June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Genetic variation at the GPC6 gene is reproducibly associated with keratoconus in a genome-wide association study
Author Affiliations & Notes
  • Kathryn P Burdon
    Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
    Ophthalmology, Flinders Univeristy, Adelaide, SA, Australia
  • Yi Lu
    QIMR Berghofer Institute for Medical Research, Brisbane, QLD, Australia
  • Paul N Baird
    Centre for Eye Research Australia, Melbourne, VIC, Australia
  • Richard A Mills
    Ophthalmology, Flinders Univeristy, Adelaide, SA, Australia
  • Yelena Bykhovskaya
    Cornea Genetic Eye Institute, Beverley Hills, CA
    Regenerative Medicine Institute, Cedars-Sinai Medical Centre, Los Angeles, CA
  • Srujana Sahebjada
    Centre for Eye Research Australia, Melbourne, VIC, Australia
  • Yaron S Rabinowitz
    Cornea Genetic Eye Institute, Beverley Hills, CA
    Regenerative Medicine Institute, Cedars-Sinai Medical Centre, Los Angeles, CA
  • Xiaohui Li
    Harbor-UCLA Medical Center, Institute for Translational Genomics and Population Sciences, Los Angeles, CA
  • Stuart MacGregor
    QIMR Berghofer Institute for Medical Research, Brisbane, QLD, Australia
  • Jamie E Craig
    Ophthalmology, Flinders Univeristy, Adelaide, SA, Australia
  • Footnotes
    Commercial Relationships Kathryn Burdon, None; Yi Lu, None; Paul Baird, None; Richard Mills, None; Yelena Bykhovskaya, None; Srujana Sahebjada, None; Yaron Rabinowitz, None; Xiaohui Li, None; Stuart MacGregor, None; Jamie Craig, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2515. doi:
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    • Get Citation

      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)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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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