Genes and Myopia
The etiology of myopia , however, is still a subject of contention, and scientists have conjectured that myopia is genetically inherited (2). Though myopia has high heritability (3), the recent prevalence increase in the condition is not due to genetic shifts, but is driven by trends in behavioral and environmental factors (1, 2). The conceptualization of myopia as a genetic disease has been traditionally explained through family studies focused on inheritability of parental myopia, occurrence of myopia in twins and among family members, and myopia prevalence in ethnic groups, and occurrence of myopia due to genetic syndromes and diseases.
Studies on parental myopia were the beginning point in conjecturing myopia as a genetic condition. In their 1994 study on impacts of parental myopia on children’s ocular size, Zadnik et al. studied 716 children aged 6 to 14 years old and noted that children born to myopic parents had a higher risk of developing myopia. In their study, the researchers noted that 11% of children with both parents myopic and 5% of children with a myopic parent developed the condition while only 2% of children without any myopic parent developed the disease (5). Similar findings were reported by Edwards (1998) four years later when she studied the occurrence of myopia in children born to two myopic parents in China (6). Ip et al. (2007) conducted a 12-year follow up study on the impact of parental myopia on children and noted that parental myopia increased the probability of myopia development in children. (7). In their meta-analytic study on worldwide prevalence of myopia, Pan, Ramamurthy and Saw (2012) note that parental myopia was traditionally used as a marker of myopic genes and
Studies on myopia among family members also contributed to the conceptualization of myopia as a genetic condition. Family studies on myopia have traditionally identified high risks of the condition among family members, supporting the hypothesis that the shared genetic traits among relatives indicate that myopia is inherited genetically (9). The familial nature of myopia has been established in more modern studies that controlled for the influence of environmental factors. In their 2004 study aptly titled Impact of Family History of High Myopia on Level and Onset of Myopia, Liang et al. studied 887 Taiwanese subjects aged 17-45 years old while controlling for environmental factors, such as early exposure to near work, to establish whether familial history of myopia predisposes individuals to the condition. In this study, the authors studied corneal curvature, axial length, and anterior chamber depth among participants and found that there was a high correlation between parental myopia and myopia in the offspring, but the association of myopia between siblings was very weak (10). This study indicates that family history should be considered a risk factor in myopia. In another 2008 study on the same subject, Berg et al. (2008) studied the relationship between myopia and personality in family members using a sample of 633 twins between 18 and 83 years old and 278 close relatives between 11 and 90 years old. The researchers found that twins had a myopia prevalence of
Among family studies on myopia, twin studies have been the most common in explaining myopia as a genetic condition. Twin studies on myopia can be traced back to the 1980s. In 1987, Lin and Chen (1987) studied 126 pairs of Chinese twins enrolled for ophthalmological examination and used data on their axial length, corneal curvatures, and ocular refractions to explain the prevalence of myopia. The authors found an 84% concordance rate on corneal curvatures, 65% on ocular refractions, and 59% on axial length, leading to the conclusion that myopia had a high prevalence in twins because they share genetic traits (12). In 1988, Terikari et al. conducted a population study on 23,570 Finnish twins using data from the Finnish Police Force. The study established that there was high concordance on myopia indicators in twins, implying that the condition had high heritability (13). Recent twin studies on myopia also indicate that there is a genetic component in the development of myopia. In 2008, Dirani, Shekar, and Baird conducted a twin study on 1224 Caucasian twins between 18 and 86 years old and found that adult-onset myopia depends on genetic traits (14). In 2009, Tsai et al. studied 130 Taiwanese twins and also concluded that heritability plan s a crucial role in the onset of myopia. In their study, Tsai et al. (2009) controlled for environmental factors (15).
Some comments on heritability. The core of twin heritability studies is the comparison of MZ twins with DZ twins. Give or take a little bit, MZ twins are genetically identical, whereas DZ twins share only 50% of their genome. So the logic is that if MZ twins are more similar than DZ twins, then this must be due to genetics. But, since twins are very similar in environmental exposures, and it is possible that MZ twins are more similar in their environmental exposures than DZ twins (makes sense after all). A little later, Rob makes the point that MZ twins are always of the same gender, whereas half of the DZ twins are of different genders. If myopia depends on education and time outdoors, and boys and girls differ in these parameters, then you would expect that MZ twins would be more discordant on environmental grounds than DZ twins, and thus it is impossible to draw real conclusions once what is known as the “common environment assumption” is not valid. All you can conclude is that the twin heritability must be higher the reality, if this assumption does not apply. More generally, it seems plausible that heritability is likely to be over-estimated, because parents are likely to treat MZ twins more similarly than DZ twins. The mathematical process follows these biases, because it assumes that genetic similarities explain the phenotypic similarities, and environmental factors explain the residual variation, and concludes that this proves phenotypic variation depends on genetic variation, which it is hardly surprising because it assumes that it does. But you could start with the assumption that environmental factors explain the phenotypic similarities with similar validity, but this is hard to do until you know what the relevant environmental factors are, and how to measure them. The bottom line is that twin studies do not prove anything. At most they give results consistent with the assumption that genetic variation is important.
The real test for heritability comes when you look for the assumed genetic contribution to phenotypic variation with modern molecular techniques. In simple cases, this works. But in the context of complex diseases, it is a general rule that must less than the predicted amount of associated genetic variation is found. This phenomenon has come to be known as missing heritability, although it is actually the associated genetic variation which is missing. To deal with this problem, those who believe in genetics argue that the problem is statistical – that when looking at genome-wide significance you have to use significance cut-offs adjusted for very large numbers of comparisons. So they argue that if you make the assumption that all associations which are significant at the unadjusted level are in facto significant (this can’t actually be true, but the error will not be too bad), then you can add up all those “significant as the unadjusted level” associations to see how much they could account for. In some cases this works quite well, but there are also documented cases in which there is no improvement in explanatory power. In the case of myopia, compared to 80-90% heritability, the genetic estimates are more like 25-35%. A true believer in genetics would then argue that bigger sample numbers, and rare mutations will fill in the gap, but this is a statement of belief, not a guarantee. However, whatever way you argue it, there is clearly a case for environmental effects, which were initially ruled out. When we can additionally argue that, at least in some circumstances, environmental change has rapidly increased the prevalence from 20-30% to 80-90%, then environmental effects can be massive. End of story.
Traditionally, prevalence variations of myopia in different ethnic groups have also been used to conceptualize the condition as a genetic problem.
This logic is flawed. While it is a common assumption, modern molecular biology tells us that human populations are very similar genetically, whereas they can have very different environmental exposures. For example, there are places where children hardly go to school, and others where schooling is intensive. So, it is more likely that ethnic differences are based on environmental exposures rather than genetic differences. The genetic similarities are particularly high if they concern common variations, and since in some populations myopic can affect over 90% of cohorts, so-called “genetic susceptibility” variants are certainly common. This means they are unlikely to be specific to populations. None of the GWAS results suggest significant ethnic differences. Moreover, the fact that myopia is very low in India, but very high in those of Indian ancestry in Singapore, suggests that it is the myopigenic environment of Singapore which is the real issue. In contrast, genetic variations which underlie high myopia are much rarer, and are thus more likely to vary by population.
Numerous studies have been conducted in the past two decades to illustrate the differences in prevalence in individuals of different nationalities. In 2004, Kempen et al. studied myopia occurrence in a population sample of 29,281 individuals from the United States, Australia, and Western Europe. The authors noted that myopia prevalence in the three nations was 25.4%, 16.4% and 26.6% respectively, indicating that different Traditionally, researchers did not seek to establish the causes of variation in myopia prevalence in different ethnic groups, but rather concluded that such differences were explained by the genetic differences in different ethnicities. Besides ethnic variations, genetic syndromes and diseases were used in the 1990s and the early 2000s to explain the development of myopia. According to Morgan and Rose (2005), congenital syndromes such as stationary night blindness and abnormalities caused by mutations related to collagen, retinal structure, and ocular connective tissue components were identified as risk factors for myopia to support the hypothesis that the condition is genetic (9).
While it is undeniable that genes significantly affect the development of myopia, it should be noted that family and twin studies on myopia are faced with key weaknesses that harm their validity. The key weakness of twin studies and family studies on myopia is the majority have been conducted on individuals sharing the same environment (9). Notably, twin studies have been the pillar on which the consideration of myopia as genetic is founded. Twin studies usually compare myopia prevalence in monozygotic (MZ) or identical, and dizygotic (DZ) or non-identical twins, and have always found higher heritability values in monozygotic twins. The limitation of these studies is that they do not take account of conflicting factors such as the shared environment . In other word, the issue with monozygotic and dizygotic twin pairs is that, in most cases, any pair will share the same environment but only monozygotic twins will share the same genes, thereby controlling for environment. The accounts of twin studies given above don’t always have enough detail about the comparison of monozygotic and dizygotic pairs. In essence, twin studies on myopia underestimate the impact of the environment on the development of the refractive error.
Another limitation of the classic twin methodology on myopia is that it compares intrapair genetic variations without factoring confounding factors. In his their critique of the twin study approach, Dirani et al. (2006) report that classic twin studies on the genes in myopia do not explore potentially confounding factors such as sex comparisons, ocular biometrics, and the impact of age ranges (16). Simply put, classic twin studies, and even family studies, on the genetics of myopia fail to factor in the effects of age, sex, gender, lifestyle, socioeconomic status, general health, and other demographic and biometric factors that may affect the development of myopia even in monozygotic . Despite these limitations, it is important to note that the heritability values and genetic correlations obtained in twin and family studies denote that genes play a vital role in myopia development, but more sophisticated study designs and comprehensive analytic approaches are required (9).
In addition to the limitations of earlier twin studies on myopia, recent studies on the etiology of the disease indicate that the high heritability of myopia does not adequately explain the development of the refractive error. In their article aptly titled The impact of Severity of Parental Myopia on Myopia in Chinese Children, Xiang, He and Morgan (2012) built on existing research to study the relationship between genetics and myopia development in an objective manner. In this study, the authors studied 1,567 children aged 12-15 years and noted that highly myopic parents increased the risk of development of myopia in their children. However, the researchers also found that 43.5% of myopic children had parents without myopia (17). In addition, the authors found that more of the children with very severe myopia had non-myopic parents. From this study, the authors concluded that while genes influence the development of the condition, environmental factors also affect the occurrence of the disease and affect its severity even in individuals in which it is hereditary. In another study on a broader sample size (4364 children in Guangzhou), Xiang et al. (2012) found that 68.2% of children with myopia had parents who didn’t have myopia. The authors also noted that despite the myopic status of their parents, most individuals with myopia developed the disease by the time they were 15 years old (18). These population-based epidemiological studies on myopia indicate that myopia occurs due to genetic factors as well as non-genetic factors. Such studies, which are increasing in number as researchers seek to explain the non-genetic causes of the increasingly important health condition, clearly imply the conjecture that myopia is totally genetically determined should be disregarded, despite the condition’s high heritability.
In modern studies, environmental factors are used to explain the prevalence variations of myopia in different ethnic groups. For example, in 2012, Pan et al. studied the variations in myopia prevalence in two generations of Singaporean Indians and provided important evidence that myopia development is significantly affected by environmental factors. In their study, Pan et al. (2012) used a sample size of 3,400 Singaporean Indians who classified into two generations. The first-generation Singaporean Indians were defined as Indians who immigrated to Singapore while the second-generation immigrants were Indians born to immigrant Indian parents in Singapore. The researchers found that myopia prevalence was 30.2% for the first-generation, while the prevalence of myopia among the second-generation immigrants was lower; it was 23.4% (19). The authors explained the variation in prevalence as a function of the differences in environmental conditions posed to the two generations of immigrants. Singapore has higher living standards and a different environment compared to India, and the authors used this difference to explain why Indians who immigrated to Singapore from India had higher myopia prevalence compared to Indians born in Singapore (19). Notably, in this study, the possibly confounding factor of genetics was controlled for by the use of different generations of individuals from the same ethnic group who had been raised in different environmental conditions.
Besides epidemiological studies and use of environmental variations to explain ethnicity-related differences in myopia prevalence, another factor that aids in negating the conceptualization of myopia as only a genetic condition is the fact that genome-wide association studies (GWAS) have not identified any genetic explanations for myopia. GWAS are used to examine genetic variants in different individuals to provide an explanation of the genetic traits that lead to a genetic factor. One of the largest GWAS on myopia was conducted by Kiefer on 45,771 individuals from a European population (4). The study identified only 20 loci associated with myopia development. Using a set of 8,323 myopic participants who developed the condition before age 10, Kiefer et al. replicated 10 of the novel loci identified (20). This study replicated similar GWAS findings that did not identify strong genetic explanations for myopia development (4). GWAS results on myopia explain the missing heritability in twin and family studies on the disease.
To provide evidence that myopia development is influenced by non-genetic factors, numerous studies have been published on environmental factors that are risk factors for myopia. One of the key environmental factors associated with higher prevalence of myopia is education. In their population-based studies on the relationship between education and myopia prevalence Virginie et al. (2013) and Williams et al. (2015) noted that the incidence and prevalence of the refractive error is higher in individuals with higher levels of education (21, 22). However, Williams et al. (2015) observed that education was an additive factor and not explanatory of the rising prevalence of myopia (22). Another environmental and behavior factor that has been associated with the increase in myopia prevalence is physical activity and time spent outdoors. In their study on 12 and 13 years old, O’Donoghue et al. (2015) noted that children who led sedentary lives had a higher risk of developing myopia compared to children who were physically active (23). Similarly, French et al. (2013) elucidated that spending time outdoors involves light-stimulation of the retina to release dopamine which decreases the probability of developing myopia by inhibiting axial elongation (24).
Conclusively, the rapid increase of myopia prevalence is not due to only genes, it must be due to changes in environmental factors as well .
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Do you need to explain what this is?
“family members other than parents”
Something is missing from this explanation. The raw prevalence of myopia in two groups of people says nothing about genetics, other than it looking like twins as a group have a lower prevalence of myopia than non-twins do.
What does “concordance” mean here? e.g. did 59% of twin pairs have the same axial length within a pair, down to the micron level of measurement?
What does “concordance” mean in this study? Which myopia indicators? What counts as “high”
What does “depends” mean here? This conclusion is stated as established fact. What was the incontrovertible evidence they produced?
“plays”. How did they decide this? How convincing is their evidence?
You can’t equate nationality with ethnicity, especially in countries like the US and Australia which have experienced extensive immigration from a wide range of other countries.
You need to say that monozygotic twins are always the same sex, whereas dizygotic twins can be different sexes. To the extent there are differing cultural constraints on the activities of males and females, the environmental similarity of monozygotic twin pairs as a group is likely to be higher than the environmental similarity of dizygotic twin pairs.
At this point in the paper no support for the claim of underestimation has been put forward.
It would be better to be more explicit.
“…due to non-genetic as well as genetic…”
Is there another chapter on environmental factors? If not, you should go into more detail about the environmental studies.
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