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Alison J Hardcastle, Pirro G Hysi, Karla Rojas-Lopez, Petra Liskova, Alice E Davidson, Manir Ali, Kathryn P Burdon, David O'Brart, Chris Inglehearn, Paul N Baird, Christopher J Hammond, Stephen J Tuft; Genome-wide association study on a large multi-ethnic sample identifies new genetic loci that predispose to keratoconus. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4249. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Keratoconus (KC) is an important cause for visual loss in children and young adults worldwide. However, the underlying pathophysiology for KC is poorly understood. There is a clear genetic component, but previous genetic studies have either been underpowered or primarily focused on quantitative parameters measured in healthy populations that are correlated with disease risk. The purpose of this study was to identify new genetic risk factors predisposing to KC in the largest genome-wide association study (GWAS) to date.
We recruited 3,947 KC patients of European (N=2,149) African (N=416), Indian (N=810) or other descent. Samples were genotyped using the UK Biobank Axiom array (Thermofisher, Waltham, MA), and quality-checked and imputed following established protocols. Subsequently, genotypes for each ethnic group were compared using the same protocols with 75,000 ethnicity and sex-matched participants from the UK Biobank. Logistic regression models were used for the analyses and appropriate multiple testing correction procedures were applied to the results.
Our GWAS replicated the association of previously known KC loci, and has identified over a dozen new genes that are associated with disease. The strongest associations were observed for the loci previously associated with central corneal thickness and KC, such as the FOXO1 locus (OR=1.63, 95%CIs 1.49-1.78, p=4.1x10-24for rs2721051 in Europeans), and COL5A1 (p=2.67x10-15and p=6.68x10-12for rs3118519 in Europeans and Indians respectively). Among the new loci, the strongest association was observed for markers on a region around the PDD/PIDDC1/SLC25A22gene cluster, previously associated with Fuchs endothelial corneal dystrophy (p=4.37x10-18).
Our results from the most powered GWAS for KC to date have identified numerous genetic loci that predispose to KC. These data also highlight the complexity of the genetic architecture of corneal disease, given the genetic similarities between multiple corneal phenotypes and different ethnic groups. This is an important step towards the full identification of genetic factors underlying KC, and raises the hope for better risk prediction and treatment in the future.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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