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Yi-Ju Li, Jeremy A. Guggenheim, Anuradha Bulusu, Ravikanth Metlapally, Diana Abbott, Francois Malecaze, Patrick Calvas, Thomas Rosenberg, Sandrine Paget, Rosalind C. Creer, George Kirov, Michael J. Owen, Bei Zhao, Tristan White, David A. Mackey, Terri L. Young; An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia. Invest. Ophthalmol. Vis. Sci. 2009;50(7):3116-3127. doi: 10.1167/iovs.08-2781.
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purpose. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites.
methods. Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphere+cylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score ≥ 1.5.
results. The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPL= 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD = 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent—a 9.4-cM region (rs163016–rs1520724) driven by the Asian subset and a 13.43-cM region (rs163016–rs1520724) driven by the Caucasian subset.
conclusions. The present study is the largest linkage scan to date for familial high-grade myopia. The outcomes will facilitate the identification of genes implicated in myopic refractive error development and ocular growth.
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