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Research Highlight
Corneal Genetics: Using Ancestry to Dissect Quantitative
Traits for Complex Disease Discovery
Alex W. Hewitt
Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Australia;
[email protected]
Central corneal thickness (CCT) is one of the most heritable of all quantitative human traits.1 Accurate pachymetry is now standard
of care in the clinical assessment of a number of ocular conditions. Since the publication of the Ocular Hypertension Treatment
Study findings, CCT measurement has assumed an important role in glaucoma care.1 Additionally, corneal thinning is a key feature
in the corneal ectasias and an accurate assessment of CCT is crucial prior to refractive surgery.1 As such, investigating the molecular
underpinnings for CCT will have important ramifications both for associated diseases and in other quantitative trait mapping.1
Unfortunately, heritability estimates do not directly reflect the underlying genetic architecture and, similar to other complex
traits, a number of loci have now been directly implicated in CCT. Recently, a genome-wide association study (GWAS) of more than
20,000 people identified 26 loci associated with CCT.2 Gao et al.’s work3 directly replicates and extends our understanding of one of
these loci. A previously associated region at chromosome 9q34 contains two annotated genes (RXRA, COL5A1) that border a
putative transcript (LOC100506532). Interestingly Gao et al.,3 through GWAS, identified a statistically significant signal at this locus
in their cohort, and by conditional analysis of the top single nucleotide polymorphism (rs3118515), implicated a variant within
LOC100506532 as conferring the major genetic effect in this region. Through RT-PCR, they then demonstrated that
LOC100506532 is expressed in the human cornea.
Despite the successful implication of many loci, one of the major ongoing challenges of GWAS interpretation is deciphering the
‘‘causative’’ variants from merely associated ‘‘marker’’ variants. Gao et al.’s work3 highlights the utility of refining loci through
GWAS in people of non–Northern European ancestry. The use of Latino individuals, recruited through the Los Angeles Latino Eye
Study, sheds important light on the role of the ‘‘RXRA-COL5A1’’ locus in determining CCT.
References
1. Dimasi DP, Burdon KP, Craig JE. The genetics of central corneal thickness. Br J Ophthalmol. 2010;94:971–976.
2. Lu Y, Vitart V, Burdon KP, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and
keratoconus. Nat Genet. 2013;45:155–163.
3. Gao X, Gauderman WJ, Liu Y, et al. A genome-wide association study of central corneal thickness in Latinos. Invest Ophthalmol Vis Sci.
2013;54:2435–2443.
DOI: 10.1167/iovs.13-12029
Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc.
www.iovs.org j ISSN: 1552-5783
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