Novel quantitative trait loci for central corneal thickness identified by candidate gene analysis of osteogenesis imperfecta genes

Osteogenesis imperfecta (OI) is a rare connective tissue disorder caused by mutations in the type I collagen genes, <i>COL1A1</i> and <i>COL1A2</i>, and is characterised by low bone mass and bone fragility. In this study, we explored the relationship between type 1 collagen genes and the quantitative trait central corneal thickness (CCT). CCT was measured in a cohort of 28 Australian type I OI patients and mean CCT was found to be significantly lower compared to a normal population (<i>P</i> < 0.001). We then investigated CCT and corneal collagen fibril diameter and density in a mouse model of OI with a <i>col1a2</i> mutation. Mean CCT was significantly lower in mutant mice (<i>P</i> = 0.002), as was corneal collagen fibril diameter (<i>P</i> = 0.034), whilst collagen fibril density was significantly greater in mutants (<i>P</i> = 0.034). Finally, we conducted a genetic study to determine whether common single nucleotide polymorphisms (SNPs) in <i>COL1A1</i> and <i>COL1A2</i> are associated with CCT variation in the normal human population. Polymorphism rs2696297 (<i>P</i> = 0.003) in <i>COL1A1</i> and a three SNP haplotype in <i>COL1A2</i> (<i>P</i> = 0.007) were all significantly associated with normal CCT variation. These data implicate type 1 collagen in the determination of CCT in both OI patients and normal individuals. This provides the first evidence of quantitative trait loci that influence CCT in a normal population and has potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.