. 1992 Apr;33(5):1742-55
references: 1559774
references: Invest Ophthalmol Vis Sci. 2002 Jan;43(1):41-6
references: 11773010
references: Invest Ophthalmol Vis Sci. 1999 Jun;40(7):1364-72
references: 10359318
references: Mol Vis. 2010 Feb 02;16:144-53
references: 20142845
references: Exp Eye Res. 2011 Oct;93(4):482-90
references: 21726551
references: Invest Ophthalmol Vis Sci. 2012 Oct 11;53(11):7131-6
references: 22969067
references: Surv Ophthalmol. 2010 Nov-Dec;55(6):561-83
references: 20851442
references: Hum Mol Genet. 2011 Oct 15;20(20):4069-75
references: 21757498
references: Curr Opin Ophthalmol. 2009 Sep;20(5):356-62
references: 19587595
references: Nat Genet. 2010 Oct;42(10):897-901
references: 20835239
references: Behav Genet. 2009 Sep;39(5):580-95
references: 19526352
references: Invest Ophthalmol Vis Sci. 2011 Oct 21;52(11):8258-61
references: 21911587
references: PLoS Genet. 2009 Sep;5(9):e1000660
references: 19779542
references: Genet Epidemiol. 2008 Apr;32(3):227-34
references: 18300295
references: Int J Epidemiol. 2013 Feb;42(1):111-27
references: 22507743
references: Matrix Biol. 2010 Jul;29(6):519-24
references: 20580823
references: Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5115-9
references: 19420339
references: Genet Epidemiol. 2010 Dec;34(8):816-34
references: 21058334
references: Ophthalmic Physiol Opt. 2012 Jan;32(1):17-24
references: 22150587
references: Hum Genet. 2012 Sep;131(9):1467-80
references: 22665138
references: Physiol Rev. 1999 Oct;79(4):1283-316
references: 10508235
references: Exp Cell Res. 1998 May 1;240(2):377-87
references: 9597011
references: PLoS Genet. 2011 Dec;7(12):e1002402
references: 22144915
references: Mol Vis. 2010 Oct 02;16:1920-7
references: 21031016
references: Bioinformatics. 2010 Sep 1;26(17):2190-1
references: 20616382
references: Invest Ophthalmol Vis Sci. 2011 Jun 08;52(7):4012-20
references: 21436281
references: Clin Genet. 2011 Apr;79(4):301-20
references: 21155761
references: Front Biosci. 2003 May 01;8:d687-713
references: 12700042
references: Invest Ophthalmol Vis Sci. 2005 Jul;46(7):2317-27
references: 15980217
references: Curr Eye Res. 1998 Mar;17(3):276-85
references: 9543636
references: Nat Genet. 2010 Oct;42(10):902-5
references: 20835236
references: Am J Hum Genet. 2011 Jun 10;88(6):805-813
references: 21640322
references: Invest Ophthalmol Vis Sci. 2012 May 14;53(6):2856-65
references: 22491403
references: Nat Genet. 2010 Mar;42(3):210-5
references: 20139978
references: Mol Vis. 2007 Mar 01;13:330-6
references: 17392683
references: Ophthalmic Physiol Opt. 2012 Jan;32(1):3-16
references: 22150586
references: Arch Ophthalmol. 2009 Dec;127(12):1632-9
references: 20008719
references: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1341-7
references: 19875656
references: Hum Mol Genet. 2011 Sep 15;20(18):3693-8
references: 21665993
references: Ophthalmology. 2011 Feb;118(2):368-75
references: 21095009
references: Exp Eye Res. 2009 Jun 15;89(1):42-8
references: 19249299
references: Br J Ophthalmol. 1998 Mar;82(3):329-30
references: 9602639
references: Vision Res. 1991;31(5):833-44
references: 2035267