Gene x gene and gene x environment interactions underlying speech, language and reading development

Lead Research Organisation: University of Oxford
Department Name: Wellcome Trust Centre for Human Genetics

Abstract

About 5% of school-children have difficulties with reading skills and development of language that are not due to low intelligence or inadequate educational opportunity. These problems are called specific reading disability (dyslexia) and specific language impairment (SLI). For both disorders there is evidence for contribution from both genetic and environmental factors that probably have to act together. Research advances have now identified several of these factors of both genetic and environmental nature. The aim of this proposal is to test how different risk factors interact with one another in order to cause dyslexia and SLI, as we wanted to find the correct order for the many pieces of a complicated jigsaw puzzle.
We will carry out our research in the ALSPAC sample, a large project that has collected an extensive variety of information on more than 10,000 children born in Southwest England between 1991-92. We will be able to combine all the variables of our study in the ALSPAC sample. We can use the DNA from the children for genetic analysis, and we can access their scores on measures of language and reading skills, together with the relevant information about the environment where they are growing up. We will be able to look at data ranging from diet details to the number of books the children could access during their infancy.
This research investigates whether there is a connection between specific combinations of predisposing factors and performance in well-defined measures of language and reading skills. The aim is to identify sub-groups of children for whom it will be possible to design more targeted and, therefore, more effective intervention therapies. This project will also contribute to develop strategies for early diagnosis of these disorders, which is fundamental to the implementation of intervention programs. For example, dyslexia is currently diagnosed when children are exposed to written language at school, often too late to start a successful theraphy. The detection of predisposing genetic factors, environmental exposures and their interplay will help to identify those children of pre-school age who might benefit from receiving specialised help. The identification of environmental factors that increase the likelihood of developing dyslexia or SLI might also have an important impact on prevention.
Ultimately, this project will contribute to our understanding of the mechanisms underlying behaviour and cognition.

Technical Summary

Dyslexia is a specific difficulty in learning to read that cannot be explained by obvious causes. Specific Language Impairment (SLI) is a marked impairment in the development of expressive and/or receptive language. Both SLI and dyslexia are complex traits most likely caused by multiple genetic and environmental factors. Research progress to date has identified several individual risk factors both of genetic and environmental nature.
The major aim of this project is to investigate how these factors interact with one another by specifically conducting 1) a gene x gene interaction analysis to test whether the interaction of different dyslexia and SLI susceptibility variants contribute to determine the two disorders; 2) a gene x environment interaction analysis to test whether environmental factors contribute in modulating the effect of genes associated with dyslexia and SLI; and 3) an analysis to test whether the observed co-morbidity between dyslexia and SLI is determined by shared genetic or environmental factors and whether it is possible to identify a correlation between genetic/environmental background and specific sub-groups of phenotypes.
We will conduct our analysis in the ALSPAC sample, a large epidemiological cohort characterised by comprehensive longitudinal records of the pregnancies and deliveries, socio-economical and medical conditions, assessments on a wide range of physical, behavioural and neuropsychological traits. We will genotype the entire ALSPAC cohort (N = 10,000) for markers within candidate genes for dyslexia and SLI, using the Sequenom iPLEX technology which allows the analysis of up to 40 markers simultaneously. For the analysis we will select a wide range of measures of reading, language and articulation which have been collected from participants at ALSPAC annual visits from years 7 and 13. We will also use related cognitive phenotype measures of attention and hyperactivity behaviour since attention deficit hyperactivity disorder (ADHD) shows extensive co-morbidity with both dyslexia and SLI. The environmental factors will include measures that have already been proposed as risk factors for dyslexia and SLI such as home literacy environment and Omega-3 fatty acid consumption, or family structure and parental sensitivity.
The understanding of the interplay of multiple factors will be crucial to define the aetiology of these common disorders as well as the mechanisms underlying important aspects of cognition and behaviour, such as language and literacy skills. This project will have important clinical implications in the future for diagnosis and implementation of more effective therapies.

Publications

10 25 50
 
Description Butterfield Awards
Amount £3,000 (GBP)
Organisation The Great Britain Sasakawa Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2015 
End 02/2016
 
Description Collaborative Research Fund (as co-applicannt; Prof Cammie McBride is the PI)
Amount HK$7,511,385 (HKD)
Funding ID CUHK8/CRF/13G 
Organisation Research Grants Council Hong Kong 
Sector Public
Country China
Start 05/2014 
End 04/2018
 
Description Deutsche Forschungsgemeinschaft (DFG) Mobility Fellowship; A multi-level approach on the relation between laterality and neurodevelopmental traits.
Amount € 80,000 (EUR)
Organisation German Research Foundation 
Sector Public
Country Germany
Start 04/2019 
End 03/2021
 
Description Hong Kong : Scotland Collaborative Research Partnerships
Amount £20,000 (GBP)
Organisation Government of Scotland 
Department Scottish Funding Council
Sector Public
Country United Kingdom
Start 01/2015 
End 12/2015
 
Description ISSF
Amount £150,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 10/2015
 
Description PhD Scholarship
Amount £64,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Reading, writing, and mathematics: Behavioral genetics and neuromarkers of early academic achievement in Hong Kong Chinese children Renewal
Amount HK$8,669,815 (HKD)
Organisation Research Grants Council Hong Kong 
Sector Public
Country China
Start 01/2018 
End 12/2022
 
Description Research Grant
Amount £150,000 (GBP)
Funding ID RG110387 
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 05/2015
 
Description Royal Society Enhancement Award
Amount £92,500 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 05/2018 
End 04/2022
 
Description Royal Society International Seminars
Amount £5,000 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 04/2016 
End 04/2016
 
Description St Leonards Interdisciplinary Scholarship
Amount £70,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 09/2019 
End 08/2022
 
Description Startup package
Amount £250,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 12/2016
 
Description The Waterloo Foundation Grant
Amount £38,228 (GBP)
Funding ID 797/1720 
Organisation The Waterloo Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2016
 
Description Two PhD scholarships
Amount £110,000 (GBP)
Organisation University of St Andrews 
Sector Academic/University
Country United Kingdom
Start 09/2013 
End 08/2016
 
Description University Research Fellowship
Amount £521,713 (GBP)
Organisation The Royal Society 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2016
 
Description Vacation Scholarship
Amount £1,500 (GBP)
Organisation University of St Andrews 
Department Institute of Behavioural and Neural Sciences (IBANS)
Sector Academic/University
Country United Kingdom
Start 05/2012 
End 07/2012
 
Description Wolfson Intercalated Degree Awards 2012/13
Amount £5,000 (GBP)
Organisation Royal College of Physicians of London 
Sector Academic/University
Country United Kingdom
Start 02/2013 
End 05/2013
 
Title ALSPAC sample/phenotype identification 
Description Through our analysis we have identified children with dyslexia and language problems in the ALSPAC samples and derived some phenotypic measures to conduct genetic association analysis. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2010 
Provided To Others? Yes  
Impact This analytical tools have been entered in the ALSPAC database and can now be used by other reserchers for future research. 
 
Description ALSPAC 
Organisation University of Bristol
Department Avon Longitudinal Study of Parents and Children (ALSPAC)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been working with partners at the Univ. St Andrews to assess the contributions of genetic across known candidate genes to language/reading ability in the ALSPAC cohort
Collaborator Contribution ALPSAC hold the data, Univ of St Andrews lead the project
Impact We have had three papers published using the ALPSAC data and continue to use this as a replication cohort.
Start Year 2010
 
Description ALSPAC 
Organisation University of St Andrews
Department School of Medicine St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been working with partners at the Univ. St Andrews to assess the contributions of genetic across known candidate genes to language/reading ability in the ALSPAC cohort
Collaborator Contribution ALPSAC hold the data, Univ of St Andrews lead the project
Impact We have had three papers published using the ALPSAC data and continue to use this as a replication cohort.
Start Year 2010
 
Description Currie 
Organisation University of St Andrews
Department School of Medicine St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution We will analyse gene x enviroment interactions at the basis of early puberty which is associated with a wide range of poor health outcomes. We will conduct secondary analysis on exisitng datasets. I lead the genetic analysis.
Collaborator Contribution my collaborator leads the phenotypic and behavioural analyses.
Impact This is a multidisciplinary collaboration bridging expertise in human genetics, epidemiology and public health. From 2015 Prof. Candace and I are co-supervising a PhD student
Start Year 2013
 
Description Dholakia 
Organisation University of St Andrews
Department School of Physics and Astronomy
Country United Kingdom 
Sector Academic/University 
PI Contribution Contribute cell and molecular biology side of the project
Collaborator Contribution Biophotonics technology applied to investigate biological questions
Impact Funding for a PhD scholarship Multidisciplinary: physics and genetics
Start Year 2013
 
Description Kent 
Organisation University of St Andrews
Department School of Medicine St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution Gene expression analysis
Collaborator Contribution Access to sudden death brain collection
Impact none
Start Year 2012
 
Description MPI 
Organisation Max Planck Society
Country Germany 
Sector Charity/Non Profit 
PI Contribution Collaboration in a large GWAS
Collaborator Contribution Collaboration on a large GWAS
Impact Two papers published and other in preparation
Start Year 2012
 
Description McBride 
Organisation Chinese University of Hong Kong
Department Department of Psychology
Country China 
Sector Academic/University 
PI Contribution We will take forward the genetic association with quantitative measures of handedness in additional cohorts. We will conduct genetic and statistical analyses.
Collaborator Contribution Prof McBride (Chinese University of Hing Kong) will implete the collection of phenotypic measures for handedness in a cohort of bilingual twins aimed at study language and literacy development.
Impact This collaboration has led to the award of two grants: 1) led by Prof McBride and awarded through the Research Grant funding (Hong Kong) Collaborative Reaserch Greant Scheme 2) led by myself and awarded by the Hong Kong : Scotland Collaborative Research Partnerships scheme This collaboration is a multidisciplinary bridging expertise in human genetics, behavioural genetics, genomics, psychology and child development.
Start Year 2013
 
Description Nacenta 
Organisation University of St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution Describe problem/solution to advance my research program
Collaborator Contribution Expertise to implement solution, develop computer-base cognitive test to collect data in the clinics where we recruit study participants fr fenetic studies
Impact NA
Start Year 2015
 
Description Petretto 
Organisation University of Cagliari
Country Italy 
Sector Academic/University 
PI Contribution DNA collection from patients
Collaborator Contribution Genetic screening
Impact Visiting Professor at University of Cagliari award Multidisciplinary: psychology and genetics
Start Year 2012
 
Description RAINE sample 
Organisation Telethon Kids Institute
Country Australia 
Sector Academic/University 
PI Contribution We have started this collaboration with with the University of Western Australia to use the RAINE cohort (Australia) as a replication sample of our results obtained in ALSPAC. We are applying the statistical analysis we use for the ALSPAC sample on the RAINE cohort.
Collaborator Contribution Through this collaboration we have access to the RAINE cohort to replicate our genetic associations with cognitive phenotypes
Impact We have published one paper: Paracchini S, Ang QW, Stanley FJ, Monaco AP, Pennell CE, and Whitehouse AJO. (2010) Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population. Genes, Brain and Behavior. And we have a manuscript in preparation This is a multidisciplinary collaboration requiring genetics, psychology and epidemiology expertise. My group is mainly involved in the genetic analysis while Dr. Whitehouse has expertise in psychology.
Start Year 2010
 
Description Seki 
Organisation Tottori University
Department Department of Regional Education
Country Japan 
Sector Academic/University 
PI Contribution We will conduct genetic analysis on a cohort selected for dyslexia in Japan
Collaborator Contribution Our partner will collect participants and conduct phenotypic assessment
Impact Multidisplinary collaborations across human genetics and child psychology
Start Year 2013
 
Description Sillar 
Organisation University of St Andrews
Department School of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular biology and selection of putative functional genetic elements
Collaborator Contribution Electrophysiology and zebrafish
Impact Funding for PhD scholarship
Start Year 2013
 
Description Stella 
Organisation University of Modena and Reggio Emilia
Country Italy 
Sector Academic/University 
PI Contribution Genetic screening
Collaborator Contribution DNA collection from patients
Impact Multidisciplinary: psychology and genetics
Start Year 2013
 
Description York 
Organisation University of York
Department Centre for Reading and Language (CRL)
Country United Kingdom 
Sector Academic/University 
PI Contribution Genetic analysis
Collaborator Contribution Collection of clinical samples (biological samples and phenotypes)
Impact none
Start Year 2011
 
Description A-level workshop 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I gave a presentation about my work to A-level students visiting our department for a one-day workshop.

None
Year(s) Of Engagement Activity 2010
 
Description ABSW event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact I gave a presentation at the Association of British Science Writers: Genomics day trip event (Oxford, UK). My talk included details of this project.

none
Year(s) Of Engagement Activity 2009
 
Description Book Helping children with dyslexia 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I contributed some of the science sections in a book by author Liz Dunoon aimed at parents of children with dyslexia. My role has been to make my work accessible to a wider audience and trying to explain what dyslexia is. I specifically reported some of the results obtained in the ALSPAC cohort.

The book has had a significant success and since its release it received lots of media attention in Australia.
Year(s) Of Engagement Activity 2010
URL http://www.helpingchildrenwithdyslexia.com/
 
Description Cafe Scientifique 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Café Scientifique at the Royal Society in London. The event was very popular and followed by post in Social Media which had a reach of over > 50,000 views.
http://www.iflscience.com/health-and-medicine/why-are-some-people-left-handed
Year(s) Of Engagement Activity 2015
URL https://royalsociety.org/events/2015/02/cafe-handedness/
 
Description Genetics of handedness 
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 Public/other audiences
Results and Impact This PR was extremely successful and our results have been reported widely by the media including on-line stories, printed article and radio interviews. It has been widely covered by social media like twitter.

Following this event I have been contacted by several members of the public to further discuss our work.
Year(s) Of Engagement Activity 2013
 
Description Podcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact This podcast received significant interest via Twitter

none
Year(s) Of Engagement Activity 2011
URL http://www.ndm.ox.ac.uk/silvia-paracchini-dyslexia-and-genetics
 
Description Press release - genetics of dyslexia 
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 Media interviews following press realease for one of our papers.

none
Year(s) Of Engagement Activity 2008
URL http://uk.reuters.com/article/2008/10/01/uk-science-dyslexia-gene-idUKTRE49012H20081001
 
Description Royal Society Summer Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact I delivered six talks during the Royal Society Summer Festival 2016. The target audience were secondary school pupils but the event was open to the general public. More than 100 pupil attended each talk and they show high engagement. Each talk was followed by questions and many pupils came up afterwards to ask questions in person.
Year(s) Of Engagement Activity 2016
URL https://royalsociety.org/science-events-and-lectures/2016/07/schools-talk-paracchini/
 
Description SOS dislessia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I presented at a national meeting organised by an Italia Dyslexia charity aimed at teachers, educators and therapists. My talk was attended by more tah 600 people and generated lots of interest. I recevied many questions and positive feedback from attemdees and organisers.
Year(s) Of Engagement Activity 2017
URL http://www.sosdislessia.it/event/tinsegno-o-timparo/
 
Description press release PCSK6 gene 
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 This press release got good coverage from the media and was reported in different newspapare/magazines at International level.
We had a even highe covarage in a follow up story in 2013

Following the online publication many people wrote comments to the article when possible and this paper was discussed in dyslexia-related blogs.
Year(s) Of Engagement Activity 2010,2013
URL http://www.sciencedaily.com/releases/2013/09/130912203216.htm