Cognitive, behavioural, environmental and genetic associations of myopia in the Twins Early Development Study

Myopia, or short-sightedness, occurs when the image of a viewed object is not focused accurately onto the retina (refractive error), specifically in myopia the image is focussed in front of the retina. This results in the observer seeing a blurred image and requires correction in the form of glasses or contact lenses. Myopia is the most common eye condition worldwide. Failure of adequate correction of myopia leaves a child with a visual disability that can affect development, education and future prospects. The World Health Organization (WHO) has identified 153 million people who are visually impaired due to uncorrected refractive errors. The identification and treatment of myopia is now a WHO priority within their initiative to eliminate avoidable blindness.

People with myopia, especially those developing myopia in childhood, as they are likely to become highly myopic by adulthood, are additionally at risk of sight threatening problems such as retinal "wear and tear" degeneration or retinal detachment. The number of people with myopia is increasing; in some countries up to 80% of children leaving school are myopic, and we believe this means that there is going to be an increasing problem of blindness in middle aged and older people due to this common problem. It is not known what is driving this increase although it is known that both a person's genes and environment are influential; previous studies have identified potential risk factors such as prolonged close work, urbanisation and lack of outdoor light.

The aim of this study is to examine the complex influence of genes and environment on a person's risk of developing myopia in a large cohort of British twins. The unique Twins Early Development Study (TEDS) consists of over 10,000 twins who have been studied since birth to their current age of around18 years old. TEDS researchers have assessed the relative influence of nature (genes) and nurture (environment) on aspects of cognition, language, behaviour and education. Previous research has yielded interesting findings on shared genetic influences for diverse learning disabilities and abilities. We plan to correlate this data with the level of myopia at the age of 18. Sophisticated statistical techniques will be used to investigate the relative effects and interactions between a person's genes and their environment on the risk of developing myopia. We also plan to use advanced genetic techniques to identify potential genetic variations (changes in the DNA) that could cause myopia in this age group using DNA that 4,000 of the twins have previously provided.

This research will be carried within Kings College London by collaborators from both TEDS and the Department of Genetic Epidemiology and Twin Research (TwinsUK). The research will be undertaken by researchers in ophthalmology (doctors specialising in eye diseases), in partnership with geneticists and statisticians.

We hope this research will provide novel information on why myopia develops and why the incidence is increasing. A estimate of the level of myopia in this age group within the UK will be obtained and an increased undertstanding of the environmental and genetic influences causing the disease, which can only be obtained from twin studies. This may enable targeted lifestyle modifications or development of treatments that could reduce myopia development or progression in the future.

Aim: To examine the environmental and genetic factors for myopia using the Twins Early Development Study (TEDS)

Objectives:
1. Obtain a prevalence estimate of school-onset myopia in the UK
2. Examine the relationship between refractive error and educational, behavioural and cognitive traits
3. Determine myopia heritability at age 18 and investigate the relative effect of genes and environment
4. Perform a genome wide association study (GWAS) for myopia at this age
5. Examine the role of common variants identified from adult GWAS in myopia
6. Assess gene-environment interactions in myopia

Methodology:
Refractive data, obtained from 5,000 of the 18-year-old TEDS cohort using optometry assessments, will enable a current estimate of myopia prevalence in this age group. Measures of cognition, behaviour and education over childhood development, uniquely studied by TEDS researchers, will allow detailed exploration of environmental influences on myopia. Quantitative genetic techniques (maximum likelihood, multivariate structural equation twin models) will be used to investigate heritability and whether genetic influences on myopia and intelligence, and other factors, are shared or separate. GWAS will be used to search for novel common genetic variants for myopia in this age group and the role of variants identified in older populations will be tested. Identified genetic polymorphisms and high quality data on environmental factors during childhood, will enable examination of gene-environment interactions.

Scientific and medical opportunities:
This project will provide data, currently unavailable, on myopia prevalence in the UK young adult population, and a unique opportunity to explore aetiological factors in this age group. Exploring environmental influences on myopia, together with novel or replicated genetic variants, and their interactions, will have significant implications for future treatment development to slow progression and visual impairment.

The proposed research study is timely and important. The World Health Organisation has highlighted refractive error and the associated visual impairment as a key target in its initiative to eliminate avoidable blindness. The sight threatening problems associated with myopia, such as myopic macula degeneration and retinal detachment, are likely to become an increasing problem as the prevalence of myopia increases globally. This has implications in terms of visual impairment burden but also financially, due to the increased public costs required for appropriate detection and treatment of refractive error.

In terms of directing future research it is very relevant that myopia has a high level of heritability. Research to date has failed to fully explain this heritability in terms of genetic susceptibility loci nor distinguish which variations are correlated with school-onset myopia, the cohort in whom high myopia and its increased risk of sight threatening complications is most likely to develop. Aetiological research into environmental risk factors continues to provide clues into why myopia may develop but many studies are limited by size and retrospective bias, and crucially, to date, no study has comprehensively analysed genetic and environmental influences in parallel.

This study is unique in terms of the cohort, the largest adolescent twin cohort in the UK today, and its extensive data on childhood development. There is no comparable opportunity to study school-onset myopia in the UK and the excellent quality of the cohort means there is potential for this research to make a significant impact in our understanding of how genes and the environment can affect risk of myopia.

These findings would be of interest to a number of parties, namely ophthalmologists, optometrists, geneticists, public health bodies and the general public. Ophthalmologists, optometrists and other scientists investigating myopia aetiology will benefit from the increased understanding of how genetic traits and environmental differences through childhood development can affect myopia risk. This has benefits in terms directing further research, and aiding clinical practice. Geneticists researching myopia are yet to fully understand the traits involved in this complex disease but the increased genetic data this study alone and in collaboration with similarly aged matched cohorts will enable a greater potential to produce significant results. Public health bodies and the private sector are likely to benefit in terms of the provision of a sound evidence base for planning services required for this, the most common ocular condition. Finally the general public are likely to take a keen interest in myopia research, a condition many of them will have, in terms of an increased understanding of why they may have developed the condition, the risk to other family members and potential ways in which progression of myopia could be modified.

In the timescale of this fellowship this proposal has the potential to yield prevalence data, information of environmental risk factors, statistical analysis of the relative effects of genes and environment and potentially identify new polymorphisms associated with myopia. This impressive timescale to produce results is enabled by the previous investment of significant time and money in creating such a well-characterised twin cohort with detailed data on both childhood development and the genome. Further impact from this study may take longer to produce benefit but it would be hoped that potential lifestyle modifications and treatment development for myopia could enter the clinical trial phase in 5-10 years.