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Anthony P Khawaja, Pirro G Hysi, David C Broadway, David F Garway-Heath, Shabina Hayat, Robert Luben, Stephen J Tuft, Nicholas Wareham, Kay-Tee Khaw, Christopher J Hammond, Paul J Foster; Genome-wide association study identifies new loci associated with corneal biomechanical properties. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal hysteresis (CH) and corneal resistance factor (CRF), as measured with the Ocular Response Analyzer (ORA), represent attributes of corneal biomechanics that are altered in individuals with keratoconus and Fuchs’ endothelial corneal dystrophy. We aimed to identify the genetic determinants of CH and CRF to further our understanding of the biological basis of corneal biomechanics and its contribution to corneal disease.
A genome-wide association study (GWAS) was carried out in 6,645 Caucasian participants of the EPIC-Norfolk Eye Study (mean age 69 years, 55% women). CH and CRF were measured using the best signal value of three ORA readings for each eye. We used the mean CH/CRF of both eyes for each participant. Genotyping was undertaken using the Affymetrix UK Biobank Axiom Array and data imputed to the Phase 3 build of the 1000 Genomes project (October 2014). Associations with CH and CRF (outcome variables) were evaluated using logistic regression models assuming additive inheritance, using the imputed allelic dosage data adjusted for age and sex. Replication of significant results were sought in 2,384 participants of the Twins UK study (mean age 54 years, 98% women).
There were genome-wide significant associations with CH at two loci in ANAPC1 (rs2030500, P=2x10-11) and FOXO1 (rs2721051, P=4x10-9) which were also nominally significant in the replication cohort with the same direction of effect. There were also genome-wide significant associations with CRF at ANAPC1 and FOXO1, and additionally at loci in ZNF469 (rs12719932, P=9x10-10), TCF4 (rs149540885, P=2x10-8), and COL6A1 (rs182804464, P=3x10-9).
We identified significant associations with CH and CRF at loci in genes known to be associated with central corneal thickness (FOXO1 and ZNF469) and Fuchs’ endothelial dystrophy (TCF4), supporting the use of CH and CRF as measures of corneal biomechanics. We further identified novel loci in ANAPC1 and COL6A1, suggesting a role for protein ubiquitination and cell cycling as well as collagen VI variation in corneal biomechanics. Further work will examine the association of these variants with corneal diseases such as keratoconus.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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