Genetic Variants Associated With Central Corneal Thickness - Results From The Gutenberg Health Study

Abstract

Purpose: : To identify single nucleotide polymorphisms (SNPs) and susceptible genes, which are associated with central corneal thickness (CCT).

Methods: : A genome-wide association (GWA) study for CCT was conducted in two sets of the Gutenberg Health Study, first genoyping 2796 individuals, further 1135 study participants using the Affymetrix Genome-Wide Human SNP 6.0 Array. Results reported here are generated by combined meta-analyses. This is a population-based prospective, observational single center study in the Rhine-Main-Region in western mid-Germany with a total of 15.000 participants (age 35-74), predominantly white of European ancestry. Central corneal thickness was measured with the optical pachymeter (Pachycam, Oculus, Wetzlar, Germany). Measurements of eyes with corneal disease and individuals from non-European descent were excluded from analysis. The average of both eyes or the value of the unaffected eye were used for association analysis. Classical association analyses were performed under an additive model adjusted for age and sex followed by meta-analysis using the weighted inverse variance method implemented in METAL software.

Results: : We identified nine genome-wide significant SNPs on chromosome 16q24 nearby the zinc finger 469 (ZNF469) gene and two SNPs on chromosome 9q34 nearby the collagen 5 alpha 1 (COL5A1) gene. The ZNF469 associations can be divided into SNPs associated with higher CCT (rs9938149, p = 2.95 x 10-12; rs12448211, p = 3.15 x 10-12; rs6540223, p = 6.68 x 10-12 and rs7501109, p = 2.31 x 10-11) and lower CCT (rs7501402, p = 1.03 x 10-11; rs7500824, p = 1.21 x 10-11; rs7405095, p = 1.49 x 10-11; rs9922572, p = 4.13 x 10-9 and rs6540215, p = 1.53 x 10-8). Within COL5A1, rs3132306 (p = 3.66 x 10-10, β = 5.12, SE = 0.82) is related to thicker CCT and rs3118516 (p = 1.18 x 10-9, β = -4.96, SE = 0.82) is accompanied by thinner CCT. The residual phenotypic variance explained by each significant SNP is limited to one to two percent.

Conclusions: : Our findings reveal further SNPs nearby the candidate genes ZNF469 and COL5A1 and support the previously reported potential involvement of these genes in the regulation of CCT. These associations reflect different effects on CCT within the same gene region.

Keywords: candidate gene analysis • cornea: clinical science • genetics