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.
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.
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.
Organisations
- University of Oxford, United Kingdom (Lead Research Organisation)
- Telethon Kids Institute (Collaboration)
- University of St Andrews, United Kingdom (Collaboration)
- Max Planck Society (Collaboration)
- University of Bristol, United Kingdom (Collaboration)
- University of Modena and Reggio Emilia (Collaboration)
- Tottori University (Collaboration)
- University of Cagliari, Italy (Collaboration)
- Chinese University of Hong Kong (Collaboration)
- University of York, United Kingdom (Collaboration)
Publications

Paracchini S
(2017)
Lateralized Brain Functions


Pettigrew KA
(2015)
Lack of replication for the myosin-18B association with mathematical ability in independent cohorts.
in Genes, brain, and behavior

Nudel R
(2014)
Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment.
in Genes, brain, and behavior

Newbury DF
(2014)
Reading and language disorders: the importance of both quantity and quality.
in Genes

Brandler WM
(2014)
The genetic relationship between handedness and neurodevelopmental disorders.
in Trends in molecular medicine

Brandler WM
(2013)
Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.
in PLoS genetics

Paracchini S
(2011)
Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population.
in Genes, brain, and behavior

Paracchini S
(2011)
Dissection of genetic associations with language-related traits in population-based cohorts.
in Journal of neurodevelopmental disorders

Newbury DF
(2011)
Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects.
in Behavior genetics

Scerri TS
(2011)
PCSK6 is associated with handedness in individuals with dyslexia.
in Human molecular genetics

Newbury DF
(2009)
CMIP and ATP2C2 modulate phonological short-term memory in language impairment.
in American journal of human genetics
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 | Charity/Non Profit |
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 | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2012 |
End | 05/2015 |
Description | Royal Society Enhancement Award |
Amount | £92,500 (GBP) |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2018 |
End | 04/2022 |
Description | Royal Society International Seminars |
Amount | £5,000 (GBP) |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
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 | Charity/Non Profit |
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 | Learned Society |
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 | Hong Kong |
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 | Charity/Non Profit |
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 |