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

dc.contributor.author Bae, Ha Ae
dc.contributor.author Mills, Richard Arthur
dc.contributor.author Lindsay, Richard
dc.contributor.author Phillips, Tony
dc.contributor.author Mitchell, Paul
dc.contributor.author Wang, Jie Jin
dc.contributor.author Coster, Douglas John
dc.contributor.author Craig, Jamie E
dc.contributor.author Burdon, Kathryn Penelope
dc.date.accessioned 2014-02-27T01:35:27Z
dc.date.available 2014-02-27T01:35:27Z
dc.date.issued 2013-07-30
dc.description.abstract 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. en
dc.description.sponsorship Supported by a Project grant from the Australian National Health and Medical Research Council (NHMRC; APP1031362), the Ophthalmic Research Institute of Australia (for recruitment of this cohort), and a Career Development Award (KPB) and a Practitioner Fellowship (JEC) from the NHMRC. The Blue Mountains Eye Study (BMES) was supported by the Australian National Health & Medical Research Council (NHMRC), Canberra, Australia (Project Grants 974159, 211069, 302068, and Centre for Clinical Research Excellence Grant 529923). The BMES GWAS and genotyping costs were supported by Australian NHMRC, Canberra Australia (NHMRC Project Grants 512423, 475604, and 529912), and the Wellcome Trust, United Kingdom, as part of Wellcome Trust Case Control Consortium 2 (A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster, Grants 085475/B/08/Z and 085475/08/Z). en
dc.identifier.citation 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 en
dc.identifier.doi https://doi.org/10.1167/iovs.13-12377 en
dc.identifier.issn 0146-0404
dc.identifier.uri http://hdl.handle.net/2328/27479
dc.identifier.uri http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729241/
dc.language.iso en en_US
dc.publisher Association for Research in Vision and Ophthalmology (ARVO) en
dc.relation http://purl.org/au-research/grants/nhmrc/1031362 en
dc.relation.grantnumber NHMRC/1031362 en_US
dc.rights Copyright © Association for Research in Vision and Ophthalmology. en_US
dc.rights.holder Association for Research in Vision and Ophthalmology. en_US
dc.subject cornea en_US
dc.subject genetics en_US
dc.subject genome-wide association study en_US
dc.subject keratoconus en_US
dc.subject meta-analysis en_US
dc.title Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus en_US
dc.type Article en
local.contributor.authorOrcidLookup Lindsay, Richard: http://orcid.org/0000-0002-2430-3861 en_US
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