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An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia

¹From the Center for Human Genetics and the Departments of and ²Biostatistics Bioinformatics and ⁴Ophthalmology, Duke University Medical Center, Durham, North Carolina; the ³School of Optometry and Vision Sciences and the ⁷Department of Psychological Medicine, Cardiff University, Cardiff, Wales, United Kingdom; ⁵Inserm, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; the ⁶National Eye Clinic, Kennedy Institute, Hellerup, Denmark; and the ⁸Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, Melbourne, Australia.

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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