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Am J Hum Genet. Aug 2004; 75(2): 294–304.
Published online Jun 24, 2004. doi:  10.1086/423148
PMCID: PMC1216063

A Susceptibility Locus for Myopia in the Normal Population Is Linked to the PAX6 Gene Region on Chromosome 11: A Genomewide Scan of Dizygotic Twins


Myopia is a common, complex trait with considerable economic and social impact and, in highly affected individuals, ocular morbidity. We performed a classic twin study of 506 unselected twin pairs and inferred the heritability of refractive error to be 0.89 (95% confidence interval 0.86–0.91). A genomewide scan of 221 dizygotic twin pairs, analyzed by use of optimal Haseman-Elston regression methods implemented by use of generalized linear modeling, showed significant linkage (LOD >3.2) to refractive error at four loci, with a maximum LOD score of 6.1 at 40 cM on chromome 11p13. Evidence of linkage at this locus, as well as at the other linkage peaks at chromosomes 3q26 (LOD 3.7), 8p23 (LOD 4.1), and 4q12 (LOD 3.3), remained the same or became stronger after model fit was checked and outliers were downweighted. Examination of potential candidate genes showed the PAX6 gene directly below the highest peak at the 11p13 locus. PAX6 is fundamental to identity and growth of the eye, but reported mutations usually result in catastrophic congenital phenotypes such as aniridia. Haplotype tagging of 17 single-nucleotide polymorphisms (SNPs), which covered the PAX6 gene and had common minor allele frequencies, identified 5 SNPs that explained 0.999 of the haplotype diversity. Linkage and association analysis of the tagging SNPs showed strong evidence of linkage for all markers with a minimum χ21 of 7.5 (P=.006) but no association. This suggests that PAX6 may play a role in myopia development, possibly because of genetic variation in an upstream promoter or regulator, although no definite association between PAX6 common variants and myopia was demonstrated in this study.


Refractive error is a common, complex trait measured on a continuous scale, with myopia affecting 25%–61% of the population (Wang et al. 1994; Saw et al. 1996). Its incidence may be increasing rapidly (Tay et al. 1992), with not only economic implications but also a significant risk of permanent vision loss in individuals with high myopia (“pathological myopia”), which is also becoming more common (Rosenberg and Klie 1996; Dandona and Dandona 2001). Susceptibility loci have been identified in familial autosomal dominant high myopia (Young et al. 1998a, 1998b; Naiglin et al. 2002; Paluru et al. 2003), although, to date, these loci have not been associated with lower degrees of juvenile-onset myopia from population-based samples (“simple myopia”) (Mutti et al. 2002b). High myopia may be influenced by certain candidate genes, such as those involved in Marfan (MIM #154700) or Stickler (MIM #108300) syndromes, but high myopia accounts for only 2%–3% of cases of myopia (Dandona and Dandona 2001). To our knowledge, no susceptibility loci for simple myopia have been published elsewhere.

The mechanism of myopia development is not fully understood. Simple myopia results from a failure of emmetropization; excessive eye growth causes images from distant objects to be focused in front of the retina. Debate about the relative contributions of genes and environment (in particular, close work) has continued (Mutti et al. 1996). Cross-sectional studies suggest that the majority of individual variation around the population mean is attributable to genetic variance (Hammond et al. 2001; Mutti et al. 2002a). The rapid growth in the incidence of myopia in Southeast Asia (Tay et al. 1992), however, suggests that recent generational differences are more likely to result from environmental mechanisms, such as increased literacy, than from changes in allele frequencies. There are many potential candidate genes controlling both the fundamental development of the eye and variations in eye growth.

The PAX6 gene (MIM 607108) is a member of the paired-domain Pax family and encodes transcriptional regulators involved in oculogenesis and body development, aspects of which are conserved throughout phylogeny (Simpson and Price 2002). The gene is widely expressed in the developing eye, both in neuroectoderm and surface ectoderm, as well as in the adult eye (Ashery-Padan and Gruss 2001). Most PAX6 mutations described elsewhere are deletions resulting in premature protein truncations, haploinsufficiency, and catastrophic congenital phenotypes, rather than minor normal variations. For example, PAX6 has been the sole gene implicated in aniridia (MIM #106210), a semi-dominantly inherited condition (Glaser et al. 1992) that is characterized by severe iris hypoplasia with other associated abnormalities and that usually results in marked visual impairment (van Heyningen and Williamson 2002). Aniridia is a progressive condition, which suggests that PAX6 may also play a maintenance role in the adult eye and that it is not involved only in oculogenesis. To our knowledge, PAX6 has not been implicated in nonpathogenic myopia development in previous studies.

A classic twin study was undertaken, in which MZ and DZ twins were used to establish the heritability of refractive error. This was followed up with a genomewide linkage study for the continuous trait by use of unselected DZ sib pairs; the follow-up was conducted to ascertain potential susceptibility loci for myopia. On the basis of the linkage analysis results, an association study for the PAX6 gene was then performed.

Materials and Methods

Refractive Error Measurement

Refractive error was measured in 506 volunteer twin pairs as part of the Twin Eye Study, by use of a Humphrey 670 Autorefractor (Hammond et al. 2001). Refractive error was determined by the mean spherical equivalent (SE) for the two eyes of each individual, measured in diopters (D). The 280 DZ and 226 MZ twin pairs were part of the Twins UK Registry (Spector and MacGregor 2002) and were unselected as to eye traits, having volunteered for the registry unaware of any potential eye studies or hypotheses. Twins were excluded if they had previous interventions that might have affected refraction, such as cataract or refractive surgery. After approval of the study by the hospital research ethics committee, informed written consent was obtained from all subjects and whole blood was taken for DNA extraction. Zygosity was determined by a standardized questionnaire (Martin and Martin 1975) and confirmed by DNA short-tandem-repeat fingerprinting, in cases of doubt. Individuals in the study were considered to be randomly ascertained, because sampling was not based on a subject’s eye data.

Heritability Analysis

We have previously reported heritability of refractive error in this cohort (Hammond et al. 2001), but we repeated the analysis for the measure of mean SE used in the genomewide scan presented in this study. In short, quantitative-model fitting to twin data is based on comparisons of the covariances (or correlations) between MZ and DZ twin pairs; it allows for the partitioning of observed phenotypic variance into additive (A) or dominant (D) genetic components and common (C) or unique (E) environmental components. MZ twins are assumed to share the same A and D genetic variance, and DZ pairs, on average, share half of the A variance and a quarter of the D variance; C is assumed to be the same for both MZ and DZ twin pairs (the “equal environment” assumption) (Neale and Cardon 1992; Snieder et al. 1997).

The variance of A, C, D, E, and age were estimated by use of normal theory and maximum-likelihood methods implemented in the software package Mx (Neale 1997). The significance of the variance components A, C, D, and age was assessed by removing each sequentially and testing the deterioration in model fit. Submodels were contrasted to full models by use of nested comparisons and an asymptotic χ2 fit statistic. If there was no significant change in model fit, then the parameter could be removed, leading to a parsimonious model explaining the variance and covariance. Data handling and preliminary analyses were conducted by use of STATA (StataCorp 2003).

Genomewide Linkage Study

A genomewide linkage analysis was performed on 221 of the 280 DZ twin pairs for which there were genomic marker data from the heritability study. The genomic scan was based on DNA extracted from venous blood samples of the study subjects. Scans involved the use of standard fluorescence–based genotyping methodologies (Reed et al. 1994; Pritchard et al. 1995) for the analysis of 737 highly polymorphic microsatellite markers from the ABI Prism linkage mapping set (Applied Biosystems) and the Généthon Genetic Linkage Map (Dib et al. 1996), as has been described elsewhere (Wilson et al. 2003). The estimated genotyping error rate was <1%.

Linkage Analysis

Multipoint genomewide linkage analyses were performed by use of the unadjusted mean SE of both eyes (in D) and optimal Haseman-Elston regression methods, implemented by use of a generalized linear model (GLM) (Barber et al. 2004). This method, implemented in STATA (StataCorp), is algebraically equivalent to other likelihood techniques (Kruglyak and Lander 1995; Almasy and Blangero 1998) but has the advantage of being robust to deviations in multivariate normality by freely estimating the coefficient of variation (i.e., the mean and variance-corrected residual error) and by utilizing a robust Huber estimate of variance (Barber et al. 2004). Regression diagnostics were used to check the reliability of model fit, including an iterative regression (IR) routine applied to GLM by use of the Huber estimate, followed by biweight iterations (StataCorp 2003). On a genomewide basis, any observed divergence between GLM and GLMIR results indicated potentially poor-fitting models for specific regions.

The map positions and ordering of all marker loci were determined from the Généthon Genetic Linkage Map. Approximate support intervals were generated by use of a 1-LOD drop-interval approach. Twin pairs formed independent families, and no additional sibs were considered in the analysis.

Association Analysis

Of the known genes observed under the linkage peak on chromosome 11p13 (see table 1), only PAX6 is directly implicated in the identity and growth of the eye (Dominguez et al. 2004) and has a well-documented role in oculogenesis. We therefore undertook a three-step candidate-gene association study (Weale et al. 2003) by (1) characterizing the haplotypic structure of the gene, (2) identifying a subset of highly informative SNP markers in the region, referred to as “tagging SNPs” (tSNPs), and (3) typing the tSNPs for the clinical sample and testing these for linkage and association, by use of the quantitative transmission/disequilibrium test (QTDT) (Abecasis et al. 2000a).

Table 1
Potential Candidate Genes under Peak Area (Maximum 1-LOD, Equating to a LOD Score >5.1) on Chromosome 11 (35–45 cM)

PAX6 SNP Genotyping

SNPs were selected from public SNP databases (SNP Consortium and National Center of Biotechnology Information) by criteria that included population-frequency validation, multiple submitters, high-profile submitters, and absence of repeats masking in the sequence. To assess linkage disequilibrium (LD) in a 34-kb region on chromosome 11p13, 17 SNPs, covering 8 kb upstream and 4 kb downstream of the PAX6 gene, were genotyped for 22 individuals. Details of these 17 SNPs are given in table 2.

Table 2
Details of the 17 SNPs Selected for PAX6 Gene from Public Domain[Note]

The PCR method is based on the accumulation of fluorescence during the PCR process by degradation of an internally quenched allele-specific probe bound to the same template (Heid et al. 1996). Allelic discrimination is achieved by the use of two oligonucleotide probes, each complementary to one of the two alleles and labeled with a different fluorescent reporter dye. Applied Biosystems designed the PCR primers and allele-specific minor groove binder (MGB) probes and optimized the reaction conditions for all 17 SNPs. The company also supplied the reagents and consumables used for TaqMan PCR in our study.

The PCR reaction was performed with the GeneAmp PCR System 9700 thermal cycler (Applied Biosystems) in a volume of 25 μl, containing 12.5 μl of TaqMan 2× Universal PCR Master Mix, 20–50 ng of genomic DNA, and the optimized primer/probe solution as supplied by Applied Biosystems. The PCR program included an initial step at 95°C for 10 min, followed by 40 cycles at 92°C for 15 s and 60°C for 1 min. Endpoint reading of fluorescence and analysis of the genotypes were performed with the ABI Prism 7700 Sequence Detection System (Applied Biosystems).

Assessment of PAX6 Haplotypic Structure

LD measures r2 and D′ (Hedrick 1987) were used to assess pairwise LD between markers, both in the immediate vicinity of PAX6, by use of 17 public-domain SNPs with common minor allele frequencies (MAFs [gt-or-equal, slanted]7%), and in a 250-kb region on either side of PAX6, by use of HapMap data. tSNPs were originally identified by use of haplotype-diversity criteria (Johnson et al. 2001). However, because of the high levels of disequilibrium found in the gene, other, more recent, and potentially more efficient marker-based selection criteria were used, such as association r2 (Weale et al. 2003), which, in this case, also produced the same tagging solutions. Haplotype tagging in the 34-kb region identified five tSNPs, which explained 0.999 of the haplotype diversity arising from 17 SNPs with common MAFs (see fig. 1). The five tSNPs were subsequently genotyped in the original sample of 221 DZ twin pairs.

Figure  1
LD map for the 17 PAX6 SNPs genotyped (n=22) over a 32-kb region. The LD statistic plotted is r2. The plot orientation is 3′→5′, with SNPs 1, 9, and 16 (rs3026401, rs628224, and rs1806180) also genotyped by the HapMap Project.


The 506 twin pairs included in the heritability study were aged 49–79 years, with a mean age of 62.2 years (SD 5.7 years). Their mean refractive error (SE) was +0.39 D (SD 2.38), with a range of −12.12 D to +7.25 D. The distribution was leptokurtic (5.87 D), with a left skew (−0.91 D), in keeping with other population studies of refractive error. There were no significant differences between MZ and DZ twins for age (62.4 years vs. 62.0 years) and refractive error (mean 0.36 D vs. 0.40 D). Age accounted for only ~1% of the variance and so was excluded from further analysis.

Refractive errors for twin 1 versus twin 2 for mean SE are plotted in figure 2. The pairwise intraclass correlation coefficient was 0.89 for MZ twins and 0.49 for DZ twins, suggesting a significant genetic contribution to the variance. Univariate model–fitting results for mean SE are displayed in table 3 and show the best-fitting model to be the one that explained the variation of SE due to additive genetic effects (A) and to unique environmental effects (E). The effects of shared family environment (C) and dominant genes (D) could be eliminated without significant deterioration in model fit. The parameter estimates for mean SE obtained by this model suggested a very high heritability of 0.89 (95% CI 0.86–0.91), with the rest of variance (0.11 [95% CI 0.09–0.14]) explained by individual environmental effects. These results do not differ significantly from those of our previous heritability analysis, in which right and left eyes were studied separately (Hammond et al. 2001).

Figure  2
Scatter plots of refractive error measured as mean SE for each twin (in D), plotted for twin 1 versus twin 2 in 226 MZ and 280 DZ twin pairs.
Table 3
Model-Fitting Results for Univariate Analysis of Mean SE

The 221 DZ twin pairs included in the genomewide linkage analysis did not significantly differ from the whole cohort (mean age 61.4 years, mean SE +0.31 D). Maximum evidence of linkage in the twins was observed at chromosome 11p13 (LOD 6.1), with further loci at chromosomes 3q26 (LOD 3.7), 4q12 (LOD 3.3), 8p23 (LOD 4.1), and 11q23-24 (LOD 2.9), as shown in figure 3. Evidence for these loci became stronger after model-fit residuals were checked and after unduly influential outliers were downweighted by use of GLMIR, as displayed in table 4. The linkage results for the four peaks with LOD scores >3.2 are displayed in figure 4, with marker information. To examine whether this linkage pertained to myopia, as opposed to hyperopia (farsightedness), twin pairs were divided into myopes (mean SE [less-than-or-eq, slant]0; 85 pairs) and hyperopes (mean SE >0; 136 pairs) by use of the arbitrary threshold of zero. Figure 4 demonstrates that the linkage signal was maintained in the myopic group, despite the smaller numbers (albeit with a lower LOD score), as well as in the hyperopic group. This suggests that the locus is likely to confer myopia susceptibility across the whole spectrum of refractive errors.

Figure  3
Linkage peaks in genomewide scan of 221 twin pairs
Figure  4
Linkage analysis results for the four peaks with LOD scores >3.2 (on chromosomes 3, 4, 8, and 11) for all sib pairs, “myopic” pairs (mean SE [less-than-or-eq, slant]0), and “hyperopic” pairs (mean SE >0). Marker positions ...
Table 4
Significant Linkage Loci (LOD >2.0) in Genomewide Scan[Note]

The nearest markers to the maximum LOD score of 6.1 at 40 cM from the p-terminal on chromosome 11p13 were D11S904 (37 cM; two-point LOD score 4.28) and D11S935 (49 cM; two-point LOD score 2.2). Support intervals, which used the maximum 1-LOD approach, equated to 35–45 cM, in which there are 44 described genes or potential genes. Some possible candidate genes are listed in table 1. The most likely candidate gene in this area is PAX6, at 39–42 cM, directly beneath the highest linkage peak at 40 cM. We therefore attempted to determine whether PAX6 was associated with myopia in this population.

Analysis of the tSNP genotypes and haplotypes by use of QTDT showed strong evidence of linkage for all markers (minimum χ21=7.5; P=.006), as detailed in table 5. There was marginal evidence for population stratification for SNP1 and SNP3 (and the resulting haplotypes). All five SNP polymorphisms were in Hardy-Weinberg equilibrium, and no evidence for phenotypic association with any of the SNPs or haplotypes was found by use of tests of total association or tests of association robust to population stratification (Abecasis et al. 2000b). Tests of linkage, controlling for association, also did not significantly reduce the observed linkage signal.

Table 5
Results of Linkage, Association, and Combined (Linkage and Association) Tests by Use of QTDT


These results show a high heritability for refractive error of 0.89. This is the first study of myopia, to our knowledge, that has demonstrated significant linkage to susceptibility loci by use of a genomewide screen. In this population-based sample, we have found four loci with LOD scores >3.2. A QTL in the vicinity of PAX6 that predisposes individuals to myopia has not been reported elsewhere; to date, only major developmental eye abnormalities have been associated with mutations in this gene. This means that PAX6 may play an important role postnatally in continued eye growth.

The strong evidence of linkage to PAX6 suggests that genetic variants are located in the vicinity of the gene, perhaps within regulatory or promoter regions of PAX6. The important role (Kellis et al. 2003) and greater numbers of these variants are increasingly being recognized (Dermitzakis et al. 2003). There have also been advances in the understanding of the control of eye growth: the dosage of PAX6 may be important, and overexpression of PAX6 in transgenic mice led to reduced eye size (Schedl et al. 1996). Recent work on Drosophila melanogaster eyes has shown that two distinct Pax genes control eye identity and growth separately and that these equate to the PAX6 and PAX6(5a) isoforms of the gene in humans (Dominguez et al. 2004). This raises the exciting possibility that PAX6 or one of its isoforms may be involved in eye growth in childhood, and, therefore, it may play a role in the etiology of myopia.

Animal studies have suggested that eye growth is regulated by the quality of the retinal image (“emmetropization”) (Flitcroft 1998). If humans have the same mechanism, human myopia may occur if a child inherits a dysfunctional emmetropization mechanism (Norton 1994), with the trigger being close work. The exact mechanisms are unclear. Humoral interactions occur between scleral and choroidal layers in response to negative and positive fitted lenses in chicks (Marzani and Wallman 1997), and this effect is also seen in primates (Hung et al. 2000). Retinoic acid may have a mediating role between vision and growth (Mertz and Wallman 2000). Further examination of the four loci significantly linked to myopia in this study may allow further elucidation of the mechanisms of myopia development.

The high heritability of myopia in this twin cohort (0.89 [95% CI 0.86–0.91]) is almost identical to that reported in the Danish twin study (0.91 [95% CI 0.86–0.94) (Lyhne et al. 2001) and is consistent with other family studies (Zadnik et al. 1994; Framingham Offspring Eye Study Group 1996). The possibility of ascertainment bias was reduced because the twins in this study were unselected for refractive error, having volunteered for osteoporosis and other studies. The twins in this study are representative of the general population for many common traits and exposures, such as those in the cardiovascular and musculoskeletal systems (Andrew et al. 2001), supporting the generalizability of these results. Although the LOD scores of these loci are impressive for a common complex trait, we need to confirm them in a replication study to prioritize potential regions of interest for further research.

The failure to find a phenotypic association with a common SNP in the PAX6 gene could have occurred for one of several reasons: (1) the variant(s) lies within the gene and has been missed by the tSNPs, (2) the variant lies outside the PAX6 gene, or (3) the linkage signal is a false-positive result. In the first scenario, if the potential causal variant is common, it is unlikely that one or a combination of the tSNPs we selected are not in LD with the polymorphism, since the common haplotype diversity captured was >99% (Johnson et al. 2001). In addition, in a sampling experiment in which each of the original 17 SNPs was sequentially dropped (Weale et al. 2003), the three- or four-tSNP solution exactly predicted the dropped SNP (r2=1 in all cases). The exception was rs2239789 (SNP8), for which r2 was 21%. This is because SNP8 lies in a region of the gene with low LD between exons 8 and 9 (see figs. figs.11 and and5).5). It is possible that a (combination of) rare variant(s) not in LD with the common tSNPs may be associated with myopia; sequencing would be required for their identification.

Figure  5
Schematic representation of PAX6 gene and the positions of SNPs (presented from 3′ to 5′). Exons are represented as vertical lines, and introns are depicted as the horizontal line between the exons. tSNPs that were used in this study are ...

However, if common and rare functional polymorphisms within the PAX6 gene are ruled out, then the alternative explanations for the linkage signal are either a different gene nearby (such as ELP4 [see table 1]) or a variant in a nearby regulator of PAX6. Further detailed examination of PAX6 and its isoforms and regulatory regions is required.


Myopia is a common trait that is increasing in incidence and is strongly heritable. Four loci have been identified from a genomewide linkage analysis, with the highest peak on chromosome 11p13 (LOD 6.1). We found strong linkage for refractive error in the vicinity of PAX6, a candidate gene at this locus. Further mapping is required to confirm whether the linkage to PAX6 is due to regulatory loci or to linkage to an unrecognized nearby gene.


The authors thank the Wellcome Trust, which funded the original phenotyping, and the Chronic Diseases Research Foundation, for continuing support. We acknowledge Sequenom for genotyping information, and we thank Mathew Barber for his help with data analysis early in the project and Kourosh Ahmadi for his expert advice on candidate-gene SNP tagging. Finally, we are grateful to all the twin volunteers for their ongoing help and support.

Electronic-Database Information

The URLs for data presented herein are as follows:

HapMap, http://www.hapmap.org/ (for HapMap data)
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for PAX6, Marfan syndrome, Stickler syndrome, and aniridia)
University of California–Santa Cruz Genome Browser Gateway (July 2003 version), http://www.genome.ucsc.edu/cgi-bin/hgGateway?db=hg8 (for SNPs in )


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