An international collaborative family-based whole genome quantitative trait linkage scan for myopic refractive error.

PURPOSE: To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites. METHODS: Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses. RESULTS: We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13-6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1-35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23-7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype. CONCLUSIONS: Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13-16.1 and chromosome 5q35.1-35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.

Genetic association of insulin-like growth factor-1 polymorphisms with high-grade myopia in an international family cohort.

PURPOSE: Evidence from human myopia genetic mapping studies (MYP3 locus), modulated animal models, and observations of glycemic control in humans suggests that insulin-like growth factor (IGF)-1 plays a role in the control of eye growth. This study was conducted to determine whether IGF-1 polymorphisms are associated with myopia in a large, international dataset of Caucasian high-grade myopia pedigrees. METHODS: Two hundred sixty-five multiplex families with 1391 subjects participated in the study. IGF-1 genotyping was performed with 13 selected tag single nucleotide polymorphisms (SNPs) using allelic discrimination assays. A family-based pedigree disequilibrium test (PDT) was performed to test for association. Myopia status was defined using sphere (SPH) or spherical equivalent (SE), and analyses assessed the association of (1) high-grade myopia (

COL1A1 and COL2A1 genes and myopia susceptibility: evidence of association and suggestive linkage to the COL2A1 locus.

PURPOSE: Collagen involvement in myopia development via scleral remodeling is well-known. Recently, COL1A1 and COL2A1 gene polymorphisms were reported to be associated with high-grade and common myopia, respectively. This study was conducted to investigate whether these collagen genes are associated and/or genetically linked with myopia in large Caucasian family datasets. METHODS: High-grade myopia was defined as

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

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.

Heritability of refractive value and ocular biometrics.

The aim of this work was to analyse genetic influences on ocular refractive value and axial length using the hypothesis of a polygenic control. The genealogical records of 55 families were used in the analyses. The cohort included 723 individuals and clinical data were collected for 445 individuals with a mean age of 37.86 years. Ocular refraction was determined by standard autorefractometry. Axial length was evaluated by scan ultrasonography. Gender, age and ethnic origin were included as covariates in the statistical analyses. Using variance component analysis via a Markov Chain Monte Carlo (MCMC) method, we estimated the heritability of refractive value and axial length in the pedigree. We then performed a segregation analysis, using Loki, a (MCMC) linkage analysis program for multilocus inheritance models, examining different inheritance models with polygenic components. Polygenic control was modelled under an additive infinitesimal model (which assumes infinite loci with small effects, with additive actions) and under a finite locus model (i.e. several causal loci). The estimates of heritability were 0.20 (95% confidence interval (CI) 0.04-0.36) for refractive value and 0.20 (95% CI 0.03-0.43) for axial length. Segregation analyses suggested that ocular refraction and axial length are under a polygenic control. A finite number of genes were identified with or without a polygenic, infinitesimal component. Ocular refraction is mildly-moderately heritable in the studied population.

Linkage analysis of high myopia susceptibility locus in 26 families.

PURPOSE: We conducted a linkage analysis in high myopia families to replicate suggestive results from chromosome 7q36 using a model of autosomal dominant inheritance and genetic heterogeneity. We also performed a genome-wide scan to identify novel loci. METHODS: Twenty-six families, with at least two high-myopic subjects (ie. refractive value in the less affected eye of -5 diopters) in each family, were included. Phenotypic examination included standard autorefractometry, ultrasonographic eye length measurement, and clinical confirmation of the non-syndromic character of the refractive disorder. Nine families were collected de novo including 136 available members of whom 34 were highly myopic subjects. Twenty new subjects were added in 5 of the 17 remaining families. A total of 233 subjects were submitted to a genome scan using ABI linkage mapping set LMSv2-MD-10, additional markers in all regions where preliminary LOD scores were greater than 1.5 were used. Multipoint parametric and non-parametric analyses were conducted with the software packages Genehunter 2.0 and Merlin 1.0.1. Two autosomal recessive, two autosomal dominant, and four autosomal additive models were used in the parametric linkage analyses. RESULTS: No linkage was found using the subset of nine newly collected families. Study of the entire population of 26 families with a parametric model did not yield a significant LOD score (>3), even for the previously suggestive locus on 7q36. A non-parametric model demonstrated significant linkage to chromosome 7p15 in the entire population (Z-NPL=4.07, p=0.00002). The interval is 7.81 centiMorgans (cM) between markers D7S2458 and D7S2515. CONCLUSIONS: The significant interval reported here needs confirmation in other cohorts. Among possible susceptibility genes in the interval, certain candidates are likely to be involved in eye growth and development.