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1.  Candidate gene and locus analysis of myopia 
Molecular Vision  2007;13:1012-1019.
A previous study has reported evidence of a strong linkage, but no association, between paired box gene 6 (PAX6) and myopia. We attempted to replicate these findings and to conduct a candidate gene and locus evaluation of genetic involvement in common forms of myopia.
Samples were collected from 517 individuals in 123 families with a myopic child participating in the Orinda Longitudinal Study of Myopia or the Contact Lens and Myopia Progression Study. Myopia in the proband children was defined as -0.75 D or more and as being present in both meridians on cycloplegic autorefraction (1% tropicamide). Affected status in parents and siblings was determined by survey. After DNA was extracted from buccal mucosal cells and genotyped using assays for microsatellite markers and single nucleotide polymorphisms (SNPs), DNA was analyzed for linkage disequilibrium. Markers on chromosomes 12 and 18 were selected as regions previously associated with pathological myopia. SNPs were also analyzed in genes where their expression pattern or their association with syndromes conveys myopia as part of the phenotype (FGF2, BDNF, COL2A1, COL18A1, and PAX6).
The SNP rs1635529 for COL2A1 on 12q13.11 showed highly significant over-transmission to affected individuals (p=0.00007). No SNP for FGF2, BDNF, COL18A1, or PAX6 showed significant over-transmission to affected individuals after correction for multiple comparisons. Markers on chromosome 12 and 18 previously associated with pathological myopia also showed no significant associations with the more common form of myopia in this study.
As reported previously by others, PAX6 showed no association with myopia. Associations in the current analysis are suggestive of involvement of COL2A1. Future studies should focus on replication in other samples and in genome-wide approaches.
PMCID: PMC2776540  PMID: 17653045
2.  Dissecting the genetic heterogeneity of myopia susceptibility in an Ashkenazi Jewish population using ordered subset analysis 
Molecular Vision  2011;17:1641-1651.
Despite many years of research, most of the genetic factors contributing to myopia development remain unknown. Genetic studies have pointed to a strong inherited component, but although many candidate regions have been implicated, few genes have been positively identified.
We have previously reported 2 genomewide linkage scans in a population of 63 highly aggregated Ashkenazi Jewish families that identified a locus on chromosome 22. Here we used ordered subset analysis (OSA), conditioned on non-parametric linkage to chromosome 22 to detect other chromosomal regions which had evidence of linkage to myopia in subsets of the families, but not the overall sample.
Strong evidence of linkage to a 19-cM linkage interval with a peak OSA nonparametric allele-sharing logarithm-of-odds (LOD) score of 3.14 on 20p12-q11.1 (ΔLOD=2.39, empirical p=0.029) was identified in a subset of 20 families that also exhibited strong evidence of linkage to chromosome 22. One other locus also presented with suggestive LOD scores >2.0 on chromosome 11p14-q14 and one locus on chromosome 6q22-q24 had an OSA LOD score=1.76 (ΔLOD=1.65, empirical p=0.02).
The chromosome 6 and 20 loci are entirely novel and appear linked in a subset of families whose myopia is known to be linked to chromosome 22. The chromosome 11 locus overlaps with the known Myopia-7 (MYP7, OMIM 609256) locus. Using ordered subset analysis allows us to find additional loci linked to myopia in subsets of families, and underlines the complex genetic heterogeneity of myopia even in highly aggregated families and genetically isolated populations such as the Ashkenazi Jews.
PMCID: PMC3123157  PMID: 21738393
3.  Hepatocyte growth factor and myopia: Genetic association analyses in a caucasian population 
Molecular Vision  2009;15:1028-1035.
Hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (C-MET) genes have previously been reported to be associated with myopia in Asian family-based and case-control association studies, respectively. We examined whether these genes were associated with myopia in a Caucasian family dataset biased towards high myopia.
Participating families had at least one offspring with high myopia (≤-5.00 diopters [D]). Genotyping was performed with tagging single nucleotide polymorphisms (SNPs) for each candidate gene using Taqman™ allelic discrimination assays. The data were analyzed with two family-based association methods, the pedigree disequilibrium test (PDT) and the association in the presence of linkage (APL) test. Analyses compared 1) high myopia (<-5.00 D), 2) mild to moderate myopia (-0.50 to -5.00 D), 3) any myopia (<-0.50 D) and 4) extreme high myopia (≤-10.00 D) versus emmetropia using refractive error as either sphere (SPH) or spherical equivalent (SE=sphere + [cylinder/2]). Bonferroni correction was applied to adjust for multiple testing leading to significance levels of 0.0125 for HGF and 0.008 for C-MET. Two and three-marker sliding window haplotype association tests using APL were also performed for HGF markers. Significance levels for haplotype association testing were set at 0.01 for the global tests, and 0.007 for the three marker haplotype specific tests and 0.0125 for the two marker haplotype specific tests.
A total of 146 multiplex families consisting of 649 Caucasian subjects were included. The HGF SNP, rs3735520 (APL p=0.002768 for SPH and 0.005609 for SE), and the haplotypes, rs2286194-rs3735520-rs17501108 (APL p=0.007403 for SPH and 0.062685 for SE) and rs12536657-rs2286194 (APL p=0.004219 for SPH and 0.00518 for SE), showed significant association with mild to moderate myopia versus emmetropia. A promising association between extreme high myopia and the HGF SNP, rs2286194, was also found (APL p=0.005763 for SPH and 0.004103 for SE). No evidence of association was found in the SNPs tested for C-MET.
This study supports a strong association between the mild to moderate myopia group and the HGF SNP rs3735520 and the HGF haplotypes rs2286194-rs3735520-rs17501108 and rs12536657-rs2286194, and a moderate association of the extreme high myopia with rs2286194. C-MET polymorphism statistical associations with myopia in an Asian study were not replicated in our Caucasian cohort. HGF may be a potential myopia candidate gene for further investigation.
PMCID: PMC2684748  PMID: 19471602
4.  Identification of novel suggestive loci for high-grade myopia in Polish families 
Molecular Vision  2011;17:2028-2039.
Myopia is the most common human eye disorder with complex genetic and environmental causes. To date, several myopia loci have been identified in families of different geographic origin. However, no causative gene(s) have yet been identified. The aim of this study was the characterization of Polish families with high-grade myopia, including genetic analysis.
Forty-two multiplex Polish families with non–syndromic high-grade myopia participated in the study. All family members underwent detailed ophthalmic examination and high-grade myopia was defined as ≤-6.0 diopters (D) based on the spherical refractive error. A genome-wide single nucleotide polymorphism (SNP)-based high-density linkage scan was performed using Affymetrix Human SNP Array 6.0 on a selected family (HM-32) with multiple affected individuals.
Nonparametric linkage analysis identified three novel loci in family HM-32 at chromosome 7p22.1–7p21.1 ([NPL] 8.26; p=0.006), chromosome 7p12.3–7p11.2 ([NPL] 8.23; p=0.006), and chromosome 12p12.3–12p12.1 ([NPL] 8.02; p=0.006), respectively. The effect of linkage disequilibrium on linkage due to dense SNP map was addressed by systematically pruning SNPs from the linkage panel.
Haplotype analysis with informative crossovers in affected individuals defined a 12.2; 10.9; and 9.5 Mb genomic regions for high-grade myopia spanned between SNP markers rs11977885/rs10950639, rs11770622/rs9719399, and rs4763417/rs10842388 on chromosomes 7p22.1–7p21.1, 7p12.3–7p11.2, and 12p12.3–12p12.1, respectively.
PMCID: PMC3154124  PMID: 21850178
5.  The Molecular Genetics of Human Myopia: An Update 
Myopia, or nearsightedness, is the most common human eye disorder in the world, and is a significant global public health concern. Along with cataract, macular degeneration, infectious disease, and vitamin A deficiency, myopia is one of the most important causes of visual impairment worldwide. Severe or high-grade myopia is a leading cause of blindness because of its associated ocular morbidities of retinal detachment, macular choroidal degeneration, premature cataract, and glaucoma. Ample evidence documents the heritability of the non-syndromic forms of this condition, especially for high-grade myopia, commonly referred to as myopic spherical refractive power of 5–6 diopters or higher. Multiple high-grade myopia genetic loci have been identified, and confirmatory studies identifying high-grade and moderate myopia loci have also occurred. In general, myopia susceptibility genes are unknown with few association studies performed, and without confirmation in other research laboratories or testing of separate patient cohorts.
PMCID: PMC3718050  PMID: 19104467
myopia; International Myopia Conference Sek-jin Chew lecture; human molecualr genetics; mapping studies; association studies
6.  Early Childhood Refractive Error and Parental History of Myopia as Predictors of Myopia 
A child's refractive error in the first grade and the number of myopic parents can provide an indication of the child's risk for development of myopia; however, because the sensitivity of these predictive factors is low, they may not be sufficient at this young age in situations in which making a more accurate prediction of future onset is needed.
To determine the utility of a child's first grade refractive error and parental history of myopia as predictors of myopia onset between the second and eighth grades.
Subjects were nonmyopic children in the first grade who were enrolled in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study. Myopia was defined as −0.75 D or more myopia in both meridians (by cycloplegic autorefraction). The children were classified as having a high (versus low) risk of myopia with a cycloplegic sphere cutoff of +0.75 D or less (versus more) of hyperopia. Parental myopia was determined by a parent-completed survey. Discrete-time survival models predicted the risk of myopia.
Of the 1854 nonmyopic first graders, 21.3% were at high risk of myopia. More high-risk subjects had two myopic parents, 25.4% compared with 16.5% in the low-risk group (P < 0.0001). The low-risk survival function was similar regardless of the number of myopic parents. Among high-risk eighth graders, the survival probability was lower than in the low-risk group, decreasing with an increase in the number of myopic parents. The sensitivity and specificity of first grade refractive error with the number of myopic parents as predictors for myopia onset were 62.5% and 81.9%, respectively.
First grade refractive error and the number of myopic parents can predict a child's risk of myopia; however, because the sensitivity of these factors is low, these two predictors may not be sufficient at this young age when a more accurate prediction of myopia onset is needed.
PMCID: PMC2869059  PMID: 19737876
7.  Association Mapping of the High-Grade Myopia MYP3 Locus Reveals Novel Candidates UHRF1BP1L, PTPRR, and PPFIA2 
Myopia, or nearsightedness, is a common ocular genetic disease for which over 20 candidate genomic loci have been identified. The high-grade myopia locus, MYP3, has been reported on chromosome 12q21–23 by four independent linkage studies.
We performed a genetic association study of the MYP3 locus in a family-based high-grade myopia cohort (n = 82) by genotyping 768 single-nucleotide polymorphisms (SNPs) within the linkage region. Qualitative testing for high-grade myopia (sphere ≤ −5 D affected, > −0.5 D unaffected) and quantitative testing on the average dioptric sphere were performed.
Several genetic markers were nominally significantly associated with high-grade myopia in qualitative testing, including rs3803036, a missense mutation in PTPRR (P = 9.1 × 10−4) and rs4764971, an intronic SNP in UHRF1BP1L (P = 6.1 × 10−4). Quantitative testing determined statistically significant SNPs rs4764971, also found by qualitative testing (P = 3.1 × 10−6); rs7134216, in the 3′ untranslated region (UTR) of DEPDC4 (P = 5.4 × 10−7); and rs17306116, an intronic SNP within PPFIA2 (P < 9 × 10−4). Independently conducted whole genome expression array analyses identified protein tyrosine phosphatase genes PTPRR and PPFIA2, which are in the same gene family, as differentially expressed in normal rapidly growing fetal relative to normal adult ocular tissue (confirmed by RT-qPCR).
In an independent high-grade myopia cohort, an intronic SNP in UHRF1BP1L, rs4764971, was validated for quantitative association, and SNPs within PTPRR (quantitative) and PPFIA2 (qualitative and quantitative) approached significance. Three genes identified by our association study and supported by ocular expression and/or replication, UHRF1BP1L, PTPRR, and PPFIA2, are novel candidates for myopic development within the MYP3 locus that should be further studied.
Association mapping of the MYP3 locus reveals novel candidate genes.
PMCID: PMC3621505  PMID: 23422819
8.  Genomewide Linkage Scans for Ocular Refraction and Meta-analysis of Four Populations in the Myopia Family Study 
Genomewide linkage scans were performed in Caucasian (CAUC) and Old Order Amish (OOA) families to identify genomic regions containing genes responsible for refractive error control. We also performed a meta-analysis by combining these results with our previous linkage results from Ashkenazi Jewish (ASHK) and African American (AFRAM) families.
Two hundred seventy-one CAUC and 411 OOA participants (36 and 61 families, respectively) were recruited to participate in the Myopia Family Study. Recruitment criteria were designed to enrich the sample for multiplex myopic families. Genomewide, model-free, multipoint linkage analyses were performed separately for each population by using >370 microsatellite markers. Empirical significance levels were determined via gene-dropping simulations. A meta-analysis was performed by combining linkage results from the CAUC, OOA, AFRAM, and ASHK samples, and results were compared to previously reported loci for myopia and refraction.
Suggestive evidence of linkage was found at 12q24 (LOD = 4.583, P = 0.00037) and 4q21 (LOD = 2.72, P = 0.0028) in the CAUC sample and at 5qter (LOD = 3.271, P = 0.0014) in the OOA. Meta-analysis linkage results were largely driven by population-specific signals from ASHK and AFRAM families. The meta-analysis showed suggestive evidence of linkage to 4q21-22 (meta-P = 0.00214) adjacent to the previously reported MYP9 and MYP11 loci.
The results showed suggestive evidence of linkage of ocular refraction to 12q24 and 4q21 in CAUC and to 5qter in OOA families. The meta-analysis supports the view that several genes play a role in refractive development across populations. In MFS families, four broad genomic regions (on 1p, 4q, 7p, and 12q) most likely contain genes that influence ocular refraction.
PMCID: PMC2885973  PMID: 19151385
9.  Novel locus for X linked recessive high myopia maps to Xq23–q25 but outside MYP1 
Journal of Medical Genetics  2006;43(5):e20.
High myopia is a common genetic variation in most cases, affecting 1–2% of people, and is the fourth most common disorder causing blindness worldwide. Six autosomal dominant loci and one X‐linked recessive locus have been reported, but no genes responsible for high myopia have been identified.
To report a Chinese family in which six males presented with high myopia consistent with an X linked recessive trait.
Affected individuals shared three common features: high myopia, reduced visual acuity, and fundal changes of high myopia. Protan and deutan were observed in the family, but they did not co‐segregate with the high myopia phenotype. X‐chromosome‐wide linkage analysis mapped the high myopia locus to a 25 cM (14.9 Mb) region on Xq23–q25 between DXS1210 and DXS8057, with maximum two point lod scores at θ = 0 of 2.75 and 2.29 for DXS1001 and DXS8059, respectively.
This new myopia locus is outside the linked region of the first high myopia locus (MYP1). Refinement of the linkage region with additional families and screening candidate genes for mutation may lead to the identification of the defect gene.
PMCID: PMC2564525  PMID: 16648373
X linked recessive high myopia; linkage; cone dysfunction; MYP1
10.  COL1A1 and COL2A1 Genes and Myopia Susceptibility: Evidence of Association and Suggestive Linkage to the COL2A1 Locus 
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.
High-grade myopia was defined as ≤–5.00 D. Two independent datasets comprising 146 (Duke) and 130 (Cardiff) families with high-grade myopia participated in the association study. Allelic discrimination assays were performed on tagging SNPs for COL1A1 and COL2A1. The pedigree disequilibrium test (PDT) and the association test in the presence of linkage (APL) were used for association analyses. Linkage analyses for COL2A1 locus markers were performed with the Fastlink and Merlin programs in conjunction with data obtained from our collaborative whole-genome linkage study (254 families).
Significant association was identified between five SNPs (rs1034762, rs1635529, rs1793933, rs3803183, and rs17122571) of the COL2A1 locus and high-grade myopia (P < 0.045, minimum (min) P = 0.008) and with myopia status set at ≤–0.50 or –0.75 D (min P = 0.004) in the Duke dataset. The SNP rs1635529 also showed significant association in the Cardiff dataset (≤–5.00 D, min P = 0.004; ≤–0.50 D, min P = 0.007). Linkage analyses showed suggestive linkage to the COL2A1 locus on 12q. No association was found between COL1A1 SNPs and any degree of myopia.
The COL2A1 gene was associated with high-grade myopia in two independent Caucasian family datasets. COL1A1 gene polymorphisms were not associated with myopia in our dataset, indicating possible heterogeneity across different ethnicities.
PMCID: PMC3936411  PMID: 19387081
11.  An International Collaborative Family-Based Whole-Genome Linkage Scan for High-Grade Myopia 
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.
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.
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 1343-cM region (rs163016–rs1520724) driven by the Caucasian subset.
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.
PMCID: PMC3696634  PMID: 19324860
12.  Association of Matrix Metalloproteinase Gene Polymorphisms with Refractive Error in Amish and Ashkenazi Families 
The role of polymorphisms in matrix metalloproteinase genes with variations in refractive error among Orthodox Ashkenazi Jewish and Old Order Amish families was investigated. The results showed statistically significant genetic associations of refraction with two markers in MMP regions in the Amish population, but not among the Ashkenazim.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in scleral extracellular matrix remodeling and have shown differential expression in experimental myopia. The genetic association of refractive error and polymorphisms in MMP and TIMP genes in Old Order Amish (AMISH) and Ashkenazi Jewish (ASHK) families was investigated.
Individuals from 55 AMISH and 63 ASHK families participated in the study. Ascertainment was designed to enrich the families for myopia; the mean spherical equivalent (MSE) refractive error (SD) was −1.61 (2.72) D in the AMISH, and −3.56 (3.32) D in the ASHK. One hundred forty-six common haplotype tagging SNPs covering 14 MMP and 4 TIMP genes were genotyped in 358 AMISH and 535 ASHK participants. Association analyses of MSE and the spherical component of refraction (SPH) were performed separately for the AMISH and the ASHK. Bonferroni-corrected significance thresholds and local false discovery rates were used to account for multiple testing.
After they were filtered for quality-control, 127 SNPs were included in the analyses. No polymorphisms showed statistically significant association to refraction in the ASHK (minimum P = 0.0132). In AMISH, two SNPs showed evidence of association with refractive phenotypes: rs1939008 (P = 0.00016 for SPH); and rs9928731 (P = 0.00026 for SPH). These markers were each estimated to explain <5% of the variance of SPH in the AMISH sample.
Statistically significant genetic associations of ocular refraction to polymorphisms near MMP1 and within MMP2 were identified in the AMISH but not among the ASHK families. The results suggest that the MMP1 and MMP2 genes are involved in refractive variation in the AMISH. Genetic and/or environmental heterogeneity most likely contribute to differences in association results between ethnic groups.
PMCID: PMC3066601  PMID: 20484597
13.  Refinement of the X-linked Nonsyndromic High-Grade Myopia Locus MYP1 on Xq28 and Exclusion of 13 Known Positional Candidate Genes by Direct Sequencing 
Myopia affects more people worldwide than any other chronic condition, and it is increasing in all populations across the globe. It affects ∼25% of the U.S. general population between the ages of 12 and 54 years. The present study is a genetic investigation of X-linked high-grade myopia that maps to Xq28.
Myopia is a common vision problem affecting almost one third of the world's population. It can occur as an isolated genetic condition or be associated with other anomalies and/or syndromes. Seventeen myopia loci have been identified on various chromosomes; however, no specific gene mutations have yet been identified.
Two large multigeneration Asian Indian pedigrees (UR006 and UR077) with isolated, nonsyndromic myopia were studied, in which the condition appeared to segregate as an X-linked recessive trait (MYP1; MIM 310460). The degree of myopia was variable in both families, ranging from −6 to −23 D (mean, –8.48 D) with the majority >7.0 D. To map the myopia locus in these families, polymorphic microsatellite markers covering the entire X chromosome were used in linkage analyses performed on 42 genomic DNA samples (13 affected and 29 normal) from both families.
Marker DXYS154, which is located within the pseudoautosomal region in distal Xq28 (PAR2; pseudoautosomal region 2), gave a combined maximum LOD score of 5.3 at θ = 0 under an autosomal recessive model. Other markers in the region (near but not within the PAR2 region) that showed no recombination with the phenotype in both the families included DXS1108, DXS8087, and F8i13.
Observation of recombination in family UR006 refined the disease locus to a ∼1.25-Mb region flanked by the proximal marker DXS1073 and distal marker DXYS154. Mutation search in exons and splice junctions of candidate genes CTAG2, GAB3, MPP1, F8Bver, FUNDC2, VBP1, RAB39B, CLIC2, TMLHE, SYBL, IL9R, SPRY3, and CXYorf1 did not detect a pathogenic or predisposing variant.
PMCID: PMC3176007  PMID: 21357393
14.  Prevalence of Myopia in Students of Srinagar City of Kashmir, India 
Myopia is a common ocular disorder. Prevalence data with regard to myopia is scarce in India and almost nonexistent in Kashmir.
To determine the prevalence of myopia in Srinagar City and to evaluate risk factors associated with the disease.
38 schools in the Srinagar were selected randomly and students were examined by our optometrist team. Children with refractive error of −0.25 D to −5.9 D were considered myopic, while those with −6 D and above were considered high myopic.
Statistical analysis used:
χ2 Tests were used as appropriate to test whether potential risk factors were significantly associated with myopia. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for risk factors that were independently associated with myopia in this population.
A total of 4,360 students of mean age 12.11 (95% confidence interval [CI] = 11.99 – 12.22: range, 7–18) participated in the study. Myopia was found in 4.74% students. Increasing age was associated with the increased risk of having myopia. Girl students were more likely to have myopia than boys (OR = 1.52). The prevalence of myopia among girls was more than that of boys. Students from low socioeconomic conditions were having higher prevalence of myopia than their counterparts from higher socioeconomic counterparts.
Reduced vision because of myopia is an important health problem in students in Srinagar City. Most of these students do not have the necessary correction spectacles. Effective strategies are needed to eliminate the cause of a significant visual problem.
PMCID: PMC3068712  PMID: 21475475
Myopia; Prevalence; Kashmiri population
15.  Genetic Association of Insulin-like Growth Factor-1 Polymorphisms with High-Grade Myopia in an International Family Cohort 
This article reports the association of IGF-1 with human myopia and supports previous studies in animal models on IGF-1's role in axial ocular growth during myopia development.
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.
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 (≤ −5.00 D), and (2) any myopia (≤ −0.50 D) with IGF-1 markers. Results were declared significant at P ≤ 0.0038 after Bonferroni correction. Q values that take into account multiple testing were also obtained.
In all, three SNPs—rs10860860, rs2946834, and rs6214—were present at P < 0.05. SNP rs6214 showed positive association with both the high-grade– and any-myopia groups (P = 2 × 10−3 and P = 2 × 10−3, respectively) after correction for multiple testing.
The study supports a genetic association between IGF-1 and high-grade myopia. These findings are in line with recent evidence in an experimental myopia model showing that IGF-1 promotes ocular growth and axial myopia. IGF-1 may be a myopia candidate gene for further investigation.
PMCID: PMC2941166  PMID: 20435602
16.  Identification of a locus for autosomal dominant high myopia on chromosome 5p13.3-p15.1 in a Chinese family 
Molecular Vision  2010;16:2043-2054.
Myopia and its extreme form, high myopia, are common vision disorders worldwide, especially in Asia. Identifying genetic markers is a useful step toward understanding the genetic basis of high myopia, particularly in the Chinese population, where it is highly prevalent. This study was conducted to provide evidence of linkage for autosomal dominant high myopia to a locus on chromosome 5p13.3-p15.1 in a large Chinese family.
After clinical evaluation, genomic DNA from 29 members of this family was genotyped. A genome-wide screen was then performed using 382 markers with an average inter-marker distance of 10 cM, and two-point linkage was analyzed using the MLINK program. Mutation analysis of the candidate genes was performed using direct sequencing.
Linkage to the known autosomal dominant high myopia loci was excluded. The genome-wide screening identified a maximum two-point LOD score of 3.71 at θ=0.00 with the microsatellite marker D5S502. Fine mapping and haplotype analysis defined a critical region of 11.69 cM between D5S2096 and D5S1986 on chromosome 5p13.3-p15.1. Sequence analysis of the candidate genes inside the linked region did not identify any causative mutations.
A genetic locus was mapped to chromosome 5p13.3-p15.1 in a large Chinese family with autosomal dominant high myopia.
PMCID: PMC2965568  PMID: 21042559
17.  A single nucleotide polymorphism analysis of the LAMA1 gene in Japanese patients with high myopia 
Although a myopia susceptibility gene has not yet been elucidated, ten candidate regions (MYP1–MYP10) have been associated with myopia by linkage analysis employing large pedigrees. We report herein on the results of our analysis pertaining to polymorphisms of LAMA1 (alpha subunit of laminin), a promising candidate gene for high myopia present in the MYP2 region of Japanese subjects with high myopia. Three hundred and thirty Japanese subjects with high myopia at a level of greater than −9.25 D and ethnically and sex matched 330 normal controls without high myopia was enrolled in this study. The thirteen SNPs located on the LAMA1 gene were analyzed using PCR and SNP-specific fluorogenic probes. Two of the SNPs were monomorphic and none of the 11 SNPs showed statistically significant association with high myopia in the Japanese population. There is no convincing evidence to prove a connection between nucleotide sequence variations in LAMA1 and high myopia. The pairwise linkage disequilibrium (LD) mapping disclosed a strong value (D' > 0.8) and narrow ranged block within these SNPs.
PMCID: PMC2701124  PMID: 19668483
18.  Clinical and linkage study on a consanguineous Chinese family with autosomal recessive high myopia 
Molecular Vision  2009;15:312-318.
A linkage study on autosomal recessive high myopia (arHM) has not been reported, although several loci for autosomal dominant high myopia (adHM) have been mapped. Data from a consanguineous Chinese family with arHM were collected to map the genetic locus associated with this condition.
Phenotypic information and DNA samples were collected from family members. A genome-wide linkage scan combined with homozygosity mapping was performed by using 382 microsatellite DNA markers from the entire genome spaced at intervals of about 10 cM.
The pedigree and clinical data of the family indicate that the high myopia is autosomal recessive. A genome-wide scan of chromosomes 1–22 gave a LOD score greater than 1.0 for 22 markers. Linkage to most of these markers was not supported by closely flanking markers except for three possible loci on chromosomes 11, 14, and 17. Fine mapping and haplotype analysis provide evidence for a locus at 14q22.1-q24.2 in a 25.23 Mb region between markers D14S984 and D14S999 with a maximum LOD score of 2.19. All 11 microsatellite markers inside the linkage interval as well as haplotype construction point to a gene at this locus. Linkage elsewhere on chromosome 11 and chromosome 17 could not be excluded due to the small size of the family.
Pedigree and clinical data suggest that an autosomal recessive gene is responsible for high myopia in a consanguineous Chinese family. Genome-wide linkage analysis was used to map the gene for high myopia to a few limited loci. The resultant information should help future studies identify the gene for arHM. To our knowledge, this report is the first clinical and linkage study on a consanguineous family with arHM.
PMCID: PMC2635848  PMID: 19204786
19.  Juvenile myopia progression, risk factors and interventions 
Saudi Journal of Ophthalmology  2011;26(3):293-297.
The development and progression of early onset myopia is actively being investigated. While myopia is often considered a benign condition it should be considered a public health problem for its visual, quality of life, and economic consequences. Nearly half of the visually impaired population in the world has uncorrected refractive errors, with myopia a high percent of that group. Uncorrected visual acuity should be screened for and treated in order to improve academic performance, career opportunities and socio-economic status.
Genetic and environmental factors contribute to the onset and progression of myopia. Twin studies have supported genetic factors and research continues to identify myopia genetic loci. While multiple myopia genetic loci have been identified establishing myopia as a common complex disorder, there is not yet a genetic model explaining myopia progression in populations.
Environmental factors include near work, education levels, urban compared to rural location, and time spent outdoors. In this field of study where there continues to be etiology controversies, there is recent agreement that children who spend more time outdoors are less likely to become myopic.
Worldwide population studies, some completed and some in progress, with a common protocol are gathering both genetic and environmental cohort data of great value. There have been rapid population changes in prevalence rates supporting an environmental influence.
Interventions to prevent juvenile myopia progression include pharmacologic agents, glasses and contact lenses. Pharmacological interventions over 1–2 year trials have shown benefits. Peripheral vision defocus has been found to affect the emmetropization process and may be affected by wearing glasses or contacts. Accommodation accuracy also has been implicated in myopia progression.
Further research will aim to assess both the role and interaction of environmental influences and genetic factors.
PMCID: PMC3729802  PMID: 23961008
Myopia; Refractive error; Emmetropization; Review
20.  Fine-mapping of candidate region in Amish and Ashkenazi families confirms linkage of refractive error to a QTL on 1p34-p36 
Molecular Vision  2009;15:1398-1406.
A previous genome-wide study in Orthodox Ashkenazi Jewish pedigrees showed significant linkage of ocular refraction to a Quantitative Trait Locus (QTL) on 1p34-36.1. We carried out a fine-mapping study of this region in Orthodox Ashkenazi Jewish (ASHK) and Old Order Amish (OOA) families to confirm linkage and narrow the candidate region.
Families were recruited from ASHK and OOA American communities. The samples included: 402 individuals in 53 OOA families; and 596 members in 68 ASHK families. Families were ascertained to contain multiple myopic individuals. Genotyping of 1,367 SNPs was carried out within a 35cM (~23.9 Mb) candidate QTL region on 1p34-36. Multipoint variance components (VC) and regression-based (REG) linkage analyses were carried out separately in OOA and ASHK groups, and in a combined analysis that included all families.
Evidence of linkage of refractive error was found in both OOA (VC LOD=3.45, REG LOD=3.38 at ~59 cM) and ASHK families (VC LOD=3.12, REG LOD=4.263 at ~66 cM). Combined analyses showed three highly significant linkage peaks, separated by ~11cM (or 10 Mb), within the candidate region.
In a fine-mapping linkage study of OOA and ASHK families, we have confirmed linkage of refractive error to a QTL on 1p. The area of linkage has been narrowed down to a gene-rich region at 1p34.2-35.1 containing ~124 genes.
PMCID: PMC2713730  PMID: 19626131
21.  Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium 
Verhoeven, Virginie J. M. | Hysi, Pirro G. | Saw, Seang-Mei | Vitart, Veronique | Mirshahi, Alireza | Guggenheim, Jeremy A. | Cotch, Mary Frances | Yamashiro, Kenji | Baird, Paul N. | Mackey, David A. | Wojciechowski, Robert |  Ikram, M. Kamran | Hewitt, Alex W. | Duggal, Priya | Janmahasatian, Sarayut | Khor, Chiea-Chuen | Fan, Qiao | Zhou, Xin | Young, Terri L. | Tai, E-Shyong | Goh, Liang-Kee | Li, Yi-Ju | Aung, Tin | Vithana, Eranga | Teo, Yik-Ying | Tay, Wanting | Sim, Xueling | Rudan, Igor | Hayward, Caroline | Wright, Alan F. | Polasek, Ozren | Campbell, Harry | Wilson, James F. | Fleck, Brian W. | Nakata, Isao | Yoshimura, Nagahisa | Yamada, Ryo | Matsuda, Fumihiko | Ohno-Matsui, Kyoko | Nag, Abhishek | McMahon, George | Pourcain, Beate St. | Lu, Yi | Rahi, Jugnoo S. | Cumberland, Phillippa M. | Bhattacharya, Shomi | Simpson, Claire L. | Atwood, Larry D. | Li, Xiaohui | Raffel, Leslie J. | Murgia, Federico | Portas, Laura | Despriet, Dominiek D. G. | van Koolwijk, Leonieke M. E. | Wolfram, Christian | Lackner, Karl J. | Tönjes, Anke | Mägi, Reedik | Lehtimäki, Terho | Kähönen, Mika | Esko, Tõnu | Metspalu, Andres | Rantanen, Taina | Pärssinen, Olavi | Klein, Barbara E. | Meitinger, Thomas | Spector, Timothy D. | Oostra, Ben A. | Smith, Albert V. | de Jong, Paulus T. V. M. | Hofman, Albert | Amin, Najaf | Karssen, Lennart C. | Rivadeneira, Fernando | Vingerling, Johannes R. | Eiríksdóttir, Guðný | Gudnason, Vilmundur | Döring, Angela | Bettecken, Thomas | Uitterlinden, André G. | Williams, Cathy | Zeller, Tanja | Castagné, Raphaële | Oexle, Konrad | van Duijn, Cornelia M. | Iyengar, Sudha K. | Mitchell, Paul | Wang, Jie Jin | Höhn, René | Pfeiffer, Norbert | Bailey-Wilson, Joan E. | Stambolian, Dwight | Wong, Tien-Yin | Hammond, Christopher J. | Klaver, Caroline C. W.
Human Genetics  2012;131(9):1467-1480.
Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10−12 for SNP rs634990 in Caucasians, and 9.65 × 10−4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10−23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10−2 for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-012-1176-0) contains supplementary material, which is available to authorized users.
PMCID: PMC3418496  PMID: 22665138
22.  Association analysis of retinoic acid receptor beta (RARβ) gene with high myopia in Chinese subjects 
Molecular Vision  2010;16:855-861.
High myopia or pathological myopia is a common refractive error. Individuals with high myopia are subject to increased risk of serious eye complications. Accumulating evidence has demonstrated the role for heritability in ocular growth and in the development of high myopia. Retinoic acid and retinoic acid receptors play important roles in ocular development and in experimentally induced myopia. The purpose of this study was to determine if high myopia is associated with single nucleotide polymorphism (SNP) variants in the retinoic acid receptor beta (RARβ) gene in Chinese subjects.
DNA samples were purified from venous lymphocytes of 175 unrelated Chinese patients with high myopia (less than −8.00 diopters) and 101 Chinese control subjects without high myopia (±1.00 diopters). Direct nucleotide sequence analysis in the RARβ gene was performed, and the detected variations were further confirmed by reverse sequencing. Allelic frequencies of all detected SNPs were assessed for Hardy–Weinberg equilibrium.
Five variations in RARβ were detected in Chinese subjects with high myopia, including 32574G>A, 32629G>A, 32645C>T, 32647T>G, and 151973C>T, of which only 32647T>G (NCBI notes as rs58244688 and rs2067964) had already been reported. The majority of SNP genotypes were heterozygous. While 32647T>G, 32629G>A, and 32645C>T were located in introns and 32574G>A and 151973C>T were located in coding regions, none of the SNPs affected the amino acid sequence. In the present study, no evidence of association was found between variations in the nucleotide sequence of RARβ and high myopia.
Five SNP variants in RARβ were detected in Chinese subjects with high myopia, none of them were associated significantly with high myopia. Further studies are needed to identify which genes are responsible for high myopia.
PMCID: PMC2874578  PMID: 20508731
23.  Evaluation of BLID and LOC399959 as candidate genes for high myopia in the Chinese Han population 
Molecular Vision  2010;16:1920-1927.
BH3-like motif containing, cell death inducer (BLID) and LOC399959 are two genes associated with the single nucleotide polymorphism (SNP) rs577948, which is a susceptibility locus for high myopia in Japanese subjects. The purpose of this study was to determine if BLID and LOC399959 are associated with high myopia in Chinese Han subjects.
High myopia subjects (n=476) had a spherical refractive error of less than −6.00 D in at least one eye and/or an axial length greater than 26 mm. Genomic DNA was extracted and genotyped from peripheral blood leukocytes of high myopes and controls (n=275). Using a case-control association study of candidate regions, linkage disequilibrium blocks for 19 tag SNPs (tSNPs), including rs577948, harbored within and surrounding the BLID and LOC399959 genes were analyzed on a MassArray platform using iPlex chemistry. Each of the tSNPs had an r2>0.8 and minor allele frequency >10% in the Chinese Han population. Haplotype association analysis was performed on Haploview 4.1 using Chi-square (χ2) tests.
None of the 19 tSNPs were statistically associated with high myopia.
While rs577948 may be associated with high myopia in Japanese subjects, it and the other tSNPs near the BLID and LOC399959 genes are not susceptibility loci for high myopia in the Chinese Han population. Thus, associations of SNPs with high myopia as determined by Genome-Wide Association Study (GWAS) may be restricted to certain ethnic or genetically distinct populations. Without systematic replication in other populations, the results of GWAS associations should be interpreted with great caution.
PMCID: PMC2956664  PMID: 21031016
24.  Linkage analysis of high myopia susceptibility locus in 26 families 
Molecular Vision  2008;14:2566-2574.
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.
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.
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.
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.
PMCID: PMC2613077  PMID: 19122830
25.  Visual Activity before and after the Onset of Juvenile Myopia 
Before the onset of myopia, children's near work activities did not differ from those of emmetropes. Those who became myopic had fewer sports and outdoor activity hours than emmetropes had, before, at, and after myopia onset.
To investigate visual activities before and after the onset of juvenile myopia.
The subjects were 731 incident myopes (−0.75 D or more myopia on cycloplegic autorefraction in both meridians) and 587 emmetropes (between −0.25 and +1.00 D) in the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study. Parents supplied visual activity data annually. Data from myopic children 5 years before through 5 years after myopia onset were compared to data from age-, sex-, and ethnicity-matched models of children who remained emmetropic.
Hours per week spent reading or using a computer/playing video games did not differ between the groups before myopia onset; however, hours per week for both activities were significantly greater in myopes than in emmetropes at onset and in 4 of the 5 years after onset by 0.7 to 1.6 hours per week. Hours per week spent in outdoor/sports activities were significantly fewer for children who became myopic 3 years before onset through 4 years after onset by 1.1 to 1.8 hours per week. Studying and TV watching were not significantly different before myopia onset.
Before myopia onset, near work activities of future myopic children did not differ from those of emmetropes. Those who became myopic had fewer outdoor/sports activity hours than the emmetropes before, at, and after myopia onset. Myopia onset may influence children's near work behavior, but the lack of difference before onset argues against a major causative role for near work. Less outdoor/sports activity before myopia onset may exert a stronger influence on development than near work.
PMCID: PMC3101696  PMID: 20926821

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