The genetics of myopia and refractive error: analysis of highly significant linkage loci. (360G-Wellcome-078363_Z_05_Z)

Refractive error is a common, easily and accurately measured, quantitative trait that is highly heritable, making it an ideal condition to study in an unselected, population-based set of sibling pairs, which is available using the TwinsUK Adult Volunteer Twin Registry. The prevalence of myopia is rising rapidly, and is associated with significant morbidity in those highly-affected. We have previously demonstrated a high heritability for refractive error (0.85) in a classical twin study using a total of 506 MZ and DZ pairs, and published the first genome-wide linkage analysis of this common trait, with 5 loci showing highly significant linkage. The highest linkage peak (LOD 6.1) was on chromosome 11p13, and in a tagged-SNP study we demonstrated significant linkage but not association in the vicinity of the PAX6 gene. In a replication study, we have confirmed another of our significant linkage loci at chromosome 3q26. Fine-mapping of chromosome 11 hasshown a consistent linkage locus at 11q23-24, which exactly coincides with a myopia locus found in an Ashkenazi family study. We propose to further examinethe role for these two promising genomic regions in myopia development, as well as further studying PAX6, by fine-mapping the genes and neighbouring regulatory regions using polymorphic microsatellite markers and dense sets of SNPs in an expanded cohort of 500 DZ twin pairs. We will replicate any resultsfound using two independent samples of MZ twins and unrelated individuals.