An international collaborative family-based whole-genome linkage scan for high-grade myopia

Abstract

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 >or= 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.

Figure 1

Genome-wide linkage analysis results for high myopia defined as sphere (SPH) ≤ −500 D. LOD scores are plotted on the y-axes and genetic distance (in centromeres) along each chromosome on the x-axes. Four analyses are shown: two-point parametric (2PT-Par), two-point nonparametric (2PT-Non-par), multipoint parametric (MPT-Par), and multipoint nonparametric (MPT-Non-par).

Figure 2

Genome-wide linkage analysis results for high myopia defined as spherical equivalence SE ≤ −5.00 D, plotted as in Figure 1.

Figure 3

Chromosome 12 multipoint parametric linkage results for three datasets with the use of different definitions of unaffected status: (1) the primary dataset with unaffected individuals defined as SPH < −500 D; (2) without unaffected phenotype; (3) with emmetropic state (−0.50 D ≤ SPH ≤ 0.50 D) as unaffected.