A targeted approach to genome-wide studies reveals new genetic associations with central corneal thickness

PURPOSE: To evaluate the ability of a targeted genome-wide association study (GWAS) to identify genes associated with central corneal thickness (CCT). METHODS: A targeted GWAS was used to investigate whether ten candidate genes with known roles in corneal development were associated with CCT in two Singaporean populations. The single nucleotide polymorphisms (SNPs) within a 500 kb interval encompassing each candidate were analyzed, and in light of the resulting data, members of the Wnt pathway were subsequently screened using similar methodology. RESULTS: Variants within the 500 kb interval encompassing three candidate genes, DKK1 (rs1896368, p=1.32×10(−3)), DKK2 (rs17510449, p=7.34×10(−4)), and FOXO1 (rs7326616, p=1.56×10(−4) and rs4943785, p=1.19×10(−3)), were statistically significantly associated with CCT in the Singapore Indian population. DKK2 was statistically significantly associated with CCT in a separate Singapore Malaysian population (rs10015200, p=2.26×10(−3)). Analysis of Wnt signaling pathway genes in each population demonstrated that TCF7L2 (rs3814573, p=1.18×10(−3)), RYK (rs6763231, p=1.12×10(−3) and rs4854785, p=1.11×10(−3)), and FZD8 (rs640827, p=5.17×10(−4)) were statistically significantly associated with CCT. CONCLUSIONS: The targeted GWAS identified four genes (DKK1, DKK2, RYK, and FZD8) with novel associations with CCT and confirmed known associations with two genes, FOXO1 and TCF7L2. All six participate in the Wnt pathway, supporting a broader role for Wnt signaling in regulating the thickness of the cornea. In parallel, this study demonstrated that a hypothesis-driven candidate gene approach can identify associations in existing GWAS data sets.