209 research outputs found
Dissection of genetic associations with language-related traits in population-based cohorts
No full textThe author was supported by the Wellcome Trust [076566/Z/05/Z]; [075491/Z/04] and the Medical Research Council [G0800523/86473].Recent advances in the field of language-related disorders have led to the identification of candidate genes for specific language impairment (SLI) and dyslexia. Replication studies have been conducted in independent samples including population-based cohorts, which can be characterised for a large number of relevant cognitive measures. The availability of a wide range of phenotypes allows us to not only identify the most suitable traits for replication of genetic association but also to refine the associated cognitive trait. In addition, it is possible to test for pleiotropic effects across multiple phenotypes which could explain the extensive comorbidity observed across SLI, dyslexia and other neurodevelopmental disorders. The availability of genome-wide genotype data for such cohorts will facilitate this kind of analysis but important issues, such as multiple test corrections, have to be taken into account considering that small effect sizes are expected to underlie such associations.Peer reviewe
Reading and language disorders : the importance of both quantity and quality
No full textReading and language disorders are common childhood conditions that often co-occur with each other and with other neurodevelopmental impairments. There is strong evidence that disorders, such as dyslexia and Specific Language Impairment (SLI), have a genetic basis, but we expect the contributing genetic factors to be complex in nature. To date, only a few genes have been implicated in these traits. Their functional characterization has provided novel insight into the biology of neurodevelopmental disorders. However, the lack of biological markers and clear diagnostic criteria have prevented the collection of the large sample sizes required for well-powered genome-wide screens. One of the main challenges of the field will be to combine careful clinical assessment with high throughput genetic technologies within multidisciplinary collaborations.Peer reviewe
Recent advances in handedness genetics
No full textFunding: SP is supported by the Royal Society.Around the world, about 10% people prefer using their left-hand. What leads to this fixed proportion across populations and what determines left versus right preference at an individual level is far from being established. Genetic studies are a tool to answer these questions. Analysis in twins and family show that about 25% of handedness variance is due to genetics. In spite of very large cohorts, only a small fraction of this genetic component can be pinpoint to specific genes. Some of the genetic associations identified so far provide evidence for shared biology contributing to both handedness and cerebral asymmetries. In addition, they demonstrate that handedness is a highly polygenic trait. Typically, handedness is measured as the preferred hand for writing. This is a very convenient measure, especially to reach large sample sizes, but quantitative measures might capture different handedness dimensions and be better suited for genetic analyses. This paper reviews the latest findings from molecular genetic studies as well as the implications of using different ways of assessing handedness.Peer reviewe
Hand preference and mathematical learning difficulties: New data from Greece, the United Kingdom, and Germany and two meta-analyses of the literature
No full textSP and FA are funded by the Royal Society. The UK Medical Research Council and Wellcome Trust (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Silvia Paracchini will serve as guarantors for the reporting of the ALSPAC analysis in this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf).Increased rates of atypical handedness are observed in neurotypical individuals who are low-performing in mathematical tasks as well as in individuals with special educational needs, such as dyslexia. This is the first investigation of handedness in individuals with Mathematical Learning Difficulties (MLD). We report three new studies (N = 134; N = 1,893; N = 153) and two sets of meta-analyses (22 studies; N = 3,667). No difference in atypical hand preference between MLD and Typically Achieving (TA) individuals was found when handedness was assessed with self-report questionnaires, but weak evidence of a difference was found when writing hand was the handedness criterion in Study 1 (p = .049). Similarly, when combining data meta-analytically, no hand preference differences were detected. We suggest that: (i) potential handedness effects require larger samples, (ii) direction of hand preference is not a sensitive enough measure of handedness in this context, or that (iii) increased rates of atypical hand preference are not associated with MLD. The latter scenario would suggest that handedness is specifically linked to language-related conditions rather than conditions related to cognitive abilities at large. Future studies need to consider hand skill and degree of hand preference in MLD.Peer reviewe
Novel tools and cellular models to study the function of the dyslexia susceptibility gene KIAA0319
No full textDyslexia is a disorder that impairs reading skills and is strongly influenced by genes. One of the genes more robustly associated with dyslexia is KIAA0319. This gene is highly expressed in brain during embryonic life and some studies suggest that it plays a role in neuronal migration. KIAA0319 is a transmembrane protein, the structure of which is consistent with a role in mediating interactions between cells or between cells and the extracellular matrix. Traditional molecular methods and animal models have been used to investigate its function but have failed to unveil its molecular mechanism.
The recent development of CRISPR-Cas9 has opened possibilities for the study of genes associated with disorders by simplifying the editing of DNA and the modulation of gene expression. The work described in this thesis applied these new methods to the study of KIAA0319 and led to the development of new tools to investigate genes implicated in complex disorders.
I used CRISPR-Cas9 to eliminate the start codon and to generate mutations that cause premature stop codons in KIAA0319 in RPE1 cell line. These modified cell lines present differences in attachment, migration and cilia length compared to the wild type. I have also used CRISPR-Cas9 to attach a GFP tag to the endogenous KIAA0319 in HEK293 cells to study the dynamics of the protein. The observation of this tagged cell line suggests that the expression of KIAA0319 in HEK293 is very low and restricted to a small percentage of the cells.
In parallel I developed light sensitive gene upregulation systems based on the nuclease-null dCas9, that combine dCas9 proteins originated in different species of microorganisms with a strong transcriptional activator. These systems respond to blue light and are able to upregulate an inducible GFP reporter
In Troyer Syndrome Spartin loss induces Complex I impairments and alters pyruvate metabolism
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