53 Gene-Environment Interactions in the Aetiology of Myopia
These emerging genetic associations with mild to moderate myopia set the scene for proper studies of gene-environment interactions. But because the evidence for such associations is very recent, such studies have not yet been reported. Given this situation, two factors — ethnicity and parental myopia — have been taken as potential surrogates for genetic differences.
Evidence for the Impact of Environmental Factors on Myopia Phenotypes
In contrast to the limited evidence for an impact of genetic variation in school myopia, there is abundant evidence that suggests a role for environmental factors in generating variation at the phenotypic level. We have previously reviewed this material in some detail,5 and will therefore concentrate on newer evidence that adds to the picture.
One of the long-standing pieces of evidence for environmental impacts has come from the association of higher prevalences of myopia with higher educational achievements, and with near-work-intensive occupations. This has led to a view that education, and the level of near-work and accommodation involved leads to the development of myopia, and has inspired one strand of myopia epidemiology. A number of different measures have been taken in this area, ranging from educational achievements in adults, school grades, IQ, number of books read, and attempts to determine hours spent on near-work or sustained near-work, and taking account of viewing distance, calculations of dioptre, and hours of accommodative effect. Of these various factors, educational achievements stand out as the most consistent measure, while the more quantitative estimates of near-work and accommodation have given less convincing associations. As a result, the relevance of near-work, either as a measure of accommodative effort, or as an estimate of accommodative lag and hyperopic defocus has been questioned.39 Recently, an apparently more powerful factor, time spent outdoors, has been revealed in the Orinda study40 and in the Sydney Myopia Study.41
Gene-Environment Interactions and Ethnicity
The rapid increases in prevalence of myopia, particularly in urban East Asia, over the past few decades, possibly associated with the expansion of mass intensive education in those areas, suggest that changes in gene
54 I.G. Morgan and K.A. Rose
pools cannot account for the rate of change that has been seen. However, the concentration of the epidemic of myopia in urban East Asia has been interpreted as indicating the current differences in prevalence of myopia between ethnic groups may be genetic in origin, perhaps because of a concentration of susceptibility genes in those of East Asia origin.
The available evidence does not favor this interpretation. First of all, it is clear that East Asian, or even more specifically Chinese, origin, does not necessarily lead to myopia. In addition to the earlier studies covered in our 2005 review,5 which demonstrated major variation in the prevalence of myopia for particular ethnic groups associated with different sites and times, recent work has documented the differences in prevalence of myopia in those of Chinese and Malay ethnicity, as well as Indian ethnicity, in two countries as close together as Singapore and Malaysia,42 and we have shown marked differences in the prevalence of myopia between children of Chinese origin in Singapore and Sydney.43 However, this evidence does not rule out ethnic genetic differences in susceptibility to environmental factors.
On this issue, more conclusive evidence comes from studies on migrant populations. The prevalence of myopia is generally low in children and young adults in India, but shows some evidence of an urban-rural difference.44,45 Myopia is higher in the Indian population of Malaysia,42 and even higher again in the Indian population of Singapore,46 which approaches that seen in the Chinese community. This suggests that people of Chinese, Indian and Malay origin respond to the environment of Singapore with an increased prevalence of myopia, which suggests that there is a broadly similar susceptibility to the relevant environmental factors. The fact that, in the environment of Singapore, Chinese are more myopic than Indians, who are in turn more myopic than Malays, could be an indication of differential susceptibility to the environmental factors, but given that this difference in prevalence mirrors patterns of educational success,47 and engagement in outdoor activities,48 it could also be attributed to differential environmental exposures alone. A similar picture is found in the children from ethnic groups in Sydney, where the most myopic groups, those of East Asian and South Asian origin,49 achieve higher educational outcomes, and engage in lesser amount of time in outdoor activities than those of European origin.
In collaboration with the SCORM study, we have also compared in detail children of Chinese origin growing up in Sydney with those of
55 Gene-Environment Interactions in the Aetiology of Myopia
Chinese origin growing up in Singapore, and found that the prevalence of myopia in Sydney is lower. In the case of this study, ethnicity was controlled for, and the level of parental myopia was very similar in the two parent groups.43 It, therefore, seems likely that the differences can be attributed to environmental differences, of which the most obvious was the higher amount of time spent outdoors by the children of Chinese origin in Sydney than in Singapore. Unexpectedly, the less myopic children of Chinese ethnicity in Sydney apparently performed more near-work.
It is always possible to construct an argument as to how these results could be explained in genetic terms. For example, it could be argued that the Indians who migrated to Singapore were more susceptible to the development of myopia than those who stayed at home. But to explain why the children of South Asian origin in Sydney were much less myopic, it would be necessary to postulate that those who migrated were less susceptible to myopia. Similarly, it is possible that the Chinese who migrated south to Singapore were as susceptible to the development of myopia as those who remained behind, whereas those who migrated further south to Australia were less susceptible. Despite some flaws in the study designs, the prevalence of myopia in Chinese Canadians50 also seems quite high, which might suggest that those who went north or east were more susceptible to developing myopia. Overall, a series of ad hoc hypotheses is required to interpret these data in terms of genetic differences, which is a characteristic sign of a theory in crisis.
Almost all studies that have examined the issue have given evidence of an association between high educational achievements and myopia.5 While the studies are very limited for some ethnic groups, in all the ethnic groups that have been examined there is evidence of such an association, and there is no evidence that there is any differential susceptibility to education between ethnic groups. One of the few anomalies in the literature concerns the rapid appearance of high myopia prevalence rates in the Inuit during the period of acculturation, when children were brought into settlements and commenced formal education.51 This appears to have happened when educational pressures were much lower than in Singapore, and it is possible that genetic susceptibility might be involved. But given the evidence for light exposures in reducing the prevalence of myopia, it is also possible that the Inuit were particularly susceptible to environmental change because of the pattern of light exposures characteristic of Arctic environments.
56 I.G. Morgan and K.A. Rose
Overall, with the present evidence, there is little evidence for genetic contributions to the current differences in prevalence of myopia by ethnicity, and correspondingly little evidence of a role for gene-environment interactions.
Gene-Environment Interactions and Parental Myopia
As a possible surrogate measure of differentially susceptible genomes, parental myopia is a less than satisfactory measure, because it is clear that environmental exposures are important, and that parents who are not myopic may simply have not received the necessary environmental exposures. Despite this limitation, most studies have shown a consistently higher prevalence of myopia amongst those who have myopic parents as compared with those who do not.14,15,52,53
There has been some investigation of whether there is an interaction between parental myopia and measures of education and near-work, with results from the SCORM study suggesting an interaction,52 whereas data from the Orinda study do not.14 Given the uncertainty about whether near-work is a risk factor, further work in the area is required. Recent work on the interaction between time spent outdoors and parental myopia suggests that all children are protected by time spent outdoors, and the risks decline in parallel for children with and without myopic parents.40,41 Thus, there is no real evidence of gene-environment interactions in relation to parental myopia.
Attempts have been made to explain the impact of parental myopia in terms of a tendency for myopic parents to create myopigenic environments characterized by intense education and little time spent outdoors. This area deserves further study, but the very limited data available show at most a slight tendency in this direction,40,41 and the effects would need to be highly nonlinear to explain the differences. It should be noted that studies on populations of European origin14,15,53 have shown several-fold differences in the prevalence of myopia depending on parental myopia. A study of myopia across three generations in China54 has, however, suggested that as the prevalence of myopia increases, the impact of parental myopia declines. Consistent with this, studies carried out at sites with characteristically high myopia prevalence such as Singapore52 and Guangzhou (Fan and He, personal communication), the relative risk associated with parental myopia is much more modest.