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C. L. Simpson, P. Hysi, S. S. Bhattacharya, C. J. Hammond, A. Webster, P. C. Sham, J. S. Rahi; Common Polymorphisms in the Low-Density Lipoprotein Receptor-Related Protein Are Associated With Refractive Error in the 1958 British Birth Cohort. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2817.
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We performed a candidate gene association study to identify common gene variants associated with the risk of developing of refractive error.
Subjects were drawn from 2494 people randomly selected from the 1958 British Birth Cohort (comprising everyone born in Great Britain in one week in March 1958), who had autorefraction undertaken at age 44. The mean spherical equivalent (SE) of refraction of both eyes was calculated for each individual. 596 individuals were selected at random from each of the outer tertiles of the distribution. Tagging single nucleotide polymorphisms (SNPs) were chosen using the Tagger algorithm and genotyped on the Illumina GoldenGate platform. Analysis was performed using the qualitative trait (myopic vs. non-myopic) as well as the mean SE as a quantitative trait. Individual SNP analysis was undertaken using regression in Stata. Single SNP and haplotype analyses performed using the likelihood ratio test in Whap. Overall, 2065 SNPs were chosen across 111 genes. Given the sample size, this experiment has 80% power to exclude genes contributing to more than 10% of the variance of the refractive error in this cohort.
All SNPs were in Hardy Weinberg equilibrium and the genotyping failure rate was < 5%. After accounting for multiple testing, statistically significant association (p < 0.05) was found between four SNPs in the low density lipoprotein receptor-related protein 5 (LRP5) and refractive error.
Our findings suggest that LRP5, a known component of the canonical Wnt pathway which is important in ocular development, is a biologically plausible novel candidate gene in the development of refractive error. Gene expression (underway) and functional studies in the future should determine the mechanisms of action.
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