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T. L. Young, R. Metlapally, A. Bulusu, J. Guggenheim, P. Calvas, F. Malecaze, T. Rosenberg, D. Mackey, P. Holmans, Y.-J. Li; An International Collaborative SNP-Based Whole Genome Linkage Screen for High-Grade Myopia. Invest. Ophthalmol. Vis. Sci. 2008;49(13):6087. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Myopia (nearsightedness) is a common complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and chorioretinal degeneration. Multiple family, twin, and population studies support a strong genetic component for myopic development. Several non-syndromic high-grade myopia loci have been mapped. The purpose of this study is to map new loci, refine existing locus intervals, and to identify associated genes for high-grade myopia (defined as ≤ -5.00 diopters spherical equivalent).
A total of 6008 SNPs distributed genome-wide from the Illumina Linkage Panel IVb were genotyped. After screening for Mendelian and family relationship errors using the PEDCHECK, RELPAIR and PREST programs, a collaborative 5-site international dataset of 249 multiplex high-grade myopia families (at least two affected siblings per family) and 5880 SNPs was compiled. The FASTLINK and MERLIN programs were used for 2-point and multipoint linkage analysis, respectively, with high myopia as a qualitative trait. Overall and center-specific datasets were evaluated.
FASTLINK revealed 15 SNPs on chromosomes 2, 5, and 12, with 2-point LOD scores > 2.0. The highest 2-point LOD score was 3.18 for rs581642 on chromosome 12. Parametric multipoint analysis showed a 23.5cM linkage region on chromosome 12 with all marker HLOD scores greater than 2 (peak HLOD=3.48). This interval was also supported by center-specific analysis. Other significant multipoint linkage regions were found on chromosome 2 (with a peak HLOD=2.25), and chromosomes 5, 9, and X with HLOD scores > 1.0.
The present results confirmed previously reported high myopia mapped loci on chromosomes 2 (MYP6), 12 (MYP3), and X (MYP1), with potential new linkage regions found on chromosomes 5 and 9. Linkage analyses for refractive error and other stratified datasets, as well as quantitative trait analyses are underway. This is the largest linkage screen to date for mapping risk loci for high-grade myopia.
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