Corneal Genetics: Using Ancestry to Dissect Quantitative Traits for Complex Disease Discovery

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 work ³ 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 work ³ 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.