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myopia as well as other refractive errors. Both categorical and quantitative definitions have been used with success in myopia genetic studies.
In addition to these issues, it is also important to appreciate that the refractive status of the eye has a number of underlying determinants that may be considered as sub-phenotypes. In particular, the refractive status of the eye is largely determined by the coordinated contributions of three principle ocular biometric components: ocular axial length, anterior chamber depth, and corneal curvature. A mismatch between the length of the eye and the combined refractive power of the lens and cornea leads to intercepting light rays falling short of the retina, thus leading to blurred vision.7 The sub-phenotype of axial length, independent of a person’s overall height, is a major trait as it has been reported to explain at least half of the total variance of myopia.8 Therefore, it is important to consider the complexity of the phenotypic definition of myopia when undertaking genetic studies. As will be detailed below, there has been a recent shift in studies for myopia that takes these sub-phenotypes into account. With these definitions in mind, we now turn our attention to twins and their application to the study of the genetics of myopia.
The Classical Twin Model
What is the classical twin model?
A twin can be defined as one of two offspring produced in the same pregnancy and born during the same birthing procedure. There are two main classes of twins — monozygotic and dizygotic. Monozygotic twins (also known as identical twins) develop when a single ovum (egg) is fertilized and splits into two independent embryos early during development. Monozygotic twins share one hundred per cent of their genetic material, unless there is a de novo mutation during early development. They are very similar in their physical appearance but not always completely identical due to the influence of environmental factors.
On the other hand, dizygotic twins (also known as non-identical, biovular, or fraternal twins) develop when two independent ova (eggs) are fertilized at the same time. Dizygotic twins share 50% of their genetic material and from a genetic point of view can be considered as siblings born at the same time. Dizygotic twins can be of the same sex or opposite sexes whereas monozygotic twins are always of the same sex. Dizygotic
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twins are more common than monozygotic twins, accounting for 0.8% of live births in Caucasian populations compared to 0.4% for monozygotic twins. Monozygotic twinning rates are relatively constant in different population, whereas dizygotic twinning rates vary with ethnicity, ranging from 0.4% of live births in populations of Asian descent to as high as 4.5% in Africans.
The proportion of genetic material that is shared between monozygotic twins and dizygotic twins can be exploited by genetic studies to allow an assessment of the relative importance of genes and environment in the development of myopia. As monozygotic twins share all their genetic material, this suggests that differences in the clinical expression of myopia between monozygotic twins are likely to be due to non-genetic effects. On the other hand, for dizygotic twins that share up to 50% of their genetic material, the differences in clinical expression will be due to both genetic and environmental effects. In other words, if a trait is influenced by genetic factors then one would expect that monozygotic twins would be phenotypically very similar (concordant), and that dizygotic twins would be less so. This principle is the fundamental basis of the “classical twin model” that is used to determine whether myopia is influenced by hereditary factors or non-hereditary (environmental) factors, and to what extent.
Historical perspective
The use of twins as a means to understand the aetiology of myopia and refractive errors originated in 1924 when Walter Jablonski published an article in a German journal that translates to English as,“A contribution to the hereditary refraction in human eyes.”9 This study has been buried in the literature for some time with its existence coming to the forefront by the recent publication by Liew that summarizes the original Jablonski publication.10 The Jablonski paper was pioneering for its time in that it was not only the first publication to use the “classical twin model” to analyze refraction, but it was also the first to have applied it to any trait.
The Jablonski study consisted of 40 pairs of monozygotic twins and 12 pairs of dizygotic twins, all of which underwent ophthalmic examinations. Refraction measurements were compared within each pair of twins (within-pair differences) and a comparison was made between within-pair differences for monozygotic twins compared to dizygotic twins. It was reported that the within-pair differences were less in monozygotic twin pairs than in dizygotic twin pairs. Thus, the monozygotic twins were more
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concordant for measures of refraction compared to dizygotic twins. These results provided the first clue that there may be an underlying hereditary influence to refraction. In fact, this study was well ahead of its time as it was not until much later that additional quantitative studies of this nature were undertaken.
Following the Jablonski study, a series of reports were published that supported the notion that refraction was most likely influenced by genetic factors. Here, we highlight two of them.
The first report was published in 1935 by Law and examined eight pairs of what are presumed to be monozygotic twin pairs.11 Refraction measurements were compared between monozygotic twins and their respective siblings born at different times. It was observed that refraction measurements were similar twice as often in monozygotic twins than they were in the siblings.
Another report, published in 1948 by Burns, observed a single pair of monozygotic twin pairs with similar levels of myopia.12 This study went on to examine the extended pedigree of these twins and observed a presumed transmission pattern for myopia through the generation of the family of these twins. These observations were taken together to conclude that the influences on myopia are genetic in origin.
Early studies such as the ones described above were largely observational in nature and certainly crude when measured against current methodological approaches. However, the fundamental observations are valid and they provided the first hint of evidence to suggest that refraction and myopia are influenced by genetic factors.
Statistical approaches
In 1962, Sorsby et al. published a study using the classical twin model to analyze refraction.13 The typical approach was taken whereby withinpair refraction measures were compared between monozygotic twin pairs, dizygotic twin pairs, and control pairs. As predicted from previous studies, Sorsby et al. observed a consistently smaller within-pair difference in monozygotic twins compared to dizygotic twins. This finding was not novel or unexpected, but in 1964 this work was extended by additional work from Sorsby and Fraser to include statistical measures.14
This statistical analysis from Sorsby and Fraser involved using correlation coefficients (a measure of the extent to which measures between a
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twin and their co-twin vary) to quantitate the within-pair differences between twin pairs. Correlation coefficients were calculated for monozygotic twins, dizygotic twins, and unrelated age and gender matched controls pairs. Correlation coefficients were calculated for refraction, corneal power, lens power, axial length, and anterior chamber depth, and were in all cases found to be higher in the monozygotic twin pairs. This study was important as it raised the study of twins and myopia to a new level with the introduction of statistical measures to complement previous observational studies for the classical twin model.
The statistical measures suggested by Sorsby et al. in 1962 have since been extended and refined into what is now known as the heritability study. Heritability studies aim to provide an absolute quantitation of the extent to which genetic and environmental factors contribute to myopia. Heritability (h2) is broadly defined as the proportion of phenotypic variance attributed to genetic factors. In very simple terms, heritability can be estimated by multiplying the difference between monozygotic and dizygotic twin pair within-pair correlations by a factor of two. Heritability measures range from 1.0 for a trait that is entirely influenced by genes to 0 for a trait that is influenced entirely by environmental factors. The beauty of this type of analysis is that it can be extended to quantify the proportion of phenotypic variance that is due to environmental factors such as unique environment effects (those that affect one twin but not the co-twin) and common environment effects (those that affect both twins). In real terms, the calculation of heritability and the contributions of shared and common environmental effects are more sophisticated than this. Analyzes are able to model the genetic effects to determine if there are multiple contributing genes each with small effects (additive model) or if there is one major gene (dominant model). Additionally, other factors that may affect refraction measures such as age, gender, and height can also be taken into account.
The true elegance of heritability studies come from the fact that one can determine the role of hereditary in myopia without any prior knowledge of the exact nature of the contributing genes. Similarly, the role of environmental factors can also be assessed without knowing their exact nature. Hence, twins provide a unique opportunity to study gene-environment effects and are often referred to as the “perfect natural experiment.”15 Next, we describe a selection of published heritability studies that have used twins to study myopia.