Publications by authors named "Silvia Paracchini"

39 Publications

A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures.

Hum Mol Genet 2021 Apr 16. Epub 2021 Apr 16.

School of Medicine, University of St Andrews, St Andrews, UK.

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.
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http://dx.doi.org/10.1093/hmg/ddab111DOI Listing
April 2021

Hand preference and Mathematical Learning Difficulties: New data from Greece, the United Kingdom, and Germany and two meta-analyses of the literature.

Laterality 2021 Apr 6:1-54. Epub 2021 Apr 6.

Department of Psychology, National and Kapodistrian University of Athens, Athens, Greece.

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 ( = 134;  = 1,893;  = 153) and two sets of meta-analyses (22 studies;  = 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 ( = .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.
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http://dx.doi.org/10.1080/1357650X.2021.1906693DOI Listing
April 2021

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Mol Psychiatry 2020 Oct 14. Epub 2020 Oct 14.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience and Maastricht Brain Imaging Center (M-BIC), Maastricht University, Maastricht, The Netherlands.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p  < 2.8 × 10) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p  = 8 × 10), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10), educational attainment (0.86[0.82; 0.91]; p = 2 × 10), and intelligence (0.72[0.68; 0.76]; p = 9 × 10). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.
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http://dx.doi.org/10.1038/s41380-020-00898-xDOI Listing
October 2020

Four meta-analyses across 164 studies on atypical footedness prevalence and its relation to handedness.

Sci Rep 2020 09 2;10(1):14501. Epub 2020 Sep 2.

Institute of Cognitive Neuroscience, Biopsychology, Department of Psychology, Ruhr University Bochum, Universitätsstraße 150, 44780, Bochum, Germany.

Human lateral preferences, such as handedness and footedness, have interested researchers for decades due to their pronounced asymmetries at the population level. While there are good estimates on the prevalence of handedness in the population, there is no large-scale estimation on the prevalence of footedness. Furthermore, the relationship between footedness and handedness still remains elusive. Here, we conducted meta-analyses with four different classification systems for footedness on 145,135 individuals across 164 studies including new data from the ALSPAC cohort. The study aimed to determine a reliable point estimate of footedness, to study the association between footedness and handedness, and to investigate moderating factors influencing footedness. We showed that the prevalence of atypical footedness ranges between 12.10% using the most conservative criterion of left-footedness to 23.7% including all left- and mixed-footers as a single non-right category. As many as 60.1% of left-handers were left-footed whereas only 3.2% of right-handers were left-footed. Males were 4.1% more often non-right-footed compared to females. Individuals with psychiatric and neurodevelopmental disorders exhibited a higher prevalence of non-right-footedness. Furthermore, the presence of mixed-footedness was higher in children compared to adults and left-footedness was increased in athletes compared to the general population. Finally, we showed that footedness is only marginally influenced by cultural and social factors, which play a crucial role in the determination of handedness. Overall, this study provides new and useful reference data for laterality research. Furthermore, the data suggest that footedness is a valuable phenotype for the study of lateral motor biases, its underlying genetics and neurodevelopment.
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http://dx.doi.org/10.1038/s41598-020-71478-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468297PMC
September 2020

Different laterality indexes are poorly correlated with one another but consistently show the tendency of males and females to be more left- and right-lateralized, respectively.

R Soc Open Sci 2020 Apr 15;7(4):191700. Epub 2020 Apr 15.

School of Medicine, University of St Andrews, Saint Andrews, Fife, UK.

The most common way to assess handedness is based on the preferred hand for writing, leading to a binary (left or right) trait. Handedness can also be assessed as a continuous trait with laterality indexes, but these are not time- and cost-effective, and are not routinely collected. Rarely, different handedness measures are collected for the same individuals. Here, we assessed the relationship of preferred hand for writing with four laterality indexes, reported in previous literature, derived from measures of dexterity (pegboard task, marking squares and sorting matches) and strength (grip strength), available in a range of = 6664-8069 children from the ALSPAC cohort. Although all indexes identified a higher proportion of individuals performing better with their right hand, they showed low correlation with each other (0.08-0.3). Left handers were less consistent compared to right handers in performing better with their dominant hand, but that varied across indexes, i.e. 13% of left handers performed better with their right hand on marking squares compared to 48% for sorting matches and grip strength. Analysis of sex effects on the laterality indexes showed that males and females tend to be, on all measures, more left- and right-lateralized, respectively. Males were also over-represented among the individuals performing equally with both hands suggesting they had a higher tendency to be weakly lateralized. This study shows that different handedness measures tap into different dimensions of laterality and cannot be used interchangeably. The trends observed across indexes for males and females suggest that sex effects should be taken into account in handedness and laterality studies.
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http://dx.doi.org/10.1098/rsos.191700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211879PMC
April 2020

Prevalence and heritability of handedness in a Hong Kong Chinese twin and singleton sample.

BMC Psychol 2020 Apr 22;8(1):37. Epub 2020 Apr 22.

School of Medicine, University of St Andrews, St. Andrews, Scotland.

Background: Left-handedness prevalence has been consistently reported at around 10% with heritability estimates at around 25%. Higher left-handedness prevalence has been reported in males and in twins. Lower prevalence has been reported in Asia, but it remains unclear whether this is due to biological or cultural factors. Most studies are based on samples with European ethnicities and using the preferred hand for writing as key assessment. Here, we investigated handedness in a sample of Chinese school children in Hong Kong, including 426 singletons and 205 pairs of twins, using both the Edinburgh Handedness Inventory and Pegboard Task.

Results: Based on a binary definition of writing hand, we found a higher prevalence of left-handedness (8%) than what was previously reported in Asian datasets. We found no evidence of increased left-handedness in twins, but our results were in line with previous findings showing that males have a higher tendency to be left-handed than females. Heritability was similar for both hand preference (21%) and laterality indexes (22%). However, these two handedness measures present only a moderate correlation (.42) and appear to be underpinned by different genetic factors.

Conclusion: In summary, we report new reference data for an ethnic group usually underrepresented in the literature. Our heritability analysis supports the idea that different measures will capture different components of handedness and, as a consequence, datasets assessed with heterogeneous criteria are not easily combined or compared.
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http://dx.doi.org/10.1186/s40359-020-00401-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178737PMC
April 2020

Human handedness: A meta-analysis.

Psychol Bull 2020 06 2;146(6):481-524. Epub 2020 Apr 2.

School of Medicine.

Across time and place, right hand preference has been the norm, but what is the precise prevalence of left- and right-handedness? Frequency of left-handedness has shaped and underpinned different fields of research, from cognitive neuroscience to human evolution, but reliable distributional estimates are still lacking. While hundreds of empirical studies have assessed handedness, a large-scale, comprehensive review of the prevalence of handedness and the factors that moderate it, is currently missing. Here, we report 5 meta-analyses on hand preference for different manual tasks and show that left-handedness prevalence lies between 9.3% (using the most stringent criterion of left-handedness) to 18.1% (using the most lenient criterion of nonright-handedness), with the best overall estimate being 10.6% (10.4% when excluding studies assessing elite athletes' handedness). Handedness variability depends on (a) study characteristics, namely year of publication and ways to measure and classify handedness, and (b) participant characteristics, namely sex and ancestry. Our analysis identifies the role of moderators that require taking into account in future studies on handedness and hemispheric asymmetries. We argue that the same evolutionary mechanisms should apply across geographical regions to maintain the roughly 1:10 ratio, while cultural factors, such as pressure against left-hand use, moderate the magnitude of the prevalence of left-handedness. Although handedness appears as a straightforward trait, there is no universal agreement on how to assess it. Therefore, we urge researchers to fully report study and participant characteristics as well as the detailed procedure by which handedness was assessed and make raw data publicly available. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/bul0000229DOI Listing
June 2020

A novel mutation in gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.

FASEB J 2019 10 7;33(10):11284-11302. Epub 2019 Aug 7.

Department of Medical and Surgical Sciences (DIMEC), St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Loss-of-function mutations in the gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in leads to a profound bioenergetic imbalance.-Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.
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http://dx.doi.org/10.1096/fj.201802722RDOI Listing
October 2019

Genomic Imprinting As a Window into Human Language Evolution.

Bioessays 2019 06;41(6):e1800212

School of Biology, University of St Andrews, Dyers Brae, St Andrews, KY16 9TH, UK.

Humans spend large portions of their time and energy talking to one another, yet it remains unclear whether this activity is primarily selfish or altruistic. Here, it is shown how parent-of-origin specific gene expression-or "genomic imprinting"-may provide an answer to this question. First, it is shown why, regarding language, only altruistic or selfish scenarios are expected. Second, it is pointed out that an individual's maternal-origin and paternal-origin genes may have different evolutionary interests regarding investment into language, and that this intragenomic conflict may drive genomic imprinting which-as the direction of imprint depends upon whether investment into language is relatively selfish or altruistic-may be used to discriminate between these two possibilities. Third, predictions concerning the impact of various mutations and epimutations at imprinted loci on language pathologies are derived. In doing so, a framework is developed that highlights avenues for using intragenomic conflicts to investigate the evolutionary drivers of language.
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http://dx.doi.org/10.1002/bies.201800212DOI Listing
June 2019

The dyslexia susceptibility KIAA0319 gene shows a specific expression pattern during zebrafish development supporting a role beyond neuronal migration.

J Comp Neurol 2019 11 16;527(16):2634-2643. Epub 2019 Apr 16.

School of Medicine, University of St Andrews, St Andrews, UK.

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA-interference studies in rats suggested a role in neuronal migration whereas subsequent work with double knock-out mouse models for both Kiaa0319 and its paralogue Kiaa0319-like reported effects in the auditory system but not in neuronal migration. To further understand the role of KIAA0319 during neurodevelopment, we carried out an expression study of its zebrafish orthologue at different embryonic stages. We used different approaches including RNAscope in situ hybridization combined with light-sheet microscopy. The results show particularly high expression during the first few hours of development. Later, expression becomes localized in well-defined structures. In addition to high expression in the brain, we report for the first time expression in the eyes and the notochord. Surprisingly, kiaa0319-like, which generally shows a similar expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription start site, in both zebrafish and humans. This study supports a developmental role for KIAA0319 in the brain as well as in other developing structures, particularly in the notochord which, is key for establishing body patterning in vertebrates.
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http://dx.doi.org/10.1002/cne.24696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767054PMC
November 2019

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.

Transl Psychiatry 2019 02 11;9(1):77. Epub 2019 Feb 11.

School of Life and Health Sciences, Aston University, Birmingham, UK.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10) and with all the cognitive traits tested (p = 3.07 × 10), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-10]) and negatively associated with ADHD PRS (p ~ [10-10]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
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http://dx.doi.org/10.1038/s41398-019-0402-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370792PMC
February 2019

The neuronal migration hypothesis of dyslexia: A critical evaluation 30 years on.

Eur J Neurosci 2018 11 6;48(10):3212-3233. Epub 2018 Oct 6.

Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.

The capacity for language is one of the key features underlying the complexity of human cognition and its evolution. However, little is known about the neurobiological mechanisms that mediate normal or impaired linguistic ability. For developmental dyslexia, early postmortem studies conducted in the 1980s linked the disorder to subtle defects in the migration of neurons in the developing neocortex. These early studies were reinforced by human genetic analyses that identified dyslexia susceptibility genes and subsequent evidence of their involvement in neuronal migration. In this review, we examine recent experimental evidence that does not support the link between dyslexia and neuronal migration. We critically evaluate gene function studies conducted in rodent models and draw attention to the lack of robust evidence from histopathological and imaging studies in humans. Our review suggests that the neuronal migration hypothesis of dyslexia should be reconsidered, and the neurobiological basis of dyslexia should be approached with a fresh start.
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http://dx.doi.org/10.1111/ejn.14149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282621PMC
November 2018

Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes.

J Neurodev Disord 2016 14;8:24. Epub 2016 Jun 14.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF UK.

Background: Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5-10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required.

Methods: We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia.

Results: We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study.

Conclusions: A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits.
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http://dx.doi.org/10.1186/s11689-016-9157-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908686PMC
June 2016

The handedness-associated PCSK6 locus spans an intronic promoter regulating novel transcripts.

Hum Mol Genet 2016 05 21;25(9):1771-9. Epub 2016 Feb 21.

School of Medicine, University of St Andrews, St Andrews KY169TF, UK,

We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 × 10(-8)) for a relative hand skill measure in individuals with dyslexia. PCSK6 activates Nodal, a morphogen involved in regulating left-right body axis determination. Therefore, the GWAS data suggest that the biology underlying the patterning of structural asymmetries may also contribute to behavioural laterality, e.g. handedness. The association is further supported by an independent study reporting a variable number tandem repeat (VNTR) within the same PCSK6 locus to be associated with degree of handedness in a general population cohort. Here, we have conducted a functional analysis of the PCSK6 locus combining further genetic analysis, in silico predictions and molecular assays. We have shown that the previous GWAS signal was not tagging a VNTR effect, suggesting that the two markers have independent effects. We demonstrated experimentally that one of the top GWAS-associated markers, rs11855145, directly alters the binding site for a nuclear factor. Furthermore, we have shown that the predicted regulatory region adjacent to rs11855415 acts as a bidirectional promoter controlling the expression of novel RNA transcripts. These include both an antisense long non-coding RNA (lncRNA) and a short PCSK6 isoform predicted to be coding. This is the first molecular characterization of a handedness-associated locus that supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation.
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http://dx.doi.org/10.1093/hmg/ddw047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986331PMC
May 2016

Copy Number Variation Screen Identifies a Rare De Novo Deletion at Chromosome 15q13.1-13.3 in a Child with Language Impairment.

PLoS One 2015 11;10(8):e0134997. Epub 2015 Aug 11.

School of Medicine, University of St Andrews, St Andrews, United Kingdom.

A significant proportion of children (up to 7% in the UK) present with pronounced language difficulties that cannot be explained by obvious causes like other neurological and medical conditions. A substantial genetic component is predicted to underlie such language problems. Copy number variants (CNVs) have been implicated in neurodevelopmental and psychiatric conditions, such as autism and schizophrenia, but it is not fully established to what extent they might contribute to language disorders. We conducted a CNV screen in a longitudinal cohort of young children with language-related difficulties (n = 85), focusing on single events at candidate loci. We detected a de novo deletion on chromosome 15q13.1-13.3. The adjacent 15q11-13.1 locus is disrupted in Prader-Willi and Angelman syndromes, while disruptions across the breakpoints (BP1-BP6) have previously been implicated in different neurodevelopmental phenotypes including autism, intellectual disability (ID), seizures and developmental delay (DD). This is the first report of a deletion at BP3-BP5 being linked to a deficit confined to language impairment, in the absence of ID, expanding the range of phenotypes that implicate the chromosome 15q13 locus.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532445PMC
May 2016

Reading and language disorders: the importance of both quantity and quality.

Genes (Basel) 2014 Apr 4;5(2):285-309. Epub 2014 Apr 4.

School of Medicine, University of St. Andrews, St. Andrews, Fife KY16 9AJ, UK.

Reading 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.
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http://dx.doi.org/10.3390/genes5020285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094934PMC
April 2014

The genetic relationship between handedness and neurodevelopmental disorders.

Trends Mol Med 2014 Feb 23;20(2):83-90. Epub 2013 Nov 23.

School of Medicine, University of St Andrews, St Andrews, KY16 9TF, UK. Electronic address:

Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia. The genetic nature of this correlation is not understood. Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development. Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation. Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum. These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.
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http://dx.doi.org/10.1016/j.molmed.2013.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969300PMC
February 2014

Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia.

Dev Med Child Neurol 2014 Apr 9;56(4):346-53. Epub 2013 Oct 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Aim: Sex chromosome aneuploidies increase the risk of spoken or written language disorders but individuals with specific language impairment (SLI) or dyslexia do not routinely undergo cytogenetic analysis. We assess the frequency of sex chromosome aneuploidies in individuals with language impairment or dyslexia.

Method: Genome-wide single nucleotide polymorphism genotyping was performed in three sample sets: a clinical cohort of individuals with speech and language deficits (87 probands: 61 males, 26 females; age range 4 to 23 years), a replication cohort of individuals with SLI, from both clinical and epidemiological samples (209 probands: 139 males, 70 females; age range 4 to 17 years), and a set of individuals with dyslexia (314 probands: 224 males, 90 females; age range 7 to 18 years).

Results: In the clinical language-impaired cohort, three abnormal karyotypic results were identified in probands (proband yield 3.4%). In the SLI replication cohort, six abnormalities were identified providing a consistent proband yield (2.9%). In the sample of individuals with dyslexia, two sex chromosome aneuploidies were found giving a lower proband yield of 0.6%. In total, two XYY, four XXY (Klinefelter syndrome), three XXX, one XO (Turner syndrome), and one unresolved karyotype were identified.

Interpretation: The frequency of sex chromosome aneuploidies within each of the three cohorts was increased over the expected population frequency (approximately 0.25%) suggesting that genetic testing may prove worthwhile for individuals with language and literacy problems and normal non-verbal IQ. Early detection of these aneuploidies can provide information and direct the appropriate management for individuals.
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http://dx.doi.org/10.1111/dmcn.12294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293460PMC
April 2014

Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.

PLoS Genet 2013 12;9(9):e1003751. Epub 2013 Sep 12.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom ; MRC Functional Genomics Unit, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom.

Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
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http://dx.doi.org/10.1371/journal.pgen.1003751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772043PMC
March 2014

Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort.

Eur J Hum Genet 2014 May 11;22(5):675-80. Epub 2013 Sep 11.

Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience & Maastricht Brain Imaging Institute (M-BIC), Maastricht University, Maastricht, The Netherlands.

Dyslexia is one of the most common childhood disorders with a prevalence of around 5-10% in school-age children. Although an important genetic component is known to have a role in the aetiology of dyslexia, we are far from understanding the molecular mechanisms leading to the disorder. Several candidate genes have been implicated in dyslexia, including DYX1C1, DCDC2, KIAA0319, and the MRPL19/C2ORF3 locus, each with reports of both positive and no replications. We generated a European cross-linguistic sample of school-age children - the NeuroDys cohort - that includes more than 900 individuals with dyslexia, sampled with homogenous inclusion criteria across eight European countries, and a comparable number of controls. Here, we describe association analysis of the dyslexia candidate genes/locus in the NeuroDys cohort. We performed both case-control and quantitative association analyses of single markers and haplotypes previously reported to be dyslexia-associated. Although we observed association signals in samples from single countries, we did not find any marker or haplotype that was significantly associated with either case-control status or quantitative measurements of word-reading or spelling in the meta-analysis of all eight countries combined. Like in other neurocognitive disorders, our findings underline the need for larger sample sizes to validate possibly weak genetic effects.
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http://dx.doi.org/10.1038/ejhg.2013.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992562PMC
May 2014

The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure.

PLoS One 2012 28;7(11):e50321. Epub 2012 Nov 28.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050321PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509064PMC
June 2013

Dissection of genetic associations with language-related traits in population-based cohorts.

J Neurodev Disord 2011 Dec 6;3(4):365-73. Epub 2011 Sep 6.

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK,

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.
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http://dx.doi.org/10.1007/s11689-011-9091-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230763PMC
December 2011

DCDC2, KIAA0319 and CMIP are associated with reading-related traits.

Biol Psychiatry 2011 Aug 31;70(3):237-45. Epub 2011 Mar 31.

Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

Background: Several susceptibility genes have been proposed for dyslexia (reading disability; RD) and specific language impairment (SLI). RD and SLI show comorbidity, but it is unclear whether a common genetic component is shared.

Methods: We have investigated whether candidate genes for RD and SLI affect specific cognitive traits or have broad effect on cognition. We have analyzed common risk variants within RD (MRPL19/C2ORF3, KIAA0319, and DCDC2) and language impairment (CMIP and ATP2C2) candidate loci in the Avon Longitudinal Study of Parents and Children cohort (n = 3725), representing children born in southwest England in the early 1990s.

Results: We detected associations between reading skills and KIAA0319, DCDC2, and CMIP. We show that DCDC2 is specifically associated with RD, whereas variants in CMIP and KIAA0319 are associated with reading skills across the ability range. The strongest associations were restricted to single-word reading and spelling measures, suggesting that these genes do not extend their effect to other reading and language-related skills. Inclusion of individuals with comorbidity tends to strengthen these associations. Our data do not support MRPL19/C2ORF3 as a locus involved in reading abilities nor CMIP/ATP2C2 as genes regulating language skills.

Conclusions: We provide further support for the role of KIAA0319 and DCDC2 in contributing to reading abilities and novel evidence that the language-disorder candidate gene CMIP is also implicated in reading processes. Additionally, we present novel data to evaluate the prevalence and comorbidity of RD and SLI, and we recommend not excluding individuals with comorbid RD and SLI when designing genetic association studies for RD.
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http://dx.doi.org/10.1016/j.biopsych.2011.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139836PMC
August 2011

An allele-specific gene expression assay to test the functional basis of genetic associations.

J Vis Exp 2010 Nov 3(45). Epub 2010 Nov 3.

Wellcome Trust Centre for Human Genetics, University of Oxford, UK.

The number of significant genetic associations with common complex traits is constantly increasing. However, most of these associations have not been understood at molecular level. One of the mechanisms mediating the effect of DNA variants on phenotypes is gene expression, which has been shown to be particularly relevant for complex traits. This method tests in a cellular context the effect of specific DNA sequences on gene expression. The principle is to measure the relative abundance of transcripts arising from the two alleles of a gene, analysing cells which carry one copy of the DNA sequences associated with disease (the risk variants). Therefore, the cells used for this method should meet two fundamental genotypic requirements: they have to be heterozygous both for DNA risk variants and for DNA markers, typically coding polymorphisms, which can distinguish transcripts based on their chromosomal origin. DNA risk variants and DNA markers do not need to have the same allele frequency but the phase (haplotypic) relationship of the genetic markers needs to be understood. It is also important to choose cell types which express the gene of interest. This protocol refers specifically to the procedure adopted to extract nucleic acids from fibroblasts but the method is equally applicable to other cells types including primary cells. DNA and RNA are extracted from the selected cell lines and cDNA is generated. DNA and cDNA are analysed with a primer extension assay, designed to target the coding DNA markers. The primer extension assay is carried out using the MassARRAY (Sequenom) platform according to the manufacturer's specifications. Primer extension products are then analysed by matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF/MS). Because the selected markers are heterozygous they will generate two peaks on the MS profiles. The area of each peak is proportional to the transcript abundance and can be measured with a function of the MassARRAY Typer software to generate an allelic ratio (allele 1: allele 2) calculation. The allelic ratio obtained for cDNA is normalized using that measured from genomic DNA, where the allelic ratio is expected to be 1:1 to correct for technical artifacts. Markers with a normalised allelic ratio significantly different to 1 indicate that the amount of transcript generated from the two chromosomes in the same cell is different, suggesting that the DNA variants associated with the phenotype have an effect on gene expression. Experimental controls should be used to confirm the results.
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http://dx.doi.org/10.3791/2279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157858PMC
November 2010

Identification of candidate genes for dyslexia susceptibility on chromosome 18.

PLoS One 2010 Oct 28;5(10):e13712. Epub 2010 Oct 28.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis.

Methodology/principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L).

Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965662PMC
October 2010

PCSK6 is associated with handedness in individuals with dyslexia.

Hum Mol Genet 2011 Feb 4;20(3):608-14. Epub 2010 Nov 4.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.

Approximately 90% of humans are right-handed. Handedness is a heritable trait, yet the genetic basis is not well understood. Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)]. The most highly associated marker, rs11855415 (P = 4.7 × 10(-7)), is located within PCSK6. Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill. Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 2.0 × 10(-8)). Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 0.0020). These results provide molecular evidence that cerebral asymmetry and dyslexia are linked. Furthermore, PCSK6 is a protease that cleaves the left-right axis determining protein NODAL. Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia.
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http://dx.doi.org/10.1093/hmg/ddq475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016905PMC
February 2011

Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.

Biol Psychiatry 2010 Aug 26;68(4):320-8. Epub 2010 Mar 26.

The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Background: Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral deficits and complex genetic etiology. A recent study of 517 ASD families implicated DOCK4 by single nucleotide polymorphism (SNP) association and a microdeletion in an affected sibling pair.

Methods: The DOCK4 microdeletion on 7q31.1 was further characterized in this family using QuantiSNP analysis of 1M SNP array data and reverse transcription polymerase chain reaction. Extended family members were tested by polymerase chain reaction amplification of junction fragments. DOCK4 dosage was measured in additional samples using SNP arrays. Since QuantiSNP analysis identified a novel CNTNAP5 microdeletion in the same affected sibling pair, this gene was sequenced in 143 additional ASD families. Further polymerase chain reaction-restriction fragment length polymorphism analysis included 380 ASD cases and suitable control subjects.

Results: The maternally inherited microdeletion encompassed chr7:110,663,978-111,257,682 and led to a DOCK4-IMMP2L fusion transcript. It was also detected in five extended family members with no ASD. However, six of nine individuals with this microdeletion had poor reading ability, which prompted us to screen 606 other dyslexia cases. This led to the identification of a second DOCK4 microdeletion co-segregating with dyslexia. Assessment of genomic background in the original ASD family detected a paternal 2q14.3 microdeletion disrupting CNTNAP5 that was also transmitted to both affected siblings. Analysis of other ASD cohorts revealed four additional rare missense changes in CNTNAP5. No exonic deletions of DOCK4 or CNTNAP5 were seen in 2091 control subjects.

Conclusions: This study highlights two new risk factors for ASD and dyslexia and demonstrates the importance of performing a high-resolution assessment of genomic background, even after detection of a rare and likely damaging microdeletion using a targeted approach.
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http://dx.doi.org/10.1016/j.biopsych.2010.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941017PMC
August 2010

CMIP and ATP2C2 modulate phonological short-term memory in language impairment.

Am J Hum Genet 2009 Aug 30;85(2):264-72. Epub 2009 Jul 30.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.
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http://dx.doi.org/10.1016/j.ajhg.2009.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725236PMC
August 2009

A common variant associated with dyslexia reduces expression of the KIAA0319 gene.

PLoS Genet 2009 Mar 27;5(3):e1000436. Epub 2009 Mar 27.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.
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http://dx.doi.org/10.1371/journal.pgen.1000436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653637PMC
March 2009

Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population.

Am J Psychiatry 2008 Dec 1;165(12):1576-84. Epub 2008 Oct 1.

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, OX3 7BN Oxford, UK.

Objective: The authors previously identified a haplotype on chromosome 6p22 defined by three single-nucleotide polymorphisms (SNPs) that was associated with dyslexia (reading disability) in two independent samples of families that included at least one sibling with severe reading impairment. The authors also showed that this haplotype is associated with a reduction in expression of the KIAA0319 gene. In addition, a completely independent study detected an association between KIAA0319 markers and reading disability. In the current study, the authors tested whether the KIAA0319 gene influences reading skills in the general population, rather than having an effect restricted to reading disability.

Method: The authors genotyped four SNPs that previously showed association with reading disability in the population of 7-9-year-old children in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large longitudinal cohort for which reading-related phenotypes were available for more than 6,000 individuals. The authors conducted quantitative analysis for both single markers and haplotypes.

Results: The rs2143340 SNP, which effectively tags the three-SNP risk haplotype, was significantly associated with a test for reading ability. The risk haplotype itself also showed association with poor reading performance, and as in previous research, the association was stronger when the analysis was controlled for IQ.

Conclusions: These results both support a role of the KIAA0319 gene in the development of dyslexia and suggest that this gene influences reading ability in the general population. Moreover, the data implicate the three-SNP haplotype and its tagging SNP rs2143340 as genetic risk factors for poor reading performance.
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http://dx.doi.org/10.1176/appi.ajp.2008.07121872DOI Listing
December 2008