Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
Nature Genetics (Impact Factor: 29.35). 02/2002; 30(1):86-91. DOI: 10.1038/ng792
Source: PubMed


Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.

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Available from: Javier Gayán, Oct 07, 2015
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    • "The first candidate susceptibility genes for DD were identified based on studies of rare chromosomal translocations localizing within the implicated genetic loci on chromosome 15 (DYX1, gene DYX1C1) [17] and chromosome 3 (DYX5, gene ROBO1) [18]. Parallel efforts employed genetic fine-mapping based on assessing associations at increasing resolution, and yielded two candidate DD genes on chromosome 6 (DYX2, genes DCDC2 and KIAA0319) [19] [20] [21] [22], chromosome 2 (DYX3, genes C2Orf3 and MRPL19) [23] and somewhat later on chromosome 18 (DYX6, genes MC5R, DYM and NEDD4L) [24] [25]. A cluster of additional four genes was suggested on the basis of a submicroscopic deletion of chromosome 21 (genes PCNT2, DIP2A, S100B, and PRMT2) [26], even though this locus had not been previously recognized by genetic linkage studies. "
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    ABSTRACT: Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or reading disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.
    Biochemical and Biophysical Research Communications 09/2014; 452(2). DOI:10.1016/j.bbrc.2014.07.102 · 2.30 Impact Factor
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    • "(Bates et al., 2007); HMGB1 on the longer arm of chromosome 13 (13q12.3) (Igo et al., 2006) and VAPA on the shorter arm of chromosome 18 (18p11.2) (Bates et al., 2007; Fisher, Francks, Marlow et al., 2002). "
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    ABSTRACT: Neuroimaging has had an enormous impact on the way human cognition is studied in vivo. With the advent of fMRI, scientists have been able to ask questions regarding individual differences which could not have been addressed with PET. These, are particularly important for studying developmental disorders, such as dyslexia because research suggests that participants with dyslexia (DPs) form a heterogeneous population. There are three main theories of dyslexia: the phonological (PDT), visual magnocellular (MDT) and cerebellar (CDT). The majority of neuroimaging studies, motivated by these theories, have shortcomings. First, they have relied on group comparisons which can obscure the less frequent differences between DPs and controls (CPs). Second, they mostly tested one underlying cause, postulated by one theory. Third, the majority of them focused on detecting a deficit without empirically demonstrating its relationship with reading deficit which defines this disorder. The goal of this research is to shed more light on the neural correlates of reading deficit in dyslexia and address these criticisms. First, by using a multiple case study to investigate individual differences among DPs. Such comparisons would not have been possible with PET. Second, by contrasting the predictions, of each of the main theories, on the neural correlates of the reading impairment in one sample of DPs. The behavioural studies suggest that there are subtypes of dyslexia, however, they cannot be tested by focusing on one theory. Third, by using a reading task and fMRI - which provides an opportunity for directly testing the relationship between the predictions of a given theory and the neural correlates of reading impairment. Eighteen individual DPs and 16 CPs were tested in a multiple case study. Participants were right-handed, with native English, normal vision and hearing and without clinical ADHD and DCD. To ensure that no confounds were present due to differences between a DP and CPs in IQ, handedness and age, these were entered into the analysis as covariates. The neuroimaging task involved silent reading of individual words and fixating on a cross (baseline) in an event-related design. Four findings were revealed. First, the neural correlates of reading deficit in dyslexia in all cases, except one, are consistent with the predictions of the PDT and CDT, in one case with the visual MDT and in ten cases with a hypothetical visual (not magnocellular) deficit theory; most cases are consistent with more than one theory. Second, there are considerable individual differences in the neural correlates of reading deficit. Even where they are consistent with the same theory in two DPs, the areas can differ. Third, the results reveal that the lack of deficit on a behavioural test does not mean that the neural correlates of reading are intact. Fourth, a large number of DPs who have a similar profile on the behavioural measures exhibited dissimilar profiles on the neural level. These findings suggest that endophenotypes uncovered by neuroimaging will enable researchers to find important links between the behavioural and genetic characteristics of DPs. Multidisciplinary research on individual differences, including neuroimaging, behavioural and genetic measures within a multiple-deficit model holds significant promise.
    Advances in Neuroimaging Research, Edited by Victoria Asher-Hansley, 05/2014: chapter 1: pages 1-119; Nova Science Publishers., ISBN: 978-1-63321-307-4
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    • "The affected individuals in this family showed significantly lower performance in tasks for phonological awareness, rapid naming and verbal short-term memory. A subsequent study found linkage to 3p13 in a British sample, and 3q13 in an American sample, both within the linkage region found in the initial study (Fisher et al. 2002). In that study, measures of phonological memory and reading showed significant linkage. "
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    ABSTRACT: Linkage studies have identified a locus on chromosome 3 as reading disabilities (RD) and speech and sound disorder (SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 (ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population-based sample. In this study, we conducted a family-based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms (SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation with ROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele (P = 0.001), correlated with low expression. This SNP is located ~200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples (P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene.
    Genes Brain and Behavior 03/2014; 13(4). DOI:10.1111/gbb.12126 · 3.66 Impact Factor
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