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

Lead Research Organisation: King's College London
Department Name: Diabetes & Nutritional Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Baneke AJ (2018) A twin study of cilioretinal arteries, tilted discs and situs inversus. in Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie

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Cuellar-Partida G (2017) Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study. in International journal of epidemiology

 
Description ARVO 2015 Travel Grant
Amount $1,100 (USD)
Organisation Association for Research in Vision and Ophthalmology 
Sector Charity/Non Profit
Country United States
Start 05/2015 
End 05/2015
 
Description Fight for Sight - Trainee Research Network Award
Amount £5,000 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 02/2021
 
Description Fight for Sight Award 2017
Amount £5,000 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 06/2019
 
Title TEDS Myopia dataset 
Description Database of refractive error on approximately 2000 twins from the TEDS dataset 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Collaborative publications 
 
Description CREAM 
Organisation Consortium for Refractive Error and Myopia
Country Singapore 
Sector Charity/Non Profit 
PI Contribution Data contribution to consortium for refractive error and myopia meta-analysis of genome wide association and gene environment interaction for myopia in children
Collaborator Contribution Similar contribution of above data
Impact n/a
Start Year 2013
 
Description European Eye Epidemiology Consortium 
Organisation European Epidemiology Eye Consortium
Country European Union (EU) 
Sector Charity/Non Profit 
PI Contribution Member of refractive error working group and lead analyst of meta-analysis
Collaborator Contribution Sharing and meta-analysis of epidemiological data on eye disease across Europe
Impact Two first author manuscripts in review
Start Year 2012
 
Description UK Biobank 
Organisation UK Biobank
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Joined group and attended annual meeting 2015, 2017
Collaborator Contribution Planning to become involved in future genetic analyses as data is released
Impact Publications planned
Start Year 2015
 
Description 2013 International Myopia Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Presentation at the biennial meeting for myopia researchers - sharing of ideas with other researchers in the field

strengthening established collaborations and forming new ones (eg. UK Myopia Consortium)
Year(s) Of Engagement Activity 2013
 
Description ARVO 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Research meeting

Further collaborations and publications
Year(s) Of Engagement Activity 2014
 
Description ARVO 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Conference presentation to international research community in myopia
Year(s) Of Engagement Activity 2015
 
Description ARVO 2016 and RCOphth Congress 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Conference presentations
Year(s) Of Engagement Activity 2016
 
Description ARVO 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presentation of work at a conference. I was also invited to moderate this session
Year(s) Of Engagement Activity 2017
 
Description Interview for Health Check on BBC World Service 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Radio interview at BBC headquarters for feature on myopia and my research
Year(s) Of Engagement Activity 2017
 
Description Interview for London BBC News following press release of my publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interview with myself as first author on publication of research paper
Interview with reporter at my house
Year(s) Of Engagement Activity 2018
 
Description Media interviews associated with press release for publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed on publications regarding increasing prevalence of myopia in Europe. Phone interview with independent, guardian and press teams which distributed to daily mail, and others. Radio interview with BBC West midlands.
Year(s) Of Engagement Activity 2015
 
Description Media interviews associated with press release for publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by Daily Mail, NY times magazine, La Presse (Montreal), BBC Health Check (radio interview and latter filmed for digital media)
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/p04qnwgg
 
Description Ulverscroft Research in Progress Seminar, Institute of Child Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Methodology and future plans discussed with clinicians and biostatisticians following presentation

Adjustment to analysis methods
Year(s) Of Engagement Activity 2013