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

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Bae, Ha Ae
Mills, Richard Arthur
Lindsay, Richard
Phillips, Tony
Mitchell, Paul
Wang, Jie Jin
Coster, Douglas John
Craig, Jamie E
Burdon, Kathryn Penelope
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Association for Research in Vision and Ophthalmology (ARVO)
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. 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. 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. 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.
cornea, genetics, genome-wide association study, keratoconus, meta-analysis
Bae, H. A., Mills, R. A., Lindsay, R. G., Phillips, T., Coster, D. J., Mitchell, P., Wang, J. J., Craig, J. E., Burdon, K. P. Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus. Invest. Ophthalmol. Vis. Sci. 2013;54(7):5132-35