title: Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus.
abstract: OBJECTIVE
  Keratoconus is a common complex corneal ectasia that can lead to severe visual impairment. Although a genetic component is well recognized, the genetic risk factors for keratoconus are yet to be fully elucidated. A recent genome-wide association study (GWAS) by Li et al. identified 15 potentially associated single nucleotide polymorphisms (SNPs). Here, we aimed to replicate these associations, and conduct a meta-analysis of the current and previous studies.
  
  
  METHODS
  We genotyped the 15 reported associated SNPs in 524 Australian Caucasian cases with keratoconus and 2761 controls. Association analysis was conducted in PLINK. A meta-analysis of this study with the adjusted P values of the previously published GWAS was conducted using the method of Fisher to combine P values.
  
  
  RESULTS
  Our Australian cohort showed association (P < 0.003) at SNPs near RAB3GAP1, KCND3, IMMPL2, and in a gene desert on chromosome 13q33.3, providing evidence of replication of the published results. The meta-analysis showed SNP rs4954218 near RAB3GAP1 gene was associated significantly with keratoconus, with P = 9.26 × 10(-9) passing the genome-wide significance level.
  
  
  CONCLUSIONS
  Although the mechanism of disease association is yet to be determined, SNP rs4954218 is associated consistently with keratoconus and likely tags a functional variant that contributes to disease susceptibility.
authors.affiliation: Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Ha Ae
authors.initials: HA
authors.lastname: Bae
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Mills
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lindsay
authors.forename: Tony
authors.initials: T
authors.lastname: Phillips
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Coster
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.forename: Jie Jin
authors.initials: JJ
authors.lastname: Wang
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
mesh_terms: D000328:Adult; D001315:Australia; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020692:rab3 GTP-Binding Proteins / Q000235:genetics*
chemical_list: C580955:RAB3GAP1 protein, human; D020692:rab3 GTP-Binding Proteins
keywords: cornea; genetics; genome-wide association study; keratoconus; meta-analysis