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1.  Replication study of significant single nucleotide polymorphisms associated with myopia from two genome-wide association studies 
Molecular Vision  2011;17:3290-3299.
Two previous genome-wide association studies (GWAS) of high myopia in a Japanese population found several single nucleotide polymorphisms (SNPs) associated with the disease. The present study examined whether these markers are associated with myopia in a Chinese population.
Individuals with or without complex myopia were recruited from Chinese university students, and probands with early onset high myopia were identified in the Pediatric and Genetic Eye Clinic of the Zhongshan Ophthalmic Center. DNA was prepared from venous leukocytes. Three SNPs, rs577948 and rs11218544 at chromosome position 11q24.1 and rs2839471 at chromosome position 21q22.3, were genotyped. The allele and genotype frequencies of these SNPs were compared between the myopia cases and controls using a χ2 test.
A total of 2,870 subjects were examined in this study, including 1,255 individuals with complex myopia (−10.00 diopter (D)
We did not find evidence for the association of myopia with rs577948, rs11218544, or rs2839471 in the Chinese population studied.
PMCID: PMC3244484  PMID: 22194655
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
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
PLoS ONE  2013;8(4):e61805.
Myopia is the most common ocular disease worldwide. We investigated the association of high myopia with the common single nucleotide polymorphisms (SNPs) of five candidate genes – early growth response 1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), jun oncogene (JUN), vasoactive intestinal peptide (VIP), and vasoactive intestinal peptide receptor 2 (VIPR2). We recruited 1200 unrelated Chinese subjects with 600 cases (spherical equivalent ≤−8.00 diopters) and 600 controls (spherical equivalent within ±1.00 diopter). A discovery sample set was formed from 300 cases and 300 controls, and a replication sample set from the remaining samples. Tag SNPs were genotyped for the discovery sample set, and the most significant haplotypes and their constituent SNPs were followed up with the replication sample set. The allele and haplotype frequencies in cases and controls were compared by logistic regression adjusted for sex and age to give Pa values, and multiple comparisons were corrected by permutation test to give Paemp values. Odd ratios (OR) were calculated accordingly. In the discovery phase, EGR1, JUN and VIP did not show any significant association while FOS and VIPR2 demonstrated significant haplotype association with high myopia. In the replication phase, the haplotype association for VIPR2 was successfully replicated, but not FOS. In analysis combining both sample sets, the most significant association signals of VIPR2 were the single marker rs2071625 (Pa = 0.0008, Paemp = 0.0046 and OR = 0.75) and the 4-SNP haplotype window rs2071623-rs2071625-rs2730220-rs885863 (omnibus test, Pa = 9.10e-10 and Paemp = 0.0001) with one protective haplotype (GGGG: Paemp = 0.0002 and OR = 0.52) and one high-risk haplotype (GAGA: Paemp = 0.0027 and OR = 4.68). This 4-SNP haplotype window was the most significant in all sample sets examined. This is the first study to suggest a role of VIPR2 in the genetic susceptibility to high myopia. EGR1, JUN, FOS and VIP are unlikely to be important in predisposing humans to high myopia.
PMCID: PMC3630195  PMID: 23637909
Polymorphisms in the insulin-like growth factor 1 (IGF1) gene were previously associated with high or extreme myopia in Caucasian and Chinese populations. In the present study, we investigated whether IGF1 polymorphisms are associated with high myopia in a Japanese population.
A total of 446 Japanese patients with high myopia (≤−9.00 diopters) and 481 Japanese healthy controls (+1.50 diopters to −1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs) in IGF1 and assessed allelic and haplotypic diversity in cases and controls.
There were no statistically significant differences in the allele frequencies of IGF1 SNPs and genotypes between cases and controls (P>0.05). However, the A allele of rs5742629 and the G allele of rs12423791 were associated with a moderately increased risk of high myopia (odds ratio [OR] =1.20 and OR =1.21, respectively) with borderline statistical significance (P=0.0502, corrected P (Pc) =0.21 and P=0.064, Pc=0.29, respectively). The haplotype consisting of the A allele of rs5742629 and the G allele of rs12423791 was marginally associated with the risk of high myopia (P=0.041; OR =1.21); this association was not significant after correction (Pc=0.19).
We found that the IGF1 SNPs are not significantly associated with high myopia in our Japanese population. Our results are in contrast to a previous study in which extreme myopia cases had significantly higher frequencies of the G allele of rs5742629 and the C allele of rs12423791 than controls. Therefore, the IGF1 SNPs may not be important factors for susceptibility to high myopia in all populations. Further genetic studies are needed to elucidate the possible contributions of the IGF1 region to the development of high myopia.
PMCID: PMC3804590  PMID: 24204106
high myopia; IGF1; association study; polymorphism
Molecular Vision  2011;17:810-821.
We examined the relationship between high myopia and common polymorphisms in four candidate genes: collagen, type XI, alpha 1 (COL11A1); collagen, type XVIII, alpha 1 (COL18A1); fibrillin 1 (FBN1); and procollagen-lysine 1,2-oxoglutarate 5-dioxygenase 1 (PLOD1). These genes were selected because rare pathogenic mutations in these genes cause disease syndromes that have myopia, usually high myopia, as one of the common presenting features.
This study recruited 600 unrelated Han Chinese subjects including 300 cases with high myopia (spherical equivalent or SE≤-8.00 diopters) and 300 controls (SE within ±1.00 diopter). A total of 66 tag single nucleotide polymorphisms (SNPs) were selected for study from these four candidate genes. The study adopted a DNA pooling strategy with an initial screen of DNA pools to identify putatively positive SNPs and then confirmed the “positive” SNPs by genotyping individual samples forming the original DNA pools. DNA pools were each constructed by mixing equal amounts of DNA from 50 individuals with the same phenotype status. Six case pools were prepared from 300 cases and six control pools from 300 controls. Allele frequencies of DNA pools were estimated by analyzing the primer-extended products with denaturing high performance liquid chromatography and compared between case pools and control pools with nested ANOVA.
In the first stage, 60 SNPs from the 4 candidate genes were successfully screened using the DNA pooling approach. Of these, 6 SNPs showed a statistical significant difference in estimated allele frequencies between case pools and controls at p<0.10. In the second stage, these “positive” SNPs were followed up by individual genotyping, but failed to be confirmed via standard single-marker and haplotype analyses.
Common polymorphisms in these four candidate genes (COL11A1, COL18A1, FBN1 and PLOD1) were unlikely to play important roles in the genetic susceptibility to high myopia.
PMCID: PMC3081793  PMID: 21527992
PLoS ONE  2011;6(5):e19587.
The paired box 6 (PAX6) gene is considered as a master gene for eye development. Linkage of myopia to the PAX6 region on chromosome 11p13 was shown in several studies, but the results for association between myopia and PAX6 were inconsistent so far.
Methodology/Principal Findings
We genotyped 16 single nucleotide polymorphisms (SNPs) in the PAX6 gene and its regulatory regions in an initial study for 300 high myopia cases and 300 controls (Group 1), and successfully replicated the positive results with another independent group of 299 high myopia cases and 299 controls (Group 2). Five SNPs were genotyped in the replication study. The spherical equivalent of subjects with high myopia was ≤−8.0 dioptres. The PLINK package was used for genetic data analysis. No association was found between each of the SNPs and high myopia. However, exhaustive sliding-window haplotype analysis highlighted an important role for rs12421026 because haplotypes containing this SNP were found to be associated with high myopia. The most significant results were given by the 4-SNP haplotype window consisting of rs2071754, rs3026393, rs1506 and rs12421026 (P = 3.54×10−10, 4.06×10−11 and 1.56×10−18 for Group 1, Group 2 and Combined Group, respectively) and the 3-SNP haplotype window composed of rs3026393, rs1506 and rs12421026 (P = 5.48×10−10, 7.93×10−12 and 6.28×10−23 for the three respective groups). The results remained significant after correction for multiple comparisons by permutations. The associated haplotyes found in a previous study were also successfully replicated in this study.
PAX6 haplotypes are associated with susceptibility to the development of high myopia in Chinese. The PAX6 locus plays a role in high myopia.
PMCID: PMC3093386  PMID: 21589860
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
Molecular Vision  2013;19:2321-2329.
The fibroblast growth factor 10 (FGF10) gene polymorphism rs339501 was previously reported to be associated with high myopia in a Chinese population. In the present study, we investigated whether FGF10 polymorphisms are associated with extreme myopia in a Japanese population as well.
A total of 433 Japanese patients with extreme myopia (≤ −10.00 diopters) and 542 Japanese healthy controls (+1.50 to −1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs), including rs339501, in FGF10. We also performed an imputation analysis to evaluate the potential association of ungenotyped FGF10 SNPs, and 34 SNPs were imputed.
It was found that rs339501 and rs12517396 exhibited the strongest association with extreme myopia (p=3.9 × 10−4, corrected p [Pc]=0.0030). A significant association was also observed for rs10462070 (p=6.5 × 10−4, Pc=0.0059). These three SNPs were in strong linkage disequilibrium (D’ ≥0.99, r2 ≥0.96). However, the frequency of the A allele of rs339501 was increased in cases compared to controls, which differs from the increased frequency of the G allele in cases in the previous Chinese population.
Three FGF10 SNPs in complete linkage disequilibrium—rs339501, rs12517396, and rs10462070—were associated with extreme myopia in the Japanese population, and the risk allele of rs339501 differed from the previous Chinese population. Therefore, these three SNPs may not be an important risk factor for susceptibility to extreme myopia. Further studies are needed to elucidate the possible contribution of the FGF10 region in the development of extreme myopia.
PMCID: PMC3834595  PMID: 24265547
Journal of Ophthalmology  2015;2015:729463.
High myopia is one of the leading causes of blindness worldwide. However, the exact etiology of high myopia remains unraveled despite numerous attempts of elucidation. Previous genome-wide association study (GWAS) has revealed that four single nucleotide polymorphisms (SNPs), including rs2969180, rs1652333, rs9307551, and rs7837791, were associated with high myopia in Caucasians. The present study was conducted to investigate whether these genetic variants were associated with high myopia in Han Chinese. These four SNPs were genotyped by SNaPshot method in a Han Chinese cohort composed of 827 patients with high myopia and 988 healthy controls. Among the SNPs genotyped, only rs9307551 was found to be significantly associated with high myopia in this study. Carriers of rs9307551A allele, AA, and AC genotypes had an increased risk of high myopia (OR = 1.33, 95% CI 1.14–1.54; OR = 1.75, 95% CI 1.28–2.38; OR = 1.59, 95% CI 1.24–2.01, resp.). Interestingly, when split by gender, the association between rs9307551 and high myopia proved to be gender-specific with significance observed only in females but not males. These findings suggested that the SNP of rs9307551 showed a gender-specific association with high myopia in the Han Chinese population. In addition, LOC100506035, a lincRNA gene, might play a crucial role in the susceptibility to high myopia.
PMCID: PMC4300030  PMID: 25628894
Molecular Vision  2013;19:1074-1081.
To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese.
A total of 1,339 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (334 cataract patients without high myopia and 1,194 healthy Japanese individuals). The mean axial length (mm±SD) in the case group was 29.18±1.85 mm, and the mean spherical equivalent (D±SD) of the phakic eyes was −12.69±4.54 D. We genotyped five tagging single nucleotide polymorphisms (SNPs) in IGF-1: rs6214, rs978458, rs5742632, rs12423791, and rs2162679. Chi-square tests for trend, multivariable logistic regression, and haplotype regression analysis were conducted.
We found no significant association between the IGF-1 SNPs and high or extreme myopia (axial length ≥28 mm in both eyes, 837 subjects) in the additive model, even when compared with the cataract and general population controls, with or without adjustments for age and sex. The evaluation using dominant and recessive models also did not reveal any significant associations. The haplotype analysis with a variable-sized sliding-window strategy also showed a lack of association of IGF-1 SNPs with high or extreme myopia.
The results of the present study using a Japanese subset do not support the proposal that the IGF-1 gene determines susceptibility to high or extreme myopia in Caucasians and Chinese. Further studies are needed to confirm our reports in other populations and to identify the underlying genetic determinants of these ocular pathological conditions.
PMCID: PMC3668686  PMID: 23734076
PLoS Genetics  2011;7(6):e1002084.
Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.
Author Summary
People with myopia see near objects more clearly than objects far away. Myopia is the most common ocular disorder worldwide, with a high prevalence in Asian (40%–70%) and Caucasian (20%–30%) populations. Although the etiologies of myopia have not yet been established, previous studies have indicated the involvement of genetic and environmental factors (such as close working habits, higher education levels, and higher socioeconomic class). Genetic factors play a critical role in the development of myopia, especially high myopia. In this study, we use exome sequencing, a powerful tool for a disease gene identification, to identify a gene involved in high myopia in a monogenic form among Han Chinese. Mutations in zinc finger protein 644 isoform 1 (ZNF644) were identified as potentially responsible for the phenotype of high myopia. The main feature of high myopia is axial elongation of the eye globe. Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, a mutant ZNF644 protein may impact the normal eye development and therefore may underlie the axial elongation of the eye globe in high myopia patients. Further study of the biological function of ZNF644 will provide insight into the pathogenesis of myopia.
PMCID: PMC3111487  PMID: 21695231
Molecular Vision  2011;17:3379-3383.
Single nucleotide polymorphisms (SNPs) in the collagen type I (COL1A1) gene have been shown to be significantly associated with high myopia in a Japanese population. This present study was conducted to investigate whether COL1A1 is associated with high myopia in a Han Chinese population.
High myopia is defined by a spherical equivalent of less than or equal to −6.00 diopter sphere and an axial length longer than or equal to 26.0 mm in the affected eye. We genotyped rs2075555 and rs2269336 SNPs in COL1A1 in a Ha n Chinese group composed of 697 high myopia patients and 762 normal controls.
Neither of the two SNPs showed significant association with high myopia (pallelic=0.252 for rs2075555, and pallelic=0.699 for rs2269336).
Our study revealed that SNPs in COL1A1 are not significantly associated with high myopia in the Han Chinese population.
PMCID: PMC3247168  PMID: 22219633
Molecular Vision  2009;15:213-222.
Three previous studies have tested for an association between high myopia and polymorphisms in the open angle glaucoma gene, myocilin (MYOC), all in subjects of Chinese ethnicity. In two of the studies, a significant association was found while in the third, there was no association. We sought to investigate the association between high myopia and polymorphisms in MYOC in subjects of European ethnicity.
Subjects were recruited from two sites, Cardiff University in the UK and Duke University in the United States. The Cardiff University cohort was comprised of 164 families with high myopia (604 subjects) plus 112 unrelated, highly myopic cases and 114 emmetropic controls. The Duke University cohort was comprised of 87 families with high myopia (362 subjects) plus 59 unrelated, highly myopic cases. Subject DNA was genotyped with a panel of MYOC single nucleotide polymorphisms (SNPs) including those found previously associated with high myopia. The Cardiff cohort was also genotyped for two flanking microsatellite markers analyzed in prior studies. Association between high myopia and MYOC polymorphisms was assessed using the Unphased program.
Since there was no evidence of heterogeneity in genotype frequencies between families and singleton samples or between cohorts, both subject groups (families and unrelated subjects) from both recruitment sites were analyzed jointly for those SNPs genotyped in common. Two variants showed significant association before correction for multiple testing. These two variants were rs16864720 (p=0.043) and NGA17 (p=0.026). However, there was no significant association after Bonferroni correction. The estimated relative risk (RR) conferred by each of the MYOC variants was low (RR<1.5).
Our results suggest that MYOC polymorphisms have a very low, or possibly negligible, influence on high myopia susceptibility in subjects of European ethnicity.
PMCID: PMC2632735  PMID: 19180258
PLoS Genetics  2012;8(6):e1002753.
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.
Author Summary
Myopic individuals exhibit an increase in ocular axial length (AL). As a highly heritable ocular biometry of refractive error, identification of quantitative trait loci influencing AL variation would be valuable in informing the biological etiology of myopia. We have determined that a genetic locus on chromosome 1q41 containing zinc-finger pseudogene ZC3H11B is associated with AL and high myopia through a meta-analysis of three genome-wide association scans on AL in Chinese and Malays, with validation for high myopia association in two additional Japanese cohorts. In addition, variations in the expression of murine gene ZC3H11A and two neighboring genes SLC30A10 and LYPLAL1 in the retina and sclera in a myopic mouse model implicate the role of these genes in myopia onset. To our knowledge, this is the first genome-wide survey of single nucleotide polymorphism (SNP) variation of AL in Asians. Our results suggest that genetic variants at chromosome 1q41 have potential roles in both common and high myopia.
PMCID: PMC3369958  PMID: 22685421
PLoS Genetics  2009;5(9):e1000660.
Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10−4 in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22×10−7 and OR of 1.37 with 95% confidence interval: 1.21–1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT–PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese.
Author Summary
Myopia is one of the most common ocular disorders with elongation of axis of the eyeball. Pathological myopia or high myopia, a subset of myopia which is characterized with excessive axial elongation and degenerative changes of the eye, is a leading cause of visual impairment. Since genetic factors play significant roles in its development, identification of genetic determinants is an urgent and important issue. Although family-based linkage analyses have isolated at least 16 susceptible chromosomal loci for pathological or common myopia, no gene responsible for the disease has been identified. We conducted the first genome-wide case/control association study of pathological myopia in a two-stage design using 411,777 markers with 830 Japanese patients and 1,911 Japanese controls. We identified a region strongly suggestive for the disease susceptibility at chromosome 11q24.1 containing BLID and LOC399959. Their expression was confirmed in human retina with RT–PCR. BLID encodes an inducer of apoptotic cell death, and apoptosis is known to play an important functional role in pathological myopia. We believe that our study contributes to further dissect the molecular events underlying the development and progression of pathological myopia.
PMCID: PMC2735651  PMID: 19779542
PLoS Genetics  2008;4(10):e1000220.
Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505–180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533–182,688 kb) and PSARL (184,386 kb; 95% CI 184,356–184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10−7, p<10−10, and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia.
Author Summary
Successful gene mapping strategies for common disease continue to require careful consideration of basic study design with the advent of genome-wide association studies. Here, we take advantage of prior information that the heritability of the quantitative trait myopia in the general population is high and shows evidence of replicated linkage to chromosome 3q26. Based on this, we conducted a fine map linkage disequilibrium association study for the region, using a high-resolution genetic map derived from population-based HapMap Phase II data. For analysis, we used efficient multi-locus tests of association using single nucleotide polymorphism markers genotyped for our sample data and placed on the genetic map measured in linkage disequilibrium units. We followed up preliminary evidence of association for the discovery samples with further genotyping in the same samples to improve the model location estimates for the common functional variants we identified. Three locations were replicated using an independent sample. Two of the identified genes are likely to play an unexpected role in myopia with both pivotal in the healthy housekeeping metabolism of retinal mitochondria. Both proteins interact with OPA1, with nonsynonymous OPA1 mutations causing the unrelated Mendelian disease Autosomal Dominant Optic Atrophy (ADOA) by triggering mitochondrial-led retinal ganglia cell apoptosis.
PMCID: PMC2556391  PMID: 18846214
PLoS ONE  2012;7(6):e40238.
Myopia is the most common ocular disorder worldwide and imposes tremendous burden on the society. It is a complex disease. The MYP6 locus at 22 q12 is of particular interest because many studies have detected linkage signals at this interval. The MYP6 locus is likely to contain susceptibility gene(s) for myopia, but none has yet been identified.
Methodology/Principal Findings
Two independent subject groups of southern Chinese in Hong Kong participated in the study an initial study using a discovery sample set of 342 cases and 342 controls, and a follow-up study using a replication sample set of 316 cases and 313 controls. Cases with high myopia were defined by spherical equivalent ≤ -8 dioptres and emmetropic controls by spherical equivalent within ±1.00 dioptre for both eyes. Manual candidate gene selection from the MYP6 locus was supported by objective in silico prioritization. DNA samples of discovery sample set were genotyped for 178 tagging single nucleotide polymorphisms (SNPs) from 26 genes. For replication, 25 SNPs (tagging or located at predicted transcription factor or microRNA binding sites) from 4 genes were subsequently examined using the replication sample set. Fisher P value was calculated for all SNPs and overall association results were summarized by meta-analysis. Based on initial and replication studies, rs2009066 located in the crystallin beta A4 (CRYBA4) gene was identified to be the most significantly associated with high myopia (initial study: P = 0.02; replication study: P = 1.88e-4; meta-analysis: P = 1.54e-5) among all the SNPs tested. The association result survived correction for multiple comparisons. Under the allelic genetic model for the combined sample set, the odds ratio of the minor allele G was 1.41 (95% confidence intervals, 1.21-1.64).
A novel susceptibility gene (CRYBA4) was discovered for high myopia. Our study also signified the potential importance of appropriate gene prioritization in candidate selection.
PMCID: PMC3389832  PMID: 22792142
Ophthalmology  2010;118(2):368-375.
To determine susceptibility genes for high myopia in Singaporean Chinese.
A meta-analysis of two genome wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese.
Participants and Controls
Two independent datasets of Singaporean Chinese individuals aged 10–12 years (SCORM -- Singapore Cohort Study of the Risk factors for Myopia: cases=65, controls=238) and aged > 21 years (SP2 -- Singapore Prospective Study Program: cases=222, controls=435) for GWA studies, and a Japanese dataset aged >20 years (cases=959, controls=2128) for replication.
Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (> HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in Japanese dataset. Fisher’s P was calculated for the combined analysis of all three cohorts.
Main outcome measures
High myopia, defined by spherical equivalent (SE) ≤ −6.00 diopters (D); controls defined by SE between −0.50D and +1.00D.
Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta- P = 1.14×10−5 and meta- P = 1.51×10−5, respectively) with strong supporting evidence in each individual dataset analysis (Max P = 1.85.x10−4 in SCORM: Max P = 8.8×10−3 in SP2). Evidence of replication was observed in Japanese dataset for rs6885224 (P = 0.035, meta-P of three datasets: 7.84×10−6).
This study identified strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.
PMCID: PMC3052933  PMID: 21095009
myopia; genome wide association; CTNND2; single nucleotide polymorphism; genetics
Retinoic acid level in the retina/choroid is altered in induced myopia models. All-trans-retinol dehydrogenase (RDH8) is an important enzyme of retinoic acid metabolism. This study aimed to investigate the association of the RDH8 gene with high myopia. Three single nucleotide polymorphisms (SNPs) [RDH851 (rs2233789), RDH8E5a (rs1644731), and RDH855b (rs3760753)] were selected, based on the linkage disequilibrium pattern of RDH8 from a previous study, and genotyped for 160 Han Chinese nuclear families with highly myopic (−10 diopters or worse) offspring as well as in an independent group with 166 highly myopic cases (−10 diopters or worse) and 211 controls. Family-based association analysis was performed using the family-based association test (FBAT) package, and genotype relative risk (GRR) was calculated using the GenAssoc program. Population-based association analysis was performed using Chi-square test. These SNPs were in linkage equilibrium with each other. SNPs RDH851 (rs2233789) and RDH8E5a (rs1644731) both did not show association with high myopia. SNP RDH855b (rs3760753) demonstrated significant association (P=0.0269) with a GRR of 0.543 (95% confidence interval=0.304–0.968, P=0.038). The association became statistically insignificant, however, after multiple comparison correction. Haplotype analysis did not show a significant association either. Population-based association analysis also showed no significant association (P>0.05). Our family- and population-based data both suggest that the RDH8 gene is unlikely to be associated with high myopia in Chinese.
PMCID: PMC2970892  PMID: 21043051
Myopia; All-trans-retinol dehydrogenase (RDH8); Single nucleotide polymorphisms; Association study; Linkage disequilibrium; Genotype relative risk
Molecular Vision  2007;13:534-544.
To test the association between myocilin gene (MYOC) polymorphisms and high myopia in Hong Kong Chinese by using family-based association study.
A total of 162 Chinese nuclear families, consisting of 557 members, were recruited from an optometry clinic. Each family had two parents and at least one offspring with high myopia (defined as -6.00D or less for both eyes). All offspring were healthy with no clinical evidence of syndromic disease and other ocular abnormality. Genotyping was performed for two MYOC microsatellites (NGA17 and NGA19) and five tag single nucleotide polymorphisms (SNPs) spreading across the gene. The genotype data were analyzed with Family-Based Association Test (FBAT) software to check linkage and association between the genetic markers and myopia, and with GenAssoc to generate case and pseudocontrol subjects for investigating main effects of genetic markers and calculating the genotype relative risks (GRR).
FBAT analysis showed linkage and association with high myopia for two microsatellites and two SNPs under one to three genetic models after correction for multiple comparisons by false discovery rate. NGA17 at the promoter was significant under an additive model (p=0.0084), while NGA19 at the 3' flanking region showed significant results under both additive (p=0.0172) and dominant (p=0.0053) models. SNP rs2421853 (C>T) exhibited both linkage and association under additive (p=0.0009) and dominant/recessive (p=0.0041) models. SNP rs235858 (T>C) was also significant under additive (p=4.0E-6) and dominant/recessive (p=2.5E-5) models. Both SNPs were downstream of NGA19 at the 3' flanking region. Positive results for these SNPs were novel findings. A stepwise conditional logistic regression analysis of the case-pseudocontrol dataset generated by GenAssoc from the families showed that both SNPs could separately account for the association of NGA17 or NGA19, and that both SNPs contributed separate main effects to high myopia. For rs2421853 and with C/C as the reference genotype, the GRR increased from 1.678 for G/A to 2.738 for A/A (p=9.0E-4, global Wald test). For rs235858 and with G/G as the reference, the GRR increased 2.083 for G/A to 3.931 for A/A (p=2.0E-2, global Wald test). GRR estimates thus suggested an additive model for both SNPs, which was consistent with the finding that, of the three models tested, the additive model gave the lowest p values in FBAT analysis.
Linkage and association was shown between the MYOC polymorphisms and high myopia in our family-based association study. The SNP rs235858 at the 3' flanking region showed the highest degree of confidence for association.
PMCID: PMC2652017  PMID: 17438518
Oman Journal of Ophthalmology  2011;4(2):57-62.
High myopia caused primarily due to abnormal emmetropization and excessive axial ocular elongation is associated with sight-threatening ocular pathology. Muscular dysfunction of ocular ciliary muscles due to altered intracellular calcium levels can result in defective mechanotransduction of the eye and retinal defocus. The vitamin D3 receptor (VDR; a intracellular hormone receptor) is known to mediate calcium homeostasis, influencing the development of myopia.
Materials and Methods:
In the present study, a total of 206 high myopia, 98 low myopia and 250 control samples were analyzed for VDR gene Fok1 (exon 2 start codon) polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.
High myopia patients revealed decrease in the frequency of ff homozygotes (8.3%) as compared to control group (14.0%), with a corresponding increase in frequency of FF homozygotes (68.9% in high myopia vs. 62.8% in controls). The frequency of f allele carriers (Ff and ff) was increased in females of high myopia (35.6%) and low myopia cases (45.4%). Elevated frequency of f allele was found only in early age at onset cases of high myopia (0.227) and later age at onset (10–20 years) cases of low myopia (0.273) as well as in low myopia cases with parental consanguinity (0.458) (P 0.035; χ2 = 6.692*).
The results suggest that VDR gene might not be playing a direct role in the development of myopia, but might contribute indirectly to the risk conferred by mechanical stress factors or growth/development related factors through its role in calcium homeostasis and regulation of ciliary muscle function.
PMCID: PMC3160070  PMID: 21897619
Axial elongation; calcium homeostasis; high myopia; myopia development; polymorphism; VDR gene; vitreo-retinal degeneration
BMC Genetics  2014;15:51.
Refractive errors and high myopia are the most common ocular disorders, and both of them are leading causes of blindness in the world. Recently, genetic association studies in European and Japanese population identified that common genetic variations located in 15q14 and 15q25 were associated with high myopia. To validate whether the same variations conferred risk to high myopia in the Han Chinese population, we genotyped 1,461 individuals (940 controls and 521 cases samples) recruited of Han Chinese origin.
We found rs8027411 in 15q25 (P = 0.012 after correction, OR = 0.78) was significantly associated with high myopia but rs634990 in 15q14 (P = 0.54 after correction), OR = 0.88) was not.
Our findings supported that 15q25 is a susceptibility locus for high myopia, and gene RASGRF1 was possible to play a role in the pathology of high myopia.
PMCID: PMC4014749  PMID: 24767175
RASGRF1 gene; High myopia; Refractive errors; Single nucleotide polymorphism; Correlation Analysis
Molecular Vision  2011;17:486-491.
The adenosine A2A receptor (A2AR) modulates collagen synthesis and extracellular matrix production in ocular tissues that contribute to eye growth and the development of myopia. We aimed to determine if single nucleotide polymorphisms (SNPs) in A2AR exons associates with high myopia found in Chinese subjects.
DNA samples were prepared from venous lymphocytes of 175 Chinese subjects with high myopia of less than –8.00 diopters (D) correction and 101 ethnically similar controls with between –1.00 D and +1.00 D correction. The coding region sequences of A2AR were amplified by PCR and analyzed by Sanger sequencing. The detected variations were confirmed by reverse sequencing. Allelic frequencies of all detected common SNPs were assessed for Hardy–Weinberg equilibrium.
Five variations in A2AR exons, 5675 A>G, 5765 C>T, 13325 G>A, 13448 C>T, and 14000 T>A, were detected in controls at a low frequency (<1%). However, one SNP, 13772 T>C (rs5751876), showed its polymorphism in 53.3% of the total study population. The rs5751876 is a synonymous substitution located in a tyrosine codon of exon 2. Despite no significant difference in genotype distribution between cases and controls, the frequency of heterozygotes with the rs5751876 genotype was significantly lower in subjects with high myopia.
The reduced frequency of the heterozygote rs5751876 genotype in subjects suggests a possible association of A2AR with high myopia in a Chinese population.
PMCID: PMC3380451  PMID: 22740769
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

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