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Kathryn P Burdon, Yi Lu, Paul N Baird, Richard A Mills, Yelena Bykhovskaya, Srujana Sahebjada, Yaron S Rabinowitz, Xiaohui Li, Stuart MacGregor, Jamie E Craig; Genetic variation at the GPC6 gene is reproducibly associated with keratoconus in a genome-wide association study. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2515.
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© ARVO (1962-2015); The Authors (2016-present)
Keratoconus is the leading indication for corneal graft. The molecular causes are not well understood, although it has a strong genetic component. Previous studies have indicated several genetic loci associated with the disease, but these only account for a small proportion of the genetic component. We have conducted the largest a genome-wide association study (GWAS) to date for keratoconus to identify additional genetic risk factors.
Genomic DNA from 632 Australian keratoconus patients was combined in equimolar amounts into 7 DNA pools and genotyped in duplicate alongside 643 examined normal controls in 4 pools on the Illumina HumanOmni5-Quad Beadchip arrays. Allele frequencies in cases and controls were estimated from the relative fluorescence intensities and tested for association with keratoconus. 52 SNPs reaching a p-value of <5x10-6 were genotyped on individual DNA samples and SNPs maintaining significance at this level were further assessed in a cohort of 212 cases and 2919 controls previously genotyped on the Illumina 370CNV array and imputed to HapMap2 reference panel.
Over 2 million SNPs were available for analysis following stringent quality control processes. Of these, 7 SNPs reached genome-wide significance and 52 SNPs were typed in individual DNA samples. All SNPs selected from the pool showed association on individual typing and four loci reached genome-wide significance (p<5x10-8; rs6465565, rs7951655, rs7986313 and rs74091611).To confirm these findings, 23 SNPs were selected for evaluation in the replication cohort of which data is currently available for 16. One of the three genome-wide significant loci assessed to date, rs7986313 on chromosome 13, in an intron of the GPC6 gene shows replication (p=0.026). GPC6 is a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan and a putative co-receptor for a number of molecules including extracellular matrix proteins.
Using pooled GWAS followed by individual confirmation and replication, we identified genetic association between SNP rs7896313 and risk of developing keratoconus. This SNP is located in a plausible candidate gene for this condition and GPC6 should be the focus of future research into the etiology of keratoconus. Further evaluation of available keratoconus GWAS data and meta-analyses are likely to identify further loci for keratoconus.
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