We performed a thorough point-by-point analysis to reveal any refraction heritability shift across a wide range of horizontal retinal scan. With the comprehensive SEM analyses, we found the highest total phenotypic variance (black line in Fig. 1) concentrated around the central retina, which gradually decreased towards periphery. When we looked at the contribution of individual phenotypic components of refraction variance, we found additive genetic influence was lowest at the foveal region, where the influence of shared environmental factors was highest. Interestingly, the decreasing total variance towards the peripheral retina, actually coincide with an increase of additive genetic influence (Fig. 2, left) accompanied by a gradual decrease in shared environmental impact (Fig. 2, centre).
The gradual increment of heritability towards the peripheral retina was distributed in such a manner that beyond specific thresholds (19 deg nasal and 22 deg temporal), it provoke a shift in the best fitting model from an environmental (CE) to a gene-environmental combined (AE) model. This deviation and the low heritability at the area surrounding the fovea suggest that variability at the central retina (around ± 20 degrees from the fovea) is greatly influenced by environmental factors than variability at the more eccentric areas of the retina. Moreover, the lower magnitude of unstandardized genetic variance around fovea would also indicate less dependence on genetic factors in this area and, hence, suggesting a higher sensitivity to the variation produced from environmental inputs. Consequently, our results would suggest that differences in myopia development are mostly explained by environmental effects that influence the eyeball at the central retinal zone. In contrast, eccentric zones of the eyeball would be less sensitive to environmental effects and dependent on genetic architecture. Concurrently, it is important to stress that the total variance and the raw shared environmental variance (Fig. 1) were both highest at central retina, suggesting greater visual exposure at central retinal region than at peripheral areas. Considering the above-discussed findings and the fact that the non-shared environmental variance remains stable across the analyzed retinal eccentricity, such environmental influences should be looked for within the shared visual exposures among siblings.
In agreement with our peripheral refraction heritability result, the study by Ding et al. in children and adolescents also reported a significant role of the additive genetic component to explain the variance of peripheral refraction.25 However, they did not provide information about central and mid-peripheral refraction heritability. We couldn’t find any other published literature on peripheral refraction inheritance. Whereas, all other studies on refraction heritability were restricted to foveal refraction only and generally suggesting a strong genetic influence on its variance.18–23 On the contrary, the foveal and mid-peripheral refraction heritability in our study population showed a lower foveal refraction heritability with increased shared environmental impact.
The higher shared visual exposures at central retina and high myopia prevalence (78%) in our study population, may most likely include myopigenic factors: prolonged near visual tasks, time spent indoors, lighting conditions and reading text contrast or polarity etc. These factors are well connected to the modern lifestyle, massive urbanization, as suggested by recent myopia studies.2,10,27−29 Our study population was also exposed to all these myopia causative factors as they are university students and belong to an urban area of a developed country. Myopia theories like ‘accommodation lag theory’ and ‘mechanical tension theory’ can further explain the mechanism of myopia development in a myopigenic environment prioritizing prolong near-work.30–32 We could further connect these results with the neural and optical limitations of the retina resulting in poor sampling resolution at the periphery. The central retina is more sensitive to visual exposures (environmental influences) than the periphery mostly due to the high retinal resolution sensitivity threshold in the fovea, which rapidly decreases towards the peripheral retina.33 Peripheral vision is compromised not only because of low cone density and limited ganglion cell density,34 but also for increased optical aberrations at the peripheral retina.17,35,36
Development of myopic refractive error is mainly related to an increase in axial length (AL), following a rule-of-thumb that every 300 microns AL growth causes one diopter rise in myopia, considering no alteration of other ocular components.37,38 However, the AL growth is unlikely to always confined at the macular area but extends to an unknown area at the posterior ocular wall. Based on biometrical and optical measures, Atchison et al.39 proposed three possible scenarios to explain ocular growth linked to myopia: global expansion of the posterior chamber, extension of the posterior chamber induced by equatorial stretching of the eyeball, and posterior pole theory with an ocular growth confined to the area surrounding the macula. However, it has been complicated to validate these theories so far due to the limitations of the methods used for retinal off-axis measures. We used an alternate approach: instead of comparing measures performed within one single eye, we analyzed a wide range of off-axis refraction between eyes of twin siblings, who share genetic inheritance and environmental exposures. Thenceforth, we computed the relative influence of individual phenotypic components on its variance of refraction. These twins were born in a developed country at the end of the twentieth century, being most of them raised in myopigenic environment. As a result, we can predict that most of them have developed myopia related to an increase in eye size and less influenced by ocular optics. In that study, we found that variance of refractive error, induced by changes in eye size, was mainly influenced by variance in environmental exposures during ocular development.24 An extensive SEM analysis of peripheral refraction applied in this sample allowed us to differentiate to which point the variance of refractive error, measured from the LOS up to of up to ± 35 degrees retinal area, was influenced by variance in genes or childhood visual exposures. The central large environmental influence found in our study participants may predict a trend of ocular axial length growth limited mainly at the posterior pole of the eyeball, in an area from the optical disk to around 20 degrees temporal, supporting the ‘posterior pole elongation’ myopia theory.
Although myopia is not a disease itself, high myopia is a risk factor for severe ocular diseases and even blindness.40–46 This study may contribute to facing this challenge, as it provides evidence and suggests mechanisms for environmentally driven myopia development. In summary, the refractive error variance showed a shift in the relative influence of genetic and environmental factors across horizontal retinal eccentricities. The total phenotypic variance showed its highest concentration at the macular region with gradual descent towards the periphery. Heritability showed an opposite pattern with its highest at the peripheral retina with gradual depletion towards fovea. We found the influence of shared-environmental factors to be the main source of individual differences explaining the central peak of total phenotypic variance.