Circadian rHythms and theiR associatiON with myOPIA

Project Information

CHRONOPIA

Grant agreement ID: 101153901

DOI

10.3030/101153901

EC signature date 17 April 2024

Start date 1 June 2024

End date 31 May 2027

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 278 435,04

Coordinated by

TARTU ULIKOOL
Estonia

Periodic Reporting for period 1 - CHRONOPIA (Circadian rHythms and theiR associatiON with myOPIA)

Reporting period: 2024-06-01 to 2026-05-31

Summary of the context and overall objectives of the project

Myopia, or short-sightedness, usually develops when the eye grows too long, causing distant images to be focused in front of the retina. Although vision can generally be corrected with glasses or contact lenses, myopia is not a harmless condition. It increases the lifetime risk of retinal detachment, glaucoma, cataract and myopic macular degeneration, all of which can lead to permanent visual impairment. Its prevalence is rising rapidly: approximately 23% of the global population was affected in 2000, and this proportion is projected to reach around 50% by 2050. The associated global economic burden has also been estimated to rise substantially, reflecting healthcare costs, loss of productivity and the effect of visual impairment on quality of life.
Both genetic and environmental factors influence myopia. Insufficient time outdoors and prolonged near work are recognised risk factors, but growing evidence also points to a relationship with sleep and circadian rhythms, the internal biological processes that organise daily patterns of behaviour and physiology. Children with myopia have been reported to have later and more irregular sleep schedules, while genetic variants associated with refractive errors are enriched near genes involved in molecular clock regulation. Previous human analyses underlying CHRONOPIA also identified associations between chronotype, social jet lag, sleep duration and refractive errors. However, observational associations alone cannot establish whether altered circadian timing contributes to abnormal eye growth, whether refractive errors themselves disturb retinal rhythms, or whether both arise through shared biological mechanisms.
CHRONOPIA addresses these gaps by investigating the relationship between circadian rhythms and myopia from several complementary perspectives. First, it examines whether changing environmental light-dark timing alters refractive development and susceptibility to myopia. Second, it investigates how experimentally induced myopia affects daily molecular rhythms and gene expression in the retina. Third, it compares genes and biological pathways identified in mouse models with human genetic findings to determine which mechanisms may be shared across species and therefore most relevant to human myopia.
The project combines controlled animal experiments, ocular imaging, retinal RNA sequencing, circadian biology, bioinformatics and human genetics. This interdisciplinary approach links experimental evidence about causality and biological mechanisms with population-level human data. In the longer term, the results are expected to improve understanding of how environmental light timing, retinal biology and genetic susceptibility interact in myopia. They may also improve the design and interpretation of experimental models, support the identification of candidate molecular targets and provide a stronger evidence base for future prevention and treatment research. Because even a modest reduction in the prevalence or progression of myopia could reduce visual impairment and its economic and societal burden, the project has potential relevance for researchers, eye-care professionals and public-health stakeholders.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the first reporting period, mice were housed under shortened, standard and extended light-dark cycles. Refractive error, ocular dimensions and corneal curvature were measured over time to determine how changes in environmental timing affected eye development. An extended light-dark cycle induced a shift towards myopia, whereas a shortened cycle did not produce a significant refractive change. Follow-up experiments examined whether these effects could still be induced or reversed in adult mice. Switching adult mice from standard to extended light-dark conditions induced myopia, while the reverse switch promoted recovery. A second experimental model was used to determine whether adult refractive plasticity was specific to altered light-dark timing or represented a broader feature of the adult mouse eye. Adult mice were susceptible to lens-induced myopia, could recover from it and could develop myopia again after a further challenge. Retinal RNA-sequencing analyses were performed to characterise molecular responses in young and adult mice. A retinal transcriptomic time-course dataset was also generated from myopic and control eyes. The remaining transcriptomic and pathway analyses are ongoing and will be completed during the incoming phase. Preparatory work for the mouse-human comparison included identification of relevant human genetic datasets, development of approaches for orthologue mapping and pathway comparison, and publication of a meta-analysis of retinal transcriptomic studies across animal models of myopia. This meta-analysis identified recurrent genes and biological pathways and established methodological groundwork for the next phase of the project.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project has produced evidence that changing only the timing of environmental light exposure can influence refractive development. This provides a new experimental basis for investigating how circadian disruption and daily light timing may affect eye growth. A particularly important finding is that adult mice retain substantially more refractive plasticity than previously recognised. Myopia could be induced and reversed in adult animals using altered light-dark timing, and adult mice also responded to lens-induced myopia. These findings challenge the prevailing assumption that mouse susceptibility to experimental myopia is largely limited to early development. The results may improve the design and interpretation of future myopia studies. Experimental models performed only at very young ages may not fully represent the later developmental timing of human myopia. Adult models may therefore provide additional opportunities to study myopia induction, recovery and recurrence. The RNA-sequencing datasets and cross-model meta-analysis provide a basis for identifying candidate genes, retinal cell types and biological pathways involved in refractive development. Further impact will be achieved by completing the ongoing analyses and integrating the results with human genetic data, as planned for the next phase of the project. The expected long-term impact is improved understanding of myopia biology and stronger foundations for future prevention and treatment research.