Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus

Ha Ae Bae, Richard Mills, Richard Lindsay, Anthony Phillips, Douglas Coster, Paul Mitchell, Jiejin Wang, Jamie Craig, Kathryn Burdon

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    22 Citations (Scopus)

    Abstract

    PURPOSE. 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 metaanalysis 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.

    Original languageEnglish
    Pages (from-to)5132-5135
    Number of pages4
    JournalInvestigative Ophthalmology and Visual Science
    Volume54
    Issue number7
    DOIs
    Publication statusPublished - 2013

    Keywords

    • Cornea
    • Genetics
    • Genome-wide association study
    • Keratoconus
    • Meta-analysis

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