September 2008
Volume 49, Issue 9
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Biochemistry and Molecular Biology  |   September 2008
A Genome-wide Scan Maps a Novel High Myopia Locus to 5p15
Author Affiliations
  • Ching Yan Lam
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Pancy O. S. Tam
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Dorothy S. P. Fan
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Bao Jian Fan
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Dan Yi Wang
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Coral W. S. Lee
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Chi Pui Pang
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
  • Dennis S. C. Lam
    From the Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
Investigative Ophthalmology & Visual Science September 2008, Vol.49, 3768-3778. doi:10.1167/iovs.07-1126
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      Ching Yan Lam, Pancy O. S. Tam, Dorothy S. P. Fan, Bao Jian Fan, Dan Yi Wang, Coral W. S. Lee, Chi Pui Pang, Dennis S. C. Lam; A Genome-wide Scan Maps a Novel High Myopia Locus to 5p15. Invest. Ophthalmol. Vis. Sci. 2008;49(9):3768-3778. doi: 10.1167/iovs.07-1126.

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      © 2016 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. This study was conducted to investigate the genetic component of three Chinese pedigrees originating from Hong Kong with autosomal dominant high myopia.

methods. A whole-genome scan was performed by using microsatellite markers spanning the whole genome with an average spacing of 10 cM. Regions containing markers that yielded LOD scores >1.0 were further analyzed by fine mapping with additional microsatellite markers. Fine-scale mapping of the linkage region was performed by genotyping a set of gene-based SNP markers on a cohort of 94 high myopia cases and 94 control subjects.

results. Two-point LOD scores >1 were observed at markers D5S630, D5S416, D7S510, D11S908, and D17S944. Additional microsatellite markers flanking D5S630 revealed a maximum two-point LOD score of 4.81 at D5S2505 at θ = 0.00. Haplotype analysis narrowed the linkage region to 5p15.33-p15.2 with a 17.45-cM interval. The coding sequences of five genes located within this region, IRX2, IRX1, POLS, CCT5, and CTNND2, were screened. No segregation of polymorphism with high myopia was found. Genotyping of 41 SNPs within this region in a Chinese cohort of 94 high myopia cases and 94 control subjects showed that the allele and genotype distributions of one SNP, rs370010, was different between cases and controls (genotype P = 0.01176, allele P = 0.00271 and trend P = 0.00375), but such association did not remain significant after false discovery rate (FDR) correction. This SNP is located within a hypothetical gene LOC442129.

conclusions. A novel autosomal dominant high myopia locus was mapped on chromosome 5p15.33-p15.2 with an interval of 17.45 cM.

Refractive errors are the most common ocular disorders worldwide. The prevalence of myopia is much higher in Asians than in Caucasians. In a cross-sectional study conducted in the United States, greater myopia prevalence was observed in Asians (19.8%) than in African Americans, Hispanics, and whites (5.2%–14.5%). 1 Chinese school children in Hong Kong aged 11 to 16 have a prevalence of myopia as high as 36.71%. 2 High myopia, defined as refractive error equal to or below −6.00 D, is also more prevalent in Chinese than Caucasians. 2 3 Individuals with high myopia have a greater chance of developing serious complications including glaucoma, retinal detachment, and choroidal neovascularization, which, if not treated early and appropriately, may lead to the serious consequences of permanent visual impairment or even blindness. 4 5 6  
A common pathologic structural abnormality in high myopia is the excessive lengthening of the posterior segment of the ocular globe. Myopic eyes are usually related to the anterior-posterior enlargement and increase in the chamber depth and therefore to the elongation of the axial length. In humans, the axial length and optical powers are in a constant process of adjustment before adulthood. Because of such a prolonged developmental period, the eye remains vulnerable to the development of myopia during the teenage years. 7 Axial elongation is a complex process involving many biological factors and pathways. Genes affecting transcription factor or other regulatory activities, plus genes modifying the activities of other genes, may play a role in such a process and lead to the complicated outcome of high myopia. 
Epidemiologic studies have suggested roles of environmental factors in myopia, including near work, living environment, and education levels. 8 9 Exposure of infants to night lights has been shown in one report to be a crucial factor, 10 but this notion has not been substantiated in subsequent studies. 11 12 However, there is strong evidence to support an important role of genetic factors in the development of myopia. Studies in dizygotic and monozygotic twins revealed a high heritability of refractive errors. 13 14 In a family study, the prevalence of myopia was found to be 45% when both parents were myopic, compared with 7.3% when neither parent had myopia and 26.2% when one parent did. 15 X-linked recessive inheritance myopia has been mapped on Xq28 and Xq23. 16 17 Other loci are all mapped for autosomal dominant inheritance. Linkage studies of different populations have identified 14 chromosomal loci that are designated as MYP2 to MYP15. 18 19 20 21 22 23 24 25 26 27 28 29  
To comprehend the genetic basis of high myopia, particularly in the Chinese population where it is highly prevalent, we performed a genome-wide scan and linkage analysis in three Hong Kong Chinese families. 
Methods
Study Subjects
All study subjects were recruited at the Hong Kong Eye Hospital and were given complete ophthalmoscopic examinations. Three Chinese families with autosomal dominant high myopia participated in linkage analysis. No participants had known diseases that predispose to myopia, such as Stickler or Marfan syndrome. Subjects meeting the criteria of refractive error equal to or greater than −6.00 D and axial length longer than 26 mm were classified as high myopes. For the association analysis, the patient group consisted of 94 unrelated Chinese subjects with high myopia, using the same classification criteria as the family subjects. The control group consisted of 94 unrelated subjects who attended the hospital for ophthalmic examination for reasons other than high myopia. They had no myopia with refractive errors greater than −1.00 D and axial length shorter than 24 mm. They and their family members did not have eye diseases except slight floaters. The study protocol was approved by the Ethics Committee for Human Research, the Chinese University of Hong Kong, and was in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained from the study subjects after explanation of the nature and possible consequences of the study. 
Microsatellite Genotyping
Peripheral venous blood was collected and DNA extracted (QIAamp DNA kit; Qiagen, Valencia, CA) according to the manufacturer’s instructions. A genome-wide scan was performed on pedigree 1 by genotyping 382 microsatellite markers spanning the entire genome with 10-cM interval resolution (ABI PRISM Linkage Mapping Set-MD; Applied Biosystems, Foster City, CA). For fine mapping, another two Chinese families with high myopia were also screened. Additional microsatellite markers spanning the 5p region were selected from the genetic map of Marshfield Center for Medical Genetics (Marshfield, WI). Markers were selected based on their positions flanking the specific markers and with heterozygosity ≥ 0.65. 
Family Linkage Analysis
Mendelian errors were checked with PedCheck software. 30 Mega2 31 was used to generate the necessary files required for analysis. Linkage analysis was performed with the LINKAGE package FASTLINK. 32 Parametric analysis was performed in an autosomal dominant mode of inheritance with a disease gene frequency of 0.0133, and the penetrance value was set to 0, 1, and 1. Recombination frequencies were assumed to be equal between males and females, and the marker allele frequencies were estimated based on the family data. The haplotype was constructed with SimWalk 2. 33  
Positional Candidate Gene Screening
The coding regions of the selected candidate genes within the linkage region were screened for all family members in the three pedigrees by PCR and direct sequencing. Oligonucleotide primer pairs were designed to amplify the exonic sequences with 50- to 100-bp extensions beyond the intron-exon boundary. 
Association Analysis Using SNP Markers
SNP markers were selected within the linkage region of 5p15 from the HapMap database and with the minor allele frequency ≥ 0.3 in the Han Chinese population in a gene-by-gene basis from the HapMap database. 34 The SNPs were genotyped (TaqMan technology; Applied Biosystems). A commercial software program (SAS/Genetics; SAS Institute, Cary, NC) was used to test for concordance with Hardy-Weinberg equilibrium (HWE). Comparisons of allele and genotype frequencies between cases and controls were performed with a χ2 test. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for the effects of high-risk allele and also for both the dominant and recessive forms of the genotypes. Multiple testing correction was performed by using the false discovery rate (FDR). Haploview version 3.2 was used to calculate D′ and r 2 between SNP pairs and to identify linkage disequilibrium (LD) blocks. 33 A commercial program was also used to test the association between haplotype and myopia (SAS/Genetics). 
Results
Three Chinese families with an autosomal dominant mode of inheritance were studied (Table 1) . The average refractive errors for the affected individuals in pedigree 1 were −16.86 ± 6.11 D (right eyes) and −13.71 ± 6.25 D (left eyes). The average axial length was 30.47 ± 3.00 mm (right eyes) and 29.41 ± 2.72 mm (left eyes). For pedigree 2, the corresponding average refractive errors were −8.17 ± 2.62 and −7.13 ± 1.13 D, and the corresponding average axial lengths were 28.07 ± 1.08 and 27.53 ± 0.64 mm. Corresponding average refractive errors for pedigree 3 were −11.59 ± 3.31 and −10.38 ± 2.99 D, and corresponding average axial length 29.13 ± 1.94 and 28.84 ± 1.58 mm. There was no obvious difference of the clinical features among the three pedigrees, except that pedigree 1 had the most severe myopia in terms of refractive errors and axial lengths. 
In pedigree 2, individual III:5 was not highly myopic when she first attended our clinic at 9 years of age, with refractive errors of −3.00 D for both eyes. She is now 12 years of age. Her myopic symptom became more severe with an increase of refractive error from −3.00 D to −4.75 and −4.25 D and also with axial lengths greater than 26 mm in both eyes. Her status was set to both unknown and affected in the linkage calculations. 
In the initial whole-genome scan, two point LOD scores > 1.0 were observed at markers D5S630, D5S416, D7S510, D11S908, and D17S944 in pedigree 1 alone. Among them, D5S630 yielded the highest two-point LOD score of 2.11 (P = 0.0139). The log-transformed nonparametric linkage (NPL) P-values were plotted against the whole genome (Fig. 1) . Only markers D5S630 and D7S510 gave P < 0.05. Therefore, depending on both the two-point LOD scores and NPL P-values obtained, the region on chromosome 5 was further investigated. To determine the significance of this linkage, 15 additional markers flanking around 10 cM telomeric and centrometric of D5S630 were selected for further fine mapping. Combining the three pedigrees, results of the fine mapping gave a two-point LOD score of 4.81 (P = 0.0008) at θ = 0.00 for marker D5S2505 (Table 2) . When the two-point LOD scores observed at marker D5S630 in pedigree 1 were combined with those in pedigrees 2 and 3, the two-point LOD score improved from 2.11 to 4.72 (P = 0.0001). The location scores from marker D5S1981 through D5S1954 also support the evidence of linkage in this region (Fig. 2) . Haplotype analysis revealed segregation of the disease-associated allele with the myopia phenotype in all the three pedigrees (Figs. 3 4 5) . Two recombinations were observed in two affected individuals, II:2 and II:9, in pedigree 1 (Fig. ). Therefore, haplotype analysis narrowed the linkage region to 5p15.33-p15.2 with a 17.45-cM interval. The empiric probability obtained by simulating an unlinked marker was <0.0001. There was no evidence of heterogeneity in the three pedigrees from the analysis according to the program HOMOG. 
Within the narrowed linkage region, 25 known genes can be found in the Ensembl database (Fig. 6)(developed by a consortium and available in the public domain at http://www.ensembl.org 35 ). Among them, five genes, IRX2, IRX1, POLS, CCT5, and CTNND2, were selected for whole gene sequence analysis on the basis of their functions: All possess transcriptional, DNA, ATP binding, and protein binding activities (Table 3) , which we attributed to be most likely associated with sclera elongation in myopia. We identified 42 polymorphisms in these genes (Table 4) . Among them, 41 were SNPs and one was an insertion of five nucleotides (ATTCT) in the untranslated region in exon 11 of CCT5. But all of these polymorphisms were observed in both affected and unaffected members within the pedigrees, and no polymorphisms segregated with myopia. 
In the association analysis, the high myopia patients (n = 94) had a mean age of 39.5 ± 13.7 years and average refractive error of −14.14 ± 5.02 D. The controls (n = 94, mean age 67.7 ± 9.60 years) were older than the cases, and it is highly unlikely that some of them will develop high myopia in the future. A total of 41 SNPs spanning the region 5p15.33-p15.2 were selected in a gene-by-gene basis from the HapMap database (Table 5) . This set of SNPs covers a genomic region of approximately 8-Mb (position 2,800,127 to 10,754,251 bp on chromosome 5) with an average distance of 194 kb between the individual SNPs (Fig. 7) . Distributions of the genotype frequencies of the SNPs were all in HWE (P > 0.05) except for three markers, rs11865, rs828332, and rs828337, which were excluded from further analysis. Significant differences of the allele and genotype frequencies were found in one SNP, rs370010, between the myopes and control subjects (genotype P = 0.01176, allele P = 0.00271 and trend P = 0.00375), but the results did not remain significant after multiple testing correction by FDR (FDR-adjusted genotype P = 0.4586, FDR-adjusted allele P = 0.0556, and FDR-adjusted trend P = 0.0556). The OR for the risk allele G of rs370010 is 1.87 (95% CI 1.24–2.82) and 3.41 (95% CI 1.49–7.81) for the dominant mode and 2.68 (95% CI 1.31–5.47) for the recessive mode. This SNP corresponds to the hypothetical gene LOC442129. Two adjacent SNPs were also selected within the hypothetical gene, but no association was found in these SNPs. Test of pair-wise LD between these three SNPs, rs370010, rs4866692, and rs2934555, showed that they were independent of each other—in other words, they were not in LD (Fig. 8) . Association test between the haplotype of these three SNPs and the trait showed no association between them (Table 6)
Discussion
To date, 13 putative autosomal loci have been mapped for myopia, but no causative gene has been identified. Within the putative linkage region of 5p15.33-p15.2 identified in this study, there are 25 known genes in the Ensembl database, 35 5 of them possess transcriptional, ATP-binding, and protein-binding activities. Because of their functions, we thought they had a higher likelihood than other genes in this region to affect scleral growth. Orthologues of IRX genes in Drosophila are essential for eye development and misexpression of these genes lead to loss of eyes. 36 37 IRX1 is expressed in the developing eyes of mouse. 38 POLS encodes proteins that catalyze nucleotidyltransferase reactions including DNA synthesis. 39 Cells deficient in POLS are prone to DNA damage. 40 CCT5 is a member of the chaperonin-containing t-complex peptide (cct complex). In zebrafish, mutations in the CCT γ subunit cause degeneration of retinal neuroepithelial cells. 41 In human, a CCT5 mutation was the cause of mutilating sensory neuropathy in a family with spastic paraplegia. 42 CTNND2, also known as NPRAP (Neural plakophilin-related armadillo-repeat protein), is predominantly expressed in neural and neuroendocrine tissues. Direct sequencing of these five genes, however, did not identify any myopia-associated polymorphism and were therefore excluded from susceptibility to myopia. Another 20 genes are located within this linkage region. Among these are hypothetical genes with no known functions, protein-coding genes not biologically relevant to the ocular structure, and genes that show no expression in the eyes. However, we cannot rule out possible contributions of these genes. Since our preliminary analysis of the five selected genes, IRX1, IRX2, POLS, CCT5, and CTNND2, did not show myopia association, further sequence characterization should be conducted on all these genes. 
In the present study, we used both family-based candidate gene search and population-based association analysis to search for the myopia gene. Linkage analysis was applied as an initial step to identify the linkage region in the entire genome, and this mapped region was further analyzed by allelic association. We gradually increased the average resolution of the marker set from the initial 10-cM-spaced microsatellite markers in the genome-wide scan, followed by 1-cM-spaced microsatellite markers in the fine mapping and then 0.4-cM-spaced (0.2-Mb-spaced) SNP markers in the gene-based SNP association study. SNP markers are densely distributed throughout the genome. Therefore, for even a small interval, a finer set of SNP markers can be selected than from microsatellite markers. Besides, they are highly abundant across the genome occurring in coding, noncoding, and untranslated regions. This strategy of gene-based SNP association to analyze the mapped regions is deemed to be efficient and effective. 43  
In the association analysis, one SNP, rs370010, which corresponds to a hypothetical protein LOC442129, was different in frequency between the high myopia cases and controls, although the association did not remain significantafter multiple testing corrections. Although we have successfully reduced the resolution of our analysis from a broad-scale mapping by microsatellite markers to finer scale mapping using SNP markers, our results showed strong signal from the linkage study which was weakened in the association study. A limitation of our study is that SNP markers were chosen on a gene-by-gene basis. Unknown areas between genes or regions with no known gene may not be fully covered by our SNP marker set. Besides, when our criteria of choosing SNP markers is used, rare SNPs such as those with minor allele frequency (MAF) ≤ 0.3 in the Han Chinese population were not included in our study. Other hypothetical genes and unknown areas also exist within the linkage region. Because there is little information about the functions and properties of the hypothetical gene LOC442129, it is not possible to predict its involvement in the etiology of myopia. Genotyping all the SNPs located at the linkage region or resequencing of the entire region would provide additional information on LOC442129. The search of the myopia gene within this linkage region is in progress. 
The pathogenesis of high myopia involved both biochemical and biomechanical alterations of the sclera. Besides, the magnitude of environmental influence and its interactions between genetic factors are still uncertain. Familial segregation provides evidence of the involvement of genetic factors in the etiology of refractive errors. 44 All these information suggests that several genes of modest effect may influence refractive errors, solely or in conjunction with environmental factors. If this is the case, then traditional linkage analysis would have limited power to detect such signals. As the genetic relative risk conferred by each locus is relatively low, it would therefore be difficult to detect the signal by genotyping a small number of individuals within a family. Besides, genes that regulate the activity of a single or a group of genes or sequence alterations that lie within the regulatory region of a gene may contribute to high myopia rather than a single functional variant within the coding gene sequence. SNP markers compared favorably with microsatellite markers in localizing disease genes in some studies. 45 46 47 Hence, the use of population-based association study by SNP markers would be an appropriate approach in localizing the susceptibility genes of high myopia and also the underlying epistasis between genes and variants. 
 
Table 1.
 
Clinical Features of the Family Members in the Three Pedigrees
Table 1.
 
Clinical Features of the Family Members in the Three Pedigrees
Subject (Sex) Affection Status Age at Exam (y) Refractive Error (OD; OS) Axial Length (OD; OS, mm)
Pedigree 1
 I:1 (M) U 62 −0.50; −0.25 25.08; 25.04
 I:2 (F) A 55 −18.00; −5.00 29.52; 25.92
 II:1 (F) U 37 −4.25; −4.00 26.34; 25.67
 II:2 (F) A 34 −18.00; −21.50 30.44; 33.23
 II:3 (M) U 32 −3.50; −5.00 26.47; 27.21
 II:4 (M) U 32 −2.75; −2.75 24.73; 24.63
 II:5 (F) A 31 −22.50; −18.00 33.26; 31.24
 II:6 (M) U 37 (45) −1.00; −1.50 (−0.75; −1.00) 24.23; 24.12 (24.11; 24.18)
 II:7 (F) A 30 (37) −8.00; −8.00 (−7.25; −7.25) 27.03; 26.84 (26.81; 26.69)
 II:8 (F) A 28 −7.50; −7.00 25.74; 26.37
 II:9 (M) A 27 (35) −20.00; −18.00 (−20.50; −19.25) 33.62; 31.11 (33.55; 32.75)
 II:10 (F) A 26 −24.00; −18.50 33.69; 31.17
 III:1 (M) U 2 −1.50; −2.25 22.91; 22.86
 III:2 (F) U 4 (12) 1.00; −0.50 (−1.50; −1.00) 22.49; 22.64 (24.84; 24.65)
Pedigree 2
 I:1 (M) A 79 −13.00; −7.50 30.00; 26.90
 I:2 (F) U 75 +5.00; +5.00 21.96; 22.21
 II:1 (M) A 54 −6.50; −6.50 27.87; 28.16
 II:4 (F) A 52 −7.25; −7.00 28.38; 28.35
 II:5 (M) U 49 (52) −0.50; −0.25 (+0.00; −0.25) 24.29; 24.24 (24.22; 24.17)
 II:6 (F) A 47 (50) −9.75; −9.00 28.42; 27.92
 II:8 (M) U 43 −2.50; −2.50
 II:9 (F) U 43 +0.50; +0.25
 III:4 (M) A 17 −7.75; −7.50 27.12; 27.11
 III:5 (F) UK/A 9 (12) −3.00; −3.00 (−4.75; −5.25) 25.47; 25.51 (26.62; 26.72)
 III:6 (M) U 5 +1.00; +0.50
Pedigree 3
 I:1 (M) A 75 −8.50; −8.00 26.83; 27.36
 II:1 (M) A 43 −10.50; −10.00 28.56; 28.23
 II:2 (F) A 43 −16.00; −16.00 31.89; 31.82
 II:3 (M) A 42 (50) −13.75; −10.75 (−16.25; −11.50) 31.51; 29.47 (31.74; 29.85)
 II:4 (F) U 38 (46) −4.00; −4.25 (−3.75; −3.25) 26.39; 26.40 (26.43; 26.15)
 II:5 (M) A 37 (45) −10.00; −10.25 (−10.00; −10.25) 27.78; 27.28 (28.48; 28.50)
 III:2 (M) A 9 (16) −4.00; −3.75 (−8.25; −6.50) 25.17; 25.32 (27.66; 27.26)
Figure 1.
 
Whole-genome linkage scan of high myopia in pedigree 1. NPL −log10 (P-values) were plotted against microsatellite markers according to their locations in the genome.
Figure 1.
 
Whole-genome linkage scan of high myopia in pedigree 1. NPL −log10 (P-values) were plotted against microsatellite markers according to their locations in the genome.
Table 2.
 
Two-Point Linkage Results on the Fine Mapping of Chromosome 5p15
Table 2.
 
Two-Point Linkage Results on the Fine Mapping of Chromosome 5p15
Marker Physical Map (Mb) Marshfield Map (cM) Parametric Two-Point LOD Scores at θ = * Zmax θmax
0.00 0.01 0.05 0.10 0.20 0.30 0.40
D5S1981, † 1.21 1.72 −∞ 0.08 0.65 0.79 0.73 0.50 0.19 0.79 0.10
D5S1970 2.50 5.43 −0.16 −0.18 −0.21 −0.18 −0.05 0.04 0.06 0.06 0.40
D5S417 3.17 6.67 −∞ 2.15 2.58 2.53 2.06 1.38 0.58 2.58 0.05
D5S406, † 5.05 11.85 0.30 0.30 0.28 0.26 0.20 0.15 0.08 0.30 0.00
D5S2505 5.87 14.30 4.81 4.72 4.38 3.94 3.00 1.96 0.86 4.81 0.00
D5S635 6.37 14.91 0.30 0.30 0.28 0.26 0.20 0.15 0.08 0.30 0.00
D5S1953 7.71 16.72 0.86 0.86 0.84 0.79 0.63 0.40 0.16 0.86 0.00
D5S580 8.19 17.87 1.74 1.69 1.52 1.31 0.89 0.52 0.20 1.74 0.00
D5S807 9.26 19.02 2.41 2.37 2.18 1.95 1.44 0.90 0.37 2.41 0.00
D5S630 9.61 19.67 4.72 4.63 4.28 3.82 2.84 1.81 0.76 4.72 0.00
D5S1486 10.19 21.10 3.44 3.36 3.05 2.68 1.98 1.27 0.51 3.44 0.00
D5S2004 10.55 21.81 3.01 2.96 2.77 2.51 1.94 1.31 0.59 3.01 0.00
D5S1987 11.44 22.34 1.81 1.78 1.65 1.49 1.13 0.74 0.33 1.81 0.00
D5S817 11.64 22.88 −∞ 0.00 0.64 0.83 0.83 0.60 0.26 0.83 0.10
D5S2081 13.53 24.48 1.81 1.78 1.65 1.49 1.13 0.74 0.33 1.81 0.00
D5S1991 14.93 26.73 −∞ −0.69 −0.13 0.01 0.08 0.09 0.07 0.09 0.30
D5S1954 15.87 28.22 −∞ −2.30 −0.03 0.77 1.18 1.01 0.54 1.18 0.02
Figure 2.
 
Multipoint location score of microsatellite markers for all the three pedigrees for the locus at 5p15. Dashed line: location score; (•) largest location score.
Figure 2.
 
Multipoint location score of microsatellite markers for all the three pedigrees for the locus at 5p15. Dashed line: location score; (•) largest location score.
Figure 3.
 
Structure and haplotype diagram of pedigree 1. Rectangular bars: disease alleles. (▪ and •) Individuals affected by high myopia.
Figure 3.
 
Structure and haplotype diagram of pedigree 1. Rectangular bars: disease alleles. (▪ and •) Individuals affected by high myopia.
Figure 4.
 
Structure and haplotype diagram of pedigree 2. Symbols are as in Figure 3 .
Figure 4.
 
Structure and haplotype diagram of pedigree 2. Symbols are as in Figure 3 .
Figure 5.
 
Structure and haplotype diagram of pedigree 3. Symbols are as in Figure 3 .
Figure 5.
 
Structure and haplotype diagram of pedigree 3. Symbols are as in Figure 3 .
Figure 6.
 
Linkage map of the microsatellite markers located at the mapped high myopia locus on chromosome 5. Markers and information were obtained from the human genetic map of the Marshfield Center for Medical Genetics (Marshfield, WI). There are 25 known genes located within the linkage region of 5p15.33–5p15.2 in the Ensembl database. 35
Figure 6.
 
Linkage map of the microsatellite markers located at the mapped high myopia locus on chromosome 5. Markers and information were obtained from the human genetic map of the Marshfield Center for Medical Genetics (Marshfield, WI). There are 25 known genes located within the linkage region of 5p15.33–5p15.2 in the Ensembl database. 35
Table 3.
 
Functions of Properties of Five Candidate Genes within the Linkage Region on 5p15.33-p15.2
Table 3.
 
Functions of Properties of Five Candidate Genes within the Linkage Region on 5p15.33-p15.2
Gene Gene Ontology
Molecular Function Biological Process Cellular Component
IRX2
Iroqouis-class homeodomain protein 2 Transcription factor activity Regulation of transcription, DNA-dependent Nucleus
IRX1
Iroqouis-class homeodomain protein 1 Transcription factor activity Regulation of transcription, DNA-dependent Nucleus
POLS
DNA polymerase sigma DNA-directed DNA polymerase activity, transferase activity, DNA binding Cytokinesis, mitosis, Sister chromatid cohesion, DNA repair, DNA replication and chromosome cycle Nucleus
CCT5
Chaperonin containing TCP1 subunit 5 ATP binding, unfolded protein binding Protein folding
CTNND2
Catenin delta-2 Protein binding, structural molecule activity Cell adhesion, Development, Neuron adhesion, Signal transduction Cytoplasm, Cytoskeleton, cell junctions
Table 4.
 
Polymorphisms Identified in IRX2, IRX1, POLS, CCT5 and CTNND2 Obtained in an Association Study between Patients with High Myopia and Control Subjects
Table 4.
 
Polymorphisms Identified in IRX2, IRX1, POLS, CCT5 and CTNND2 Obtained in an Association Study between Patients with High Myopia and Control Subjects
Gene Location Polymorphism Amino Acid Change
IRX2 Exon 3 765 G>T E255D
Intron 3–4 IVS3+20 C>G
Intron 3–4 IVS3+27 C>T
Intron 3–4 IVS3+32 G>C
Intron 3–4 IVS3+37 G>T
3′ UTR rs1540709
IRX1 Intron 1–2 rs828338
Intron 1–2 rs861185
POLS Intron 7–8 rs274682
Exon 8 rs274681 A264A
Intron 8–9 rs2279653
Intron 9–10 rs3822437
Intron 10–11 IVS10–22 T>C
Exon 13 rs274675
Exon 13 rs274674
Exon 13 3′ UTR692 T>C
CTNDD2 Intron 1–2 rs2305932
Intron 3–4 rs7719578
Intron 10–11 IVS11–15 C>T
Intron 12–13 rs1990003
Exon 13 rs2285975 G752G
CCT5 Exon 1 −134 A>G
Exon 1 rs2548546
Exon 1 rs11557651
Intron 1–2 rs2259642
Exon 3 rs2578617 G66G
Exon 4 rs1042392 R124R
Intron 4–5 rs2457156
Exon 5 rs11557649 A246A
Intron 7–8 rs2607327
Intron 9–10 rs2578642
Exon 11 rs544
Exon 11 rs699113
Exon 11 rs2578641
Exon 11 rs2662533
Exon 11 rs2607286
Exon 11 rs2578640
Exon 11 rs2578639
Exon 11 c. 2791 (insATTCT)
Exon 11 rs2578638
Exon 11 3′ UTR1427 G>A
Table 5.
 
Summary of the Information of Selected Gene-Based SNPs within the High Myopia Linkage Region on 5p15
Table 5.
 
Summary of the Information of Selected Gene-Based SNPs within the High Myopia Linkage Region on 5p15
dbSNP# Position (bp) Gene MAF-CHI
rs11432 2800127 IRX2, CEI 0.38
rs1118651 2839321 LOC391734 0.47
rs370010 2900693 LOC442129 0.43
rs4866692 2925990 LOC442129 0.48
rs2934555 2963083 LOC442129 0.34
rs160876 3135643 LOC442130 0.47
rs10512699 3490548 LOC285577 0.44
rs698147 3566485 LOC285577 0.49
rs828332 3644325 LOC389268 N/A
rs828337 3647718 LOC389269 N/A
rs844154 3653334 IRX1 N/A
rs293119 4694160 LOC153297 N/A
rs272199 5108277 LOC340094 0.42
rs187468 5199223 ADAMTS16 0.41
rs1366165 5257149 ADAMTS16 0.47
rs1019746 5297339 ADAMTS16 0.34
rs2964137 5449166 LOC442131, LOC23379 0.39
rs4702335 6373013 LOC401172 0.32
rs2250523 6424954 MED10 0.41
rs824633 6499276 LOC134111 0.37
rs182119 6538363 LOC134111 0.36
rs3756426 6666517 NSUN2, SRD5A1 0.42
rs2290618 6800453 POLS 0.47
rs1864071 7489912 ADCY2 0.49
rs1019779 7676228 ADCY2 0.48
rs4334848 7807231 ADCY2 0.44
rs326197 7897969 LOC134121 0.39
rs162049 7946121 FASTKD3, MTRR 0.48
rs40719 9224202 SEMA5A 0.48
rs40705 9322246 SEMA5A 0.48
rs1205719 9409053 SEMA5A 0.30
rs268509 9525365 SEMA5A 0.30
rs788321 9597829 SEMA5A 0.42
rs42225 9699168 TAS2R1, Pseudogene 0.36
rs2658110 10180557 LOC389271, NP_954584.1, CCT5 0.41
rs6876709 10337270 LOC134147 0.14
rs1809880 10513373 MARCH6, ROPNIL 0.50
rs2589661 10545095 LOC389273, LOC345711 0.50
rs6554589 10684808 LOC345711 0.41
rs4702718 10724040 LOC651746 0.44
rs2918395 10754251 DAP 0.40
Figure 7.
 
Single locus analysis of each gene-based SNP marker.
Figure 7.
 
Single locus analysis of each gene-based SNP marker.
Figure 8.
 
Haplotype analysis. Pair-wise locus disequilibrium, measured in r 2 and D′ values, between rs370010, rs4866692, and rs2934555, which are located within the hypothetical gene LOC442129.
Figure 8.
 
Haplotype analysis. Pair-wise locus disequilibrium, measured in r 2 and D′ values, between rs370010, rs4866692, and rs2934555, which are located within the hypothetical gene LOC442129.
Table 6.
 
Haplotype Association Analysis of the Three SNPs, rs370010, rs4866692 and rs2934555, with High Myopia
Table 6.
 
Haplotype Association Analysis of the Three SNPs, rs370010, rs4866692 and rs2934555, with High Myopia
Haplotype rs370010-rs4866692-rs2934555 Frequency Test for Association with HM
Case Control
G-C-A 0.13381 0.09248 P = 0.0603
G-C-G 0.10934 0.13675
G-T-A 0.17714 0.10106
G-T-G 0.19142 0.12715
T-C-A 0.02139 0.06313
T-C-G 0.17163 0.17573
T-T-A 0.10915 0.14227
T-T-G 0.08613 0.16143
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Figure 1.
 
Whole-genome linkage scan of high myopia in pedigree 1. NPL −log10 (P-values) were plotted against microsatellite markers according to their locations in the genome.
Figure 1.
 
Whole-genome linkage scan of high myopia in pedigree 1. NPL −log10 (P-values) were plotted against microsatellite markers according to their locations in the genome.
Figure 2.
 
Multipoint location score of microsatellite markers for all the three pedigrees for the locus at 5p15. Dashed line: location score; (•) largest location score.
Figure 2.
 
Multipoint location score of microsatellite markers for all the three pedigrees for the locus at 5p15. Dashed line: location score; (•) largest location score.
Figure 3.
 
Structure and haplotype diagram of pedigree 1. Rectangular bars: disease alleles. (▪ and •) Individuals affected by high myopia.
Figure 3.
 
Structure and haplotype diagram of pedigree 1. Rectangular bars: disease alleles. (▪ and •) Individuals affected by high myopia.
Figure 4.
 
Structure and haplotype diagram of pedigree 2. Symbols are as in Figure 3 .
Figure 4.
 
Structure and haplotype diagram of pedigree 2. Symbols are as in Figure 3 .
Figure 5.
 
Structure and haplotype diagram of pedigree 3. Symbols are as in Figure 3 .
Figure 5.
 
Structure and haplotype diagram of pedigree 3. Symbols are as in Figure 3 .
Figure 6.
 
Linkage map of the microsatellite markers located at the mapped high myopia locus on chromosome 5. Markers and information were obtained from the human genetic map of the Marshfield Center for Medical Genetics (Marshfield, WI). There are 25 known genes located within the linkage region of 5p15.33–5p15.2 in the Ensembl database. 35
Figure 6.
 
Linkage map of the microsatellite markers located at the mapped high myopia locus on chromosome 5. Markers and information were obtained from the human genetic map of the Marshfield Center for Medical Genetics (Marshfield, WI). There are 25 known genes located within the linkage region of 5p15.33–5p15.2 in the Ensembl database. 35
Figure 7.
 
Single locus analysis of each gene-based SNP marker.
Figure 7.
 
Single locus analysis of each gene-based SNP marker.
Figure 8.
 
Haplotype analysis. Pair-wise locus disequilibrium, measured in r 2 and D′ values, between rs370010, rs4866692, and rs2934555, which are located within the hypothetical gene LOC442129.
Figure 8.
 
Haplotype analysis. Pair-wise locus disequilibrium, measured in r 2 and D′ values, between rs370010, rs4866692, and rs2934555, which are located within the hypothetical gene LOC442129.
Table 1.
 
Clinical Features of the Family Members in the Three Pedigrees
Table 1.
 
Clinical Features of the Family Members in the Three Pedigrees
Subject (Sex) Affection Status Age at Exam (y) Refractive Error (OD; OS) Axial Length (OD; OS, mm)
Pedigree 1
 I:1 (M) U 62 −0.50; −0.25 25.08; 25.04
 I:2 (F) A 55 −18.00; −5.00 29.52; 25.92
 II:1 (F) U 37 −4.25; −4.00 26.34; 25.67
 II:2 (F) A 34 −18.00; −21.50 30.44; 33.23
 II:3 (M) U 32 −3.50; −5.00 26.47; 27.21
 II:4 (M) U 32 −2.75; −2.75 24.73; 24.63
 II:5 (F) A 31 −22.50; −18.00 33.26; 31.24
 II:6 (M) U 37 (45) −1.00; −1.50 (−0.75; −1.00) 24.23; 24.12 (24.11; 24.18)
 II:7 (F) A 30 (37) −8.00; −8.00 (−7.25; −7.25) 27.03; 26.84 (26.81; 26.69)
 II:8 (F) A 28 −7.50; −7.00 25.74; 26.37
 II:9 (M) A 27 (35) −20.00; −18.00 (−20.50; −19.25) 33.62; 31.11 (33.55; 32.75)
 II:10 (F) A 26 −24.00; −18.50 33.69; 31.17
 III:1 (M) U 2 −1.50; −2.25 22.91; 22.86
 III:2 (F) U 4 (12) 1.00; −0.50 (−1.50; −1.00) 22.49; 22.64 (24.84; 24.65)
Pedigree 2
 I:1 (M) A 79 −13.00; −7.50 30.00; 26.90
 I:2 (F) U 75 +5.00; +5.00 21.96; 22.21
 II:1 (M) A 54 −6.50; −6.50 27.87; 28.16
 II:4 (F) A 52 −7.25; −7.00 28.38; 28.35
 II:5 (M) U 49 (52) −0.50; −0.25 (+0.00; −0.25) 24.29; 24.24 (24.22; 24.17)
 II:6 (F) A 47 (50) −9.75; −9.00 28.42; 27.92
 II:8 (M) U 43 −2.50; −2.50
 II:9 (F) U 43 +0.50; +0.25
 III:4 (M) A 17 −7.75; −7.50 27.12; 27.11
 III:5 (F) UK/A 9 (12) −3.00; −3.00 (−4.75; −5.25) 25.47; 25.51 (26.62; 26.72)
 III:6 (M) U 5 +1.00; +0.50
Pedigree 3
 I:1 (M) A 75 −8.50; −8.00 26.83; 27.36
 II:1 (M) A 43 −10.50; −10.00 28.56; 28.23
 II:2 (F) A 43 −16.00; −16.00 31.89; 31.82
 II:3 (M) A 42 (50) −13.75; −10.75 (−16.25; −11.50) 31.51; 29.47 (31.74; 29.85)
 II:4 (F) U 38 (46) −4.00; −4.25 (−3.75; −3.25) 26.39; 26.40 (26.43; 26.15)
 II:5 (M) A 37 (45) −10.00; −10.25 (−10.00; −10.25) 27.78; 27.28 (28.48; 28.50)
 III:2 (M) A 9 (16) −4.00; −3.75 (−8.25; −6.50) 25.17; 25.32 (27.66; 27.26)
Table 2.
 
Two-Point Linkage Results on the Fine Mapping of Chromosome 5p15
Table 2.
 
Two-Point Linkage Results on the Fine Mapping of Chromosome 5p15
Marker Physical Map (Mb) Marshfield Map (cM) Parametric Two-Point LOD Scores at θ = * Zmax θmax
0.00 0.01 0.05 0.10 0.20 0.30 0.40
D5S1981, † 1.21 1.72 −∞ 0.08 0.65 0.79 0.73 0.50 0.19 0.79 0.10
D5S1970 2.50 5.43 −0.16 −0.18 −0.21 −0.18 −0.05 0.04 0.06 0.06 0.40
D5S417 3.17 6.67 −∞ 2.15 2.58 2.53 2.06 1.38 0.58 2.58 0.05
D5S406, † 5.05 11.85 0.30 0.30 0.28 0.26 0.20 0.15 0.08 0.30 0.00
D5S2505 5.87 14.30 4.81 4.72 4.38 3.94 3.00 1.96 0.86 4.81 0.00
D5S635 6.37 14.91 0.30 0.30 0.28 0.26 0.20 0.15 0.08 0.30 0.00
D5S1953 7.71 16.72 0.86 0.86 0.84 0.79 0.63 0.40 0.16 0.86 0.00
D5S580 8.19 17.87 1.74 1.69 1.52 1.31 0.89 0.52 0.20 1.74 0.00
D5S807 9.26 19.02 2.41 2.37 2.18 1.95 1.44 0.90 0.37 2.41 0.00
D5S630 9.61 19.67 4.72 4.63 4.28 3.82 2.84 1.81 0.76 4.72 0.00
D5S1486 10.19 21.10 3.44 3.36 3.05 2.68 1.98 1.27 0.51 3.44 0.00
D5S2004 10.55 21.81 3.01 2.96 2.77 2.51 1.94 1.31 0.59 3.01 0.00
D5S1987 11.44 22.34 1.81 1.78 1.65 1.49 1.13 0.74 0.33 1.81 0.00
D5S817 11.64 22.88 −∞ 0.00 0.64 0.83 0.83 0.60 0.26 0.83 0.10
D5S2081 13.53 24.48 1.81 1.78 1.65 1.49 1.13 0.74 0.33 1.81 0.00
D5S1991 14.93 26.73 −∞ −0.69 −0.13 0.01 0.08 0.09 0.07 0.09 0.30
D5S1954 15.87 28.22 −∞ −2.30 −0.03 0.77 1.18 1.01 0.54 1.18 0.02
Table 3.
 
Functions of Properties of Five Candidate Genes within the Linkage Region on 5p15.33-p15.2
Table 3.
 
Functions of Properties of Five Candidate Genes within the Linkage Region on 5p15.33-p15.2
Gene Gene Ontology
Molecular Function Biological Process Cellular Component
IRX2
Iroqouis-class homeodomain protein 2 Transcription factor activity Regulation of transcription, DNA-dependent Nucleus
IRX1
Iroqouis-class homeodomain protein 1 Transcription factor activity Regulation of transcription, DNA-dependent Nucleus
POLS
DNA polymerase sigma DNA-directed DNA polymerase activity, transferase activity, DNA binding Cytokinesis, mitosis, Sister chromatid cohesion, DNA repair, DNA replication and chromosome cycle Nucleus
CCT5
Chaperonin containing TCP1 subunit 5 ATP binding, unfolded protein binding Protein folding
CTNND2
Catenin delta-2 Protein binding, structural molecule activity Cell adhesion, Development, Neuron adhesion, Signal transduction Cytoplasm, Cytoskeleton, cell junctions
Table 4.
 
Polymorphisms Identified in IRX2, IRX1, POLS, CCT5 and CTNND2 Obtained in an Association Study between Patients with High Myopia and Control Subjects
Table 4.
 
Polymorphisms Identified in IRX2, IRX1, POLS, CCT5 and CTNND2 Obtained in an Association Study between Patients with High Myopia and Control Subjects
Gene Location Polymorphism Amino Acid Change
IRX2 Exon 3 765 G>T E255D
Intron 3–4 IVS3+20 C>G
Intron 3–4 IVS3+27 C>T
Intron 3–4 IVS3+32 G>C
Intron 3–4 IVS3+37 G>T
3′ UTR rs1540709
IRX1 Intron 1–2 rs828338
Intron 1–2 rs861185
POLS Intron 7–8 rs274682
Exon 8 rs274681 A264A
Intron 8–9 rs2279653
Intron 9–10 rs3822437
Intron 10–11 IVS10–22 T>C
Exon 13 rs274675
Exon 13 rs274674
Exon 13 3′ UTR692 T>C
CTNDD2 Intron 1–2 rs2305932
Intron 3–4 rs7719578
Intron 10–11 IVS11–15 C>T
Intron 12–13 rs1990003
Exon 13 rs2285975 G752G
CCT5 Exon 1 −134 A>G
Exon 1 rs2548546
Exon 1 rs11557651
Intron 1–2 rs2259642
Exon 3 rs2578617 G66G
Exon 4 rs1042392 R124R
Intron 4–5 rs2457156
Exon 5 rs11557649 A246A
Intron 7–8 rs2607327
Intron 9–10 rs2578642
Exon 11 rs544
Exon 11 rs699113
Exon 11 rs2578641
Exon 11 rs2662533
Exon 11 rs2607286
Exon 11 rs2578640
Exon 11 rs2578639
Exon 11 c. 2791 (insATTCT)
Exon 11 rs2578638
Exon 11 3′ UTR1427 G>A
Table 5.
 
Summary of the Information of Selected Gene-Based SNPs within the High Myopia Linkage Region on 5p15
Table 5.
 
Summary of the Information of Selected Gene-Based SNPs within the High Myopia Linkage Region on 5p15
dbSNP# Position (bp) Gene MAF-CHI
rs11432 2800127 IRX2, CEI 0.38
rs1118651 2839321 LOC391734 0.47
rs370010 2900693 LOC442129 0.43
rs4866692 2925990 LOC442129 0.48
rs2934555 2963083 LOC442129 0.34
rs160876 3135643 LOC442130 0.47
rs10512699 3490548 LOC285577 0.44
rs698147 3566485 LOC285577 0.49
rs828332 3644325 LOC389268 N/A
rs828337 3647718 LOC389269 N/A
rs844154 3653334 IRX1 N/A
rs293119 4694160 LOC153297 N/A
rs272199 5108277 LOC340094 0.42
rs187468 5199223 ADAMTS16 0.41
rs1366165 5257149 ADAMTS16 0.47
rs1019746 5297339 ADAMTS16 0.34
rs2964137 5449166 LOC442131, LOC23379 0.39
rs4702335 6373013 LOC401172 0.32
rs2250523 6424954 MED10 0.41
rs824633 6499276 LOC134111 0.37
rs182119 6538363 LOC134111 0.36
rs3756426 6666517 NSUN2, SRD5A1 0.42
rs2290618 6800453 POLS 0.47
rs1864071 7489912 ADCY2 0.49
rs1019779 7676228 ADCY2 0.48
rs4334848 7807231 ADCY2 0.44
rs326197 7897969 LOC134121 0.39
rs162049 7946121 FASTKD3, MTRR 0.48
rs40719 9224202 SEMA5A 0.48
rs40705 9322246 SEMA5A 0.48
rs1205719 9409053 SEMA5A 0.30
rs268509 9525365 SEMA5A 0.30
rs788321 9597829 SEMA5A 0.42
rs42225 9699168 TAS2R1, Pseudogene 0.36
rs2658110 10180557 LOC389271, NP_954584.1, CCT5 0.41
rs6876709 10337270 LOC134147 0.14
rs1809880 10513373 MARCH6, ROPNIL 0.50
rs2589661 10545095 LOC389273, LOC345711 0.50
rs6554589 10684808 LOC345711 0.41
rs4702718 10724040 LOC651746 0.44
rs2918395 10754251 DAP 0.40
Table 6.
 
Haplotype Association Analysis of the Three SNPs, rs370010, rs4866692 and rs2934555, with High Myopia
Table 6.
 
Haplotype Association Analysis of the Three SNPs, rs370010, rs4866692 and rs2934555, with High Myopia
Haplotype rs370010-rs4866692-rs2934555 Frequency Test for Association with HM
Case Control
G-C-A 0.13381 0.09248 P = 0.0603
G-C-G 0.10934 0.13675
G-T-A 0.17714 0.10106
G-T-G 0.19142 0.12715
T-C-A 0.02139 0.06313
T-C-G 0.17163 0.17573
T-T-A 0.10915 0.14227
T-T-G 0.08613 0.16143
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