How genetic is school myopia?

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Abstract

Myopia is of diverse aetiology. A small proportion of myopia is clearly familial, generally early in onset and of high level, with defined chromosomal localisations and in some cases, causal genetic mutations. However, in economically developed societies, most myopia appears during childhood, particularly during the school years. The chromosomal localisations characterised so far for high familial myopia do not seem to be relevant to school myopia. Family correlations in refractive error and axial length are consistent with a genetic contribution to variations in school myopia, but potentially confound shared genes and shared environments. High heritability values are obtained from twin studies, but rest on contestable assumptions, and require further critical analysis, particularly in view of the low heritability values obtained from parent–offspring correlations where there has been rapid environmental change between generations. Since heritability is a population-specific parameter, the values obtained on twins cannot be extrapolated to define the genetic contribution to variation in the general population. In addition, high heritability sets no limit to the potential for environmentally induced change. There is in fact strong evidence for rapid, environmentally induced change in the prevalence of myopia, associated with increased education and urbanisation. These environmental impacts have been found in all major branches of the human family, defined in modern molecular terms, with the exception of the Pacific Islanders, where the evidence is too limited to draw conclusions. The idea that populations of East Asian origin have an intrinsically higher prevalence of myopia is not supported by the very low prevalence reported for them in rural areas, and by the high prevalence of myopia reported for Indians in Singapore. A propensity to develop myopia in “myopigenic” environments thus appears to be a common human characteristic. Overall, while there may be a small genetic contribution to school myopia, detectable under conditions of low environmental variation, environmental change appears to be the major factor increasing the prevalence of myopia around the world. There is, moreover, little evidence to support the idea that individuals or populations differ in their susceptibility to environmental risk factors.

Introduction

Since it was first realised that highly educated people are more likely to be myopic than less educated people, there has been a continuing debate over whether myopia is inherited, or environmentally determined. This debate is encapsulated in two conflicting ideas; that those born to be myopic naturally gravitate to academic studies and near work occupations, or that engaging in these activities, particularly during development, causes myopia.

A comprehensive review of the literature led Curtin (1985) to the following conclusions:

Recent investigations convincingly indicate that the development of refraction can be influenced to some extent, in that the eye seems to develop post-natally towards emmetropia. Certain environmental factors appear capable of deranging this process and thereby produce myopia, often of high degree.

The debate around these propositions has not been settled, as the correspondence provoked by a recent clinical review (Fredrick, 2002) has demonstrated. However, the last 20 years has seen considerable clarification of some of the issues. It is now clear that myopia largely results from a failure of the eye growth control processes that normally adjust the axial length of the eye to its optical power. Excessive axial eye growth relative to the optical power of the cornea and lens is responsible for myopic refractive error, and excessive axial elongation is also responsible for myopia's longer-term pathological consequences.

It is also now clear that myopia is not one disorder, but can be classified into categories based on familial inheritance, severity, age of onset, progression and pathological consequences. This points to considerable heterogeneity in the underlying causes of the failure in control of eye growth. However, it should be cautioned that the distinctions between categories are not clear-cut. In particular, the severity of myopia does not provide a simple distinction between myopias of genetic and environmental origin.

The area of biggest concern, which will be the focus of this article, is juvenile-onset or school myopia. This category excludes early onset forms of high myopia that are often associated with clear familial inheritance (see Section 3.1), or with severe environmental distortions of visual input (see Section 5.2.3). In classical cases of school myopia, clinically significant myopic refractive errors appear over the ages 8–14, in the late primary school or early secondary school years. Further progression of myopia may occur over the next 10–15 years, up to the age of about 30, and incident cases of myopia may appear over this time. This form of myopia can affect a large proportion of the population, and is increasing dramatically in prevalence and severity in many parts of the world, in association with a decrease in the age of onset (see 4.4.1 Taiwan, 4.4.2 Singapore).

The central issue is not whether genes are involved in the development of school myopia. Eye growth is a biological process, involving tissues such as the retina, choroid and sclera. Gene expression, and changes in gene expression must therefore be involved, and the involvement of a range of biochemical pathways in the control of eye growth in animal models has been documented (for recent reviews see Feldkamper and Schaeffel, 2003; McBrien and Gentle, 2003; Morgan, 2003; Schaeffel et al., 2003). However, this only establishes that there is a biological basis for a contribution of genetic variation to refractive error. The crucial question is to what extent do genetic differences actually contribute to variations in refractive status in humans. We will consider three major questions:

  • To what extent does genetic variation contribute to individual differences in eye length and refractive error?

  • To what extent does genetic variation between populations contribute to different prevalences in myopia in different populations in different parts of the world?

  • Is the increasing prevalence of myopia seen in many parts of the world due primarily to environmental change?

Section snippets

Emmetropisation—a developmental process for matching eye length to optical power

Significant genetic contributions to eye size might be expected, in view of the abundant evidence for genetic contributions to growth processes which result, for example, in variations in height both within and between populations (Silventoinen et al., 2000; Silventoinen, 2003; Wu et al., 2003). However, the impact of differences in eye size on refractive error could be minimised due to emmetropisation—the process of eye development in both humans and other animals that involves an active

Evidence for genetic determination of myopia and eye length

Evidence for genetic determination of biological characteristics comes in the first instance from studies of familial inheritance of those characteristics. This is usually followed by the search for chromosomal localisation and ultimately molecular characterisation of the gene or genes involved.

Evidence for environmental factors in the development of school myopia

In contrast to the limited evidence for genetic determination of refractive error, there is considerable evidence of the importance of environmental factors. The first set of evidence comes from studies that have shown that the prevalence of myopia and high myopia is changing rapidly, at least in some parts of the world.

Environmental determinants of the prevalence of myopia

In the absence of sufficient information on longitudinal changes in the prevalence of myopia, evidence of the impact of environmental factors on the prevalence of myopia indicates that there is plasticity in refractive error and eye growth. Where these environmental factors are changing rapidly, it would be expected that the prevalence of myopia would change as well.

Are there differences in the intrinsic prevalence of myopia or susceptibility to environmental impacts between population groups?

The prevalence of myopia varies significantly around the world, with significant differences between different racial and ethnic groups. This is often taken as evidence for genetic determination, either of refractive error, or of susceptibility to environmental factors, where the relevant genes are differentially distributed between different populations. However, this sort of analysis must take into account the different environments that exist around the world, including the level of

Conclusions

Overall, while there is good evidence for a major role for genetic variation in familial forms of early onset high myopia, there is little evidence for a major role for genetic determination in school myopia. The high heritabilities observed in twin studies suggest that genetic factors do have a role in school myopia, but the evidence from broader family studies suggests that some of the high correlations observed between genetically related family members may be due to shared environments as

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