Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (43,360 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 19 significant associations (p < 5e-8), two of which are replications of earlier associations with refractive error. These 19 associations in total explain 2.7% of the variance in myopia age of onset, and point towards a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point towards multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans

Current trends among pediatric ophthalmologists to decrease myopia progression—an international perspective

Purpose To explore what the current worldwide preferred practice patterns of pediatric ophthalmologists are to decrease myopia progression among their patients. Methods A questionnaire was sent to all members of supranational and national pediatric ophthalmology and strabismus societies. Results The questionnaire was fully completed by most respondents 90.10% (847 of 940 responses). Fifty-seven percent (457) routinely treat to decrease myopia progression. The most common parameter to initiate treatment was a myopic increase of 1 diopter/year or more (74.8%, 246). Seventy percent (345) prescribed eye drops. Atropine 0.01% was the most popular (63.4%, 277) followed by atropine 1% (10.9%, 48) and atropine 0.5% (8.9%, 39). Eighty-six percent (394) of the respondents advised to spend more time outdoors, to reduce the amount of time viewing screens (60.2%, 277), and cutback the use of smart phones (63.9%, 294). Conclusions Most pediatric ophthalmologists treat to decrease myopia. They employ a wide variety of means to decrease myopia progression. Atropine 0.01% is the most popular and safe modality used similarly to recent reports. However, there is no consensus when treatment should be initiated. Further prospective studies are needed to elucidate the best timing to start treatment and the applicability of recent studies in the Asian population to other ethnic groups. This will improve the ability to update pediatric ophthalmologist with evidenced-based treatment options to counter the myopia epidemic

On Myopia as Rationale for Social Security

This paper revisits the role played by myopia in generating a theoretical rationale for pay-as-you-go social security in dynamically efficient economies. Contrary to received wisdom, if the real interest rate is exogenously fixed, enough myopia may justify public pensions but never alongside positive private savings. With sufficient myopia, co-existence of positive optimal pensions and positive private saving is possible if the real interest rate on saving evolves endogenously, as in a model with a neoclassical technology.myopia, pensions, social security, dynamic efficiency

Myopia and defocus: the current understanding

The current theories relating to the development and progression of myopia are related to exposure of the eye to hyperopic defocus. This paper discusses these theories and the large body of recent research investigating the evidence behind them. As both human and animal studies demonstrate, when considering the potential influence of defocus on eye growth, the duration of exposure as well as the type and magnitude of the blur are important. In addition, we must understand the defocus threshold over which an eye growth signal can be made. Investigations with respect to central defocus alone have been unable to find a unified theory due to (1) insufficient evidence showing refractive group differences in the amount of central defocus actually present and (2) unsuccessful attempts to wholely reduce myopia progression using corrective lenses. Recent research measuring peripheral blur is summarised in this paper and modelled together with previous measurements of peripheral defocus thresholds, providing an up-to-date perspective on myopia.</jats:p

Time outdoors and the prevention of myopia

Recent epidemiological evidence suggests that children who spend more time outdoors are less likely to be, or to become myopic, irrespective of how much near work they do, or whether their parents are myopic. It is currently uncertain if time outdoors also blocks progression of myopia. It has been suggested that the mechanism of the protective effect of time outdoors involves light-stimulated release of dopamine from the retina, since increased dopamine release appears to inhibit increased axial elongation, which is the structural basis of myopia. This hypothesis has been supported by animal experiments which have replicated the protective effects of bright light against the development of myopia under laboratory conditions, and have shown that the effect is, at least in part, mediated by dopamine, since the D2-dopamine antagonist spiperone reduces the protective effect. There are some inconsistencies in the evidence, most notably the limited inhibition by bright light under laboratory conditions of lens-induced myopia in monkeys, but other proposed mechanisms possibly associated with time outdoors such as relaxed accommodation, more uniform dioptric space, increased pupil constriction, exposure to UV light, changes in the spectral composition of visible light, or increased physical activity have little epidemiological or experimental support. Irrespective of the mechanisms involved, clinical trials are now underway to reduce the development of myopia in children by increasing the amount of time they spend outdoors. These trials would benefit from more precise definition of thresholds for protection in terms of intensity and duration of light exposures. These can be investigated in animal experiments in appropriate models, and can also be determined in epidemiological studies, although more precise measurement of exposures than those currently provided by questionnaires is desirable

Habit Formation and Labor Supply

This paper shows that the combination of habit formation - present consumption creating additional consumption needs in the future - and myopia may explain why some retirees are forced to ‘unretire’, i.e., unexpectedly return to work. It also shows that when myopia about habit formation leads to unretirement there is a case for government's intervention. In a first-best setting the optimal solution can be decentralized by a simple ‘Pigouvian’ (paternalistic) consumption tax (along with suitable lump-sum taxes). In a second-best setting, when personalized lump-sum transfers are not available, consumption taxes may have conflicting paternalistic and redistributive effects. We study the design of consumption taxes in such a setting when myopic individuals differ in productivity.habit formation, myopia, unretiring

On Myopia As Rationale for Social Security

It has been argued that "paternalistically motivated forced savings constitutes an important, and to some the most important, rationale for social security retirement systems." This paper revisits the role played by myopia in generating a theoretical rationale for pay-as-you-go social security in dynamically efficient economies. If the competing asset is linear storage and myopic agents are allowed to borrow against future pension benefits, there is no welfare-rationale for pay-as-you-go pensions. In that case, sufficently-strong myopia may justify such pensions only if agents cannot borrow against their future pension, and are at a zero-saving corner. With enough myopia, co-existence of positive optimal pensions and positive private saving is possible if the return to saving declines with saving, as in a model with a neoclassical technology.myopia; pensions; social security; dynamic efficiency

Myopes have significantly higher serum melatonin concentrations than non-myopes

Purpose Experimental animal models of myopia demonstrate that higher melatonin (Mel) and lower dopamine (DA) concentrations actively promote axial elongation. This study explored the association between myopia and serum concentrations of DA and Mel in humans. Methods Morning serum concentrations of DA and Mel were measured by solid phase extraction‐liquid chromatography‐tandem mass spectrometry from 54 participants (age 19.1 ± 0.81 years) in September/October 2014 (phase 1) and March/April 2016 (phase 2). Axial length (AL), corneal radii (CR) and spherical equivalent refraction (SER) were also recorded. Participants were defined as myopic if non‐cycloplegic spherical equivalent refractive error ≤−0.50 DS at phase 1. Results Nine participants were lost to follow up. Mel concentrations were measurable for all myopes (phase 1 n = 25, phase 2 n = 22) and non‐myopes (phase 1 n = 29, phase 2 n = 23). SER did not change significantly between phases (p = 0.51). DA concentrations were measurable for fewer myopes (phase 1 n = 13, phase 2 n = 12) and non‐myopes (phase 1 n = 23, phase 2 n = 16). Myopes exhibited significantly higher Mel concentrations than non‐myopes at phase 1 (Median difference: 10 pg mL−1, p &lt; 0.001) and at phase 2 (Median difference: 7.3 pg mL−1, p &lt; 0.001) and lower DA concentrations at phase 2 (Median difference: 4.7 pg mL−1, p = 0.006). Mel concentrations were positively associated with more negative SER (all r ≥ −0.53, all p &lt; 0.001), longer AL (all r ≥ 0.37, all p ≤ 0.008) and higher AL/CR ratio (all r ≥ 0.51, all p &lt; 0.001). Conclusion This study reports for the first time in humans that myopes exhibit higher serum Mel concentrations than non‐myopes. This may indicate a role for light exposure and circadian rhythm in the human myopic growth mechanism. Further research should focus on younger cohorts exhibiting more dynamic myopic progression and explore the profile of these neurochemicals alongside evaluation of sleep patterns in myopic and non‐myopic groups

Human PrimPol mutation associated with high myopia has a DNA replication defect

PrimPol is a primase-polymerase found in humans, and other eukaryotes, involved in bypassing lesions encountered during DNA replication. PrimPol employs both translesion synthesis and repriming mechanisms to facilitate lesion bypass by the replisome. PrimPol has been reported to be a potential susceptibility gene associated with the development of myopia. Mutation of tyrosine 89 to aspartic acid (PrimPolY89D) has been identified in a number of cases of high myopia, implicating it in the aetiology of this disorder. Here, we examined whether this mutation resulted in any changes in the molecular and cellular activities associated with human PrimPol. We show that PrimPolY89D has a striking decrease in primase and polymerase activities. The hydrophobic ring of tyrosine is important for retaining wild-type extension activity. We also demonstrate that the decreased activity of PrimPolY89D is associated with reduced affinities for DNA and nucleotides, resulting in diminished catalytic efficiency. Although the structure and stability of PrimPolY89D is altered, its fidelity remains unchanged. This mutation also reduces cell viability after DNA damage and significantly slows replication fork rates in vivo. Together, these findings establish that the major DNA replication defect associated with this PrimPol mutant is likely to contribute to the onset of high myopia