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(B) DEVELOPMENTAL 1. News 2. People 3. Overview 4. Research (II) CHROMOSOMES 6 & 18 (III) New!! Dyslexia / SLI Project 5. Funders 6. Publications 7. Links 8. Contact
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NEUROGENETICS & PSYCHIATRIC DISORDERS: Neurodevelopmental and Neurological Disorders Group Professor Anthony P. Monaco - Group Head
DEVELOPMENTAL DYSLEXIA RESEARCH TEAM
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DEVELOPMENTAL DYSLEXIA RESEARCH TEAM |
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| Dr Clotilde Lévecque | clotilde.levecque@well.ox.ac.uk |
| Dr Silvia Paracchini | silviap@well.ox.ac.uk |
| Mr Tom Scerri | thomas.scerri@well.ox.ac.uk |
| Dr Antonio Velayos-Baeza | avelayos@well.ox.ac.uk |
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Ms Megan Dennis (*Now working at NIH) |
dennism@od.nih.gov |
3. Overview
What is dyslexia?
About 5% of school-age 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 developmental dyslexia and specific language impairment (SLI).
Developmental dyslexia is also known as specific reading disability (ICD classification). It is the most common of the childhood learning disorders.
Children affected with developmental dyslexia have difficulty learning to read and spell, despite adequate intelligence and educational opportunity, and in the absence of any profound sensory or neurological impairment.
Reading deficits can have a major influence on the cognitive, emotional and social development of affected individuals.
The precise cause(s) of reading disability remains unknown. Different theories have been proposed to explain the underlying neurological and cognitive causes:
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Supporters of the phonological theory attribute the causes of the reading impairment exclusively to a cognitive deficit specific to the representation and processing of speech sounds.
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Conversely, although there is a general agreement in recognising the phonological deficit in dyslexic individuals, this is often considered a secondary effect of a much broader impairment.
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In fact, three other theories have connected the causes of reading impairment to auditory processing, visual processing and motor control deficits.
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The magnocellular theory is an attempt to integrate all these observations, postulating that failures in the magnocellular system (magnocells are large neurones in the brain) will affect both sensory modalities (visual, auditory, and tactile) and motor control. (More here: on magnocellular theory)
Links for further reading on dyslexia
Is dyslexia genetic?
The familial clustering of reading and spelling disability was first noted at the turn of the century.
However, the fact that dyslexia tends to run in families does not necessarily implicate genetic factors, since familial clustering can also be caused by shared family environment.
The strongest evidence of genetic influences on dyslexia has come from twin studies, which compare the concordance of the trait in identical (monozygotic) and non-identical (dizygotic) twin pairs.
A large-scale twin-study based in Colorado, USA has found that the heritability of dyslexia (i.e. the proportion of trait variability that can be explained by genetic factors) is more than 50%.
What are our goals?
We aim to track down the genes that are involved in developmental dyslexia.
We are searching for the specific genetic variants that increase the risk of developing dyslexia.
We use state-of-the-art technology to analyse hundreds of genetic markers in large numbers of families with children affected by dyslexia.
The results of our initial studies have been published in a number of scientific journals.
Our work in this area is now continuing, with the aim of improving understanding of the genetic factors influencing dyslexia. (See below: current research)
4. Research
4.1 The genetics of developmental dyslexia
There is likely to be significant involvement of genetic factors in predisposing towards dyslexia. However, dyslexia is a complex genetic disorder. It does not appear to be inherited as a single gene disorder, but instead seems to be caused by a number of different genes that combine and interact with environmental factors to produce an overall risk factor for developing dyslexia.
(More here: on complex genetic disorders).
Over the past 15 years or so, there has been remarkable success tracking down genes for single-gene disorders, such as cystic fibrosis, Duchenne muscular dystrophy and Huntington’s disease. Unfortunately, such approaches are not usually powerful enough for complex genetic disorders such as dyslexia.
Recently, however, novel strategies have been developed that are more appropriate for finding genes influencing complex disorders. We have used these techniques in our research, with the aim to identify the specific genes implicated in dyslexia.
(More here: on techniques for researching genetic disorders).
For a more comprehensive account of what we currently know about the genetics of dyslexia see this article, published in the October 2002 issue of Nature Reviews Neuroscience.
4.2 Initial studies
A number of genetic studies of dyslexia indicate that there is likely to be a gene influencing reading disability on chromosome 6. Regions on chromosomes 1, 2, 3 and 15 have also been implicated in susceptibility to reading problems.
However, prior to our investigation no-one had completed a systematic search of all the chromosomes in large samples of families with developmental dyslexia. This suggested that significant genetic effects influencing this trait might have gone undetected.
In our initial study, we therefore carried out a complete genome scan, of all chromosomes of the entire human genome, using the latest methods for genetic analysis of complex traits. We initially used two separate samples of families having a child diagnosed with dyslexia (one sample from from the UK, the other from the USA). This was the first time that a complete genome scan had been run on a large sample of dyslexic families.
As in previous analyses, we found clear support for a region on chromosome 6 being linked to dyslexia. However, what was more interesting was that we also detected a strong effect on chromosome 18. We also found evidence for regions of interest in chromosomes 2 and 3. We then replicated our findings using a new set of UK families.
The results of our initial study were published in January 2002 (1).
COMPLETE GENOME SCAN: further details here
Following on from our initial study, we looked in more detail at the region of interest on chromosome 6.
We first identified a risk haplotype for dyslexia spanning three genes in this region. The results of this study was published in 2004 (2)
Subsequently, we focused our research on the most promising of these three genes, KIAA0319 (OMIM 609269). The results of this study was published in 2006 (3).
Focus on chromosome 6: further details here
4.3 Current research
Overall, our initial studies provided us with a comprehensive genome-wide view of the most likely locations of genes influencing dyslexia in our samples. However, this is really just the starting point for the search.
As with all analyses of complex genetic disorders, we cannot be certain that we are looking at real effects until we have tracked down the specific genetic variants that are responsible. And even then it might be tough to prove!
Having scanned the entire genome and identified regions that might contain genes influencing the measures of reading disability, we and others are trying to replicate the findings in independent sets of families.
In addition, we are targeting these regions using more genetic markers and more sensitive statistical methods, to try and pin-point the positions of the risk genes as accurately as possible.
The genome screen is therefore just the first step in a long process, referred to as positional cloning, which should eventually enable us to isolate specific gene variants that influence developmental dyslexia.
Our current research focuses on the following three projects:
New Project! Dyslexia / SLI Project: "Gene-gene and gene-environment interactions underlying speech, language and reading development"
This new project ....
Focus on chromosomes 6 and 18
We are currently investigating in more detail candidate genes from regions of interest on chromosome 6 and chromosome 18.
Neurodys project
We are currently collaborating with Neurodys, a new European research consortium on dyslexia
4.4 Collaborators
The Developmental Dyslexia research team is currently working with the following collaborators:
At the Wellcome Trust Centre for Human Genetics (WTCHG):
Dr Simon Fisher: Group Head, Research Group on Dissecting Neuromolecular Mechanisms that are Critical for Speech and Language.
Dr Lon Cardon, Dr Andrew Morris: Genetic Epidemiology Research Group.
External collaborators:
University of Oxford, Department of Physiology, Anatomy and Genetics: Prof. John Stein Alex Richardson Janet Walter
The Neurodys dyslexia research consortium
University College London: Andy Copp
University of Connecticut, Department of Physiology: Joe LoTurco
Aston University, Department of Psychology: Joel Talcott Ian Richards
University of Colorado, Institute for Behavioral Genetics: John DeFries, Dr Shelley Smith Prof. Richard Olson Prof. Bruce Pennington,
5. Funders
The Developmental Dyslexia project is funded by grants from the following funders:
European Union (EU) Cordis FP6
(Sixth EU Framework Program
for Research and Technological Development)
6. Publications
Most recent publications (from 2006):
2009
New Paper! The dyslexia-associated protein KIAA0319 interacts with Adaptor Protein 2 and follows the classical clathrin-mediated endocytosis pathway.
Levecque C, Velayos-Baeza A, Holloway ZG, Monaco AP.
In Am J Physiol Cell Physiol. 2009 May 6. [Epub ahead of print] [PMID: 19419997] [Open Access pdf]
New Paper! A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene
Megan Y. Dennis, Silvia Paracchini, Thomas S. Scerri, Ludmila Prokunina-Olsson, Julian C. Knight, Richard Wade-Martins, Penny Coggill, Stephan Beck, Eric D. Green, Anthony P. Monaco.
In PLOS Genetics March 2009 vol 5(3). [Link to full article (open access pdf)]
2008
Association of the KIAA0319 Dyslexia Susceptibility Gene With Reading Skills in the General Population (2008)
Silvia Paracchini, Colin D. Steer, Lyn-Louise Buckingham, Andrew P. Morris, Susan Ring, Thomas Scerri, John Stein, Marcus E. Pembrey, Jiannis Ragoussis, Jean Golding, and Anthony P. Monaco.
Am J Psychiatry: Advanced online publication. Published October 1, 2008 doi: 10.1176/appi.ajp.2008.07121872
[Abstract]
2007
The Dyslexia-Associated Gene KIAA0319 encodes highly N- and O-Glycosylated plasma mebrane and secreted isoform (2007)
Antonio Velayos-Baeza, Claudio Toma, Silvia Paracchini, Anthony P. Monaco.
Human Molecular Genetics: Advanced online publication.
[Full article] [PubMed record]
The Genetic Lexicon of Dyslexia (2007)
Silvia Paracchini, Thomas Scerri, Anthony P. Monaco.
Annual Review of Genomics and Human Genetics: 8. September 2007
[Full article] [PubMed record]
Alternative splicing in the dyslexia-associated gene KIAA0319. (2007)
Antonio Velayos-Baeza, Claudio Toma, Stephanie da Roza, Silvia Paracchini, Anthony P. Monaco.
Mammalian Genome: Online first, September 2007.
[Abstract] [PubMed record]
2006
The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration (2006)
Silvia Paracchini, Ankur Thomas, Sandra Castro, Cecilia Lai, Murugan Paramasivam, Yu Wang, Brendan J. Keating, Jennifer M. Taylor, Douglas F. Hacking, Thomas Scerri, Clyde Francks, Alex J. Richardson, Richard Wade-Martins, John F. Stein, Julian C. Knight, Andrew J. Copp, Joseph LoTurco and Anthony P. Monaco.
Human Molecular Genetics. 15: 10 1659–1666
[Full article] [PubMed record]Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. (2006)
Harold D*, Paracchini S*, Scerri T, Dennis M, Cope N, Hill G, Moskvina V, Walter J, Richardson AJ, Owen MJ, Stein JF, Green ED, O'Donovan MC, Williams J, Monaco AP.
*Joint authorship.
Mol Psychiatry. 11(12):1085-1091.
[PubMed record]
List of all publications: Click here
7. Links
8. Contact
For all enquiries, please contact Dr Silvia Paracchini at silviap@well.ox.ac.uk
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