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T. L. Young, J. Guggenheim, D. Abbott, R. Metlapally, F. Malecaze, P. Calvas, D. Mackey, T. Rosenberg, Y.-J. Li; Quantitative Trait Analysis in a Genome Wide SNP Linkage Screen for Familial High Myopia. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3736.
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The diagnosis of myopia is based on quantitative ocular measurements such as spherical refractive error (SPH) and spherical equivalent (SE= SPH + cylinder/2). Most human myopia linkage studies have used qualitative determinants of affected refractive status, rather than quantitative trait analyses of ocular phenotypes.
A total of 1411 subject genomic DNA samples from 260 multiplex high-grade myopia (SPH or SE ≤ -5.00 diopters) families were combined from five collaborative sites, and genotyped using the Illumina Linkage Panel IVb. Linkage analyses using 5744 SNPS after quality control exclusions for high myopia were performed for SPH and SE using the variance component algorithm, SOLAR (Sequential Oligogenic Linkage Analysis Routines). Phenotype data was transformed to meet the criteria of normality using the following formulas: SPH new= 4.3xlog10 [- (SPH-0.25)] for both left and right eye and Enew = 4.4xlog10 [-(SE-0.25)]. SPH and SE data of the right and left eye were analyzed independently, using gender and high myopia affection status as covariates. Binocular data analyses were performed by including a covariate to indicate right and left eye. Ascertainment bias was adjusted by treating each collection site as a random house effect. Both two-point and multipoint linkage analyses were performed.
Affection status of high myopia was a significant covariate for all phenotypes, and was included in the final analysis model. The residual heritability for all phenotypes ranged from 14.7% to 23.4%. For two-point analysis, 15 markers had LOD scores > 1.5, with a peak LOD score of 2.2 for SNP rs1396208 on chromosome 12p. This peak marker is centered within an 11cM region with multipoint LOD scores > 1, and a peak LOD =1.5 for SE of the right eye. A second ranked two-point peak LOD score with SNP rs2063036 was noted at chromosome 15q within a 20cM interval with LOD scores > 1 from multipoint analysis, and peak LOD scores ranging from 1.1 to 1.99 for binocular SPH and SE for right eye analyses, respectively.
These loci may play a role in causing high myopia in the families studied. Additional studies are underway to refine these loci and screen potential candidate genes.
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