We will present the results from a large scale GWAS of central corneal thickness (CCT) and show that the findings from this endophenotype are directly relevant to the common eye diseases keratoconus and glaucoma.
We performed a meta-analysis on >20,000 individuals which identified 27 (16 novel) CCT-associated loci at genome-wide significant level. Most loci associated in Europeans also influenced CCT in Asians, with the 27 loci collectively explaining 8.3% and 7% of additive variance in Europeans and Asians, respectively. We showed that the majority of the loci identified in normal individuals also associated with the slightly lower CCT range in glaucoma patients, suggesting similar pathways regulating CCT regardless of disease status. Using a novel pathway analysis method we demonstrate that CCT loci converge to collagen and extracellular matrix pathways.
To determine clinical relevance of the identified CCT loci, we tested these loci for association with disease. We found that six CCT-associated loci were further associated with keratoconus risk (tested in two cohorts with 874 cases and 6,085 controls), of which two exceeded genome-wide significance (FOXO1 and FNDC3B). The findings at FOXO1 and FNDC3B are particularly noteworthy as these represent the first genome-wide significant loci for keratoconus. We further show that the novel CCT locus FNDC3B is also associated with primary open angle glaucoma (tested in three cohorts with 2,979 cases and 7,399 controls).
We leverage a precisely measured endophenotype and show that several of the quantitative trait loci confer surprisingly large increases in risk of eye disease (odds ratios up to 1.6). A risk profile based on even just these SNPs yields a reasonable risk prediction: ~1% of the population who carry the risk alleles at all six loci are at 7.2 fold increased risk of keratoconus relative to the ~1% of the population who do not carry any risk allele. Further evaluation of the clinical relevance of these SNPs is merited.