Search

Funding: EE, GA, BM, BSP, CF and SEF are supported by the Max Planck Society (Germany). The Chinese Reading Study was supported by grants from the National Natural Science Foundation of China Youth Project (Grant No. 61807023), the Youth Fund for Humanities and Social Sciences Research of the Ministry of Education (Grant No. 19YJC190023 and 17XJC190010), and the Natural Science Basic Research Plan in Shaanxi Province of China (Grant No. 2021JQ-309). SP is funded by the Royal Society. Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia. Publisher PDF

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia., Nature Genetics, 54 (11), ISSN:1061-4036, ISSN:1546-1718

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30-80%, depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures: word reading, nonword reading, spelling, phoneme awareness, and nonword repetition, in samples of 13,633 to 33,959 participants aged 5-26 years. We identified genome-wide significant association with word reading (rs11208009, p=1.098 x 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP-heritability, accounting for 13-26% of trait variability. Genomic structural equation modelling revealed a shared genetic factor explaining most variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis of multivariate GWAS results with neuroimaging traits identified association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain, and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide new avenues for deciphering the biological underpinnings of uniquely human traits.

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 × 10−6) 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 pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). 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.

Additional file 1: Methods. Supplementary details in relation to magnetoencephalographic brain imaging. Table S1. Maternal characteristics during pregnancy in all FASSTT trial participants and in the sample whose children completed the FASSTT Offspring trial at 11 years. Table S2. Full Scale IQ, composite and subtest scores for the WISC-IV cognitive assessment in FASSTT Offspring trial participants. Table S3. Maternal characteristics during pregnancy in all FASSTT trial participants and in the sub-sample whose children completed the MEG assessment in the FASSTT Offspring trial.

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

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 × 10−6) 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 pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10−13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10−43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10−22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10−12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10−4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10−7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10−29). 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.

Auditory frequency discrimination has been used as an index of sensory processing in developmental language disorders such as dyslexia, where group differences have often been interpreted as evidence for a basic deficit in auditory processing that underpins and constrains individual variability in the development of phonological skills. Here, we conducted a meta-analysis to evaluate the cumulative evidence for group differences in frequency discrimination and to explore the impact of some potential moderator variables that could contribute to variability in effect-size estimations across studies. Our analyses revealed mean effect sizes for group differences on frequency discrimination tasks on the order of three-quarters of a standard deviation, but in the presence of substantial inter-study variability in their magnitude. Moderator variable analyses indicated that factors related both to participant variability on behavioural and cognitive variables associated with the dyslexia phenotype, and to variability in the task design, contributed to differences in the magnitude of effect size across studies. The apparently complex pattern of results was compounded by the lack of concurrent, standardised metrics of cognitive and reading component skills across the constituent studies. Differences on sensory processing tasks are often reported in studies of developmental disorders, but these need to be more carefully interpreted in the context of non-sensory factors, which may explain significant inter- and intra-group variance in the dependent measure of interest.

The structure of the brain is subject to very rapid developmental changes during early childhood. Pediatric studies based on Magnetic Resonance Imaging (MRI) over this age range have recently become more frequent, with the advantage of providing in vivo and non-invasive high-resolution images of the developing brain, toward understanding typical and atypical trajectories. However, it has also been demonstrated that application of currently standard MRI processing methods that have been developed with datasets from adults may not be appropriate for use with pediatric datasets. In this review, we examine the approaches currently used in MRI studies involving young children, including an overview of the rationale for new MRI processing methods that have been designed specifically for pediatric investigations. These methods are mainly related to the use of age-specific or 4D brain atlases, improved methods for quantifying and optimizing image quality, and provision for registration of developmental data obtained with longitudinal designs. The overall goal is to raise awareness of the existence of these methods and the possibilities for implementing them in developmental neuroimaging studies.

Measuring sensory sensitivity is important in studying development and developmental disorders. However, with children, there is a need to balance reliable but lengthy sensory tasks with the child's ability to maintain motivation and vigilance. We used simulations to explore the problems associated with shortening adaptive psychophysical procedures, and suggest how these problems might be addressed. We quantify how adaptive procedures with too few reversals can over-estimate thresholds, introduce substantial measurement error, and make estimates of individual thresholds less reliable. The associated measurement error also obscures group differences. Adaptive procedures with children should therefore use as many reversals as possible, to reduce the effects of both Type 1 and Type 2 errors. Differences in response consistency, resulting from lapses in attention, further increase the over-estimation of threshold. Comparisons between data from individuals who may differ in lapse rate are therefore problematic, but measures to estimate and account for lapse rates in analyses may mitigate this problem.

SP is a Royal Society University Research Fellow. Support to the analysis was provided by the St Andrews Bioinformatics Unit funded by the Wellcome Trust [grant 097831/Z/11/Z]. Analysis of the cohort was supported by a Wellcome Trust Programme Grant to MJS [WT082032MA]. EF is the recipient of a Wolfson Intercalated Award. MTMC is the recipient of the Wilkinson Junior Research Fellowship at Worcester College, Oxford and was funded by the Esther Yewpick Lee Millennium Scholarship. RN was funded by a University of Oxford Nuffield Department of Medicine Prize Studentship. DFN is an MRC Career Development Fellow. The work of the Newbury lab is funded by the Medical Research Council [G1000569/1 and MR/J003719/1]. The work of the Wellcome Trust Centre in Oxford is supported by the Wellcome Trust [090532/Z/09/Z]. 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 languagerelated 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. Publisher PDF

S.P. is a Royal Society University Research Fellow. This work was supported by the Royal Society (grant number RG110387 to S.P.); R.S. was supported by a University of St Andrews PhD scholarship. Genotyping at the Wellcome Trust Centre for Human Genetics was supported by the Wellcome Trust (090532/Z/09/Z) and a Medical Research Council Hub grant (G0900747 91070). Genetic analysis was supported by the St Andrews Bioinformatics Unit funded by the Wellcome Trust (097831/Z/11/Z). D.F.N. is an MRC Career Development Fellow supported by the MRC (G1000569/1 and MR/J003719/1). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. We recently reported the association of the PCSK6 gene with handedness through a quantitative genome-wide association study (GWAS; P < 0.5 x 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 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 characterisation of a handedness-associated locus which supports the role of common variants in non-coding sequences in influencing complex phenotypes through gene expression regulation. Publisher PDF

Impaired postural control has been associated with poor reading skills, as well as with lower performance on measures of attention and motor control variables that frequently co-occur with reading difficulties. Measures of balance and motor control have been incorporated into several screening batteries for developmental dyslexia, but it is unclear whether the relationship between such skills and reading manifests as a behavioural continuum across the range of abilities or is restricted to groups of individuals with specific disorder phenotypes. Here were obtained measures of postural control alongside measures of reading, attention and general cognitive skills in a large sample of young adults (n = 100). Postural control was assessed using centre of pressure (CoP) measurements, obtained over 5 different task conditions. Our results indicate an absence of strong statistical relationships between balance measures with either reading, cognitive or attention measures across the sample as a whole. © 2014 Loras et al.

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070 Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills. Publisher PDF

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. © 2013 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.

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.

Denne studien undersøker det veletablerte forholdet mellom rask navngiving og lesing. Rapid Automaticised Naming har et langt rykte for å være en sterk prediktor for leseevne. Til tross for omfattende forskning som spenner over fire tiår, forblir dette robuste forholdet og deres underliggende årsaker gjenstand for undersøkelse. I studien vår er vi spesielt interessert i rollen som øyebevegelser og semantisk prosessering som de to potensielle komponentene som bidrar til RAN-leserelasjonen. Vår opprinnelige prøve består av 42 studenter ved et britisk universitet. Deltakerne snakker engelsk som deres L1 og har verken lese- eller stavevansker, sammen med verken hørsels- eller synsnedsettelser. Materialene som ble brukt i studien inkluderte en ordlesningsoppgave, to konvensjonelle hurtignavningsoppgaver (objekt og siffer) og to RAN-lignende kategoriseringsoppgaver. Resultater oppnådd fra sammenkoblet t-test antydet at semantisk prosessering ikke er en komponent som hurtig navngivning tapper på, noe som innebærer at semantiske underskudd i dysleksi er en konsekvens av fonologiske underskudd, snarere enn vanskeligheter med selve semantisk prosessering. Dessuten avslørte hierarkiske multiple regresjonsanalyser at oculomotor kontroll fortsatt er en integrert del som står for varians i RAN og leseopptredener, etter at andre faktorer har blitt kontrollert. Samlet antyder dette at RAN og lesing er korrelert fordi begge krever rask og nøyaktig henting av fonologiske fremstillinger av de visuelle stimuli eller symboler og stabil koordinering av øyebevegelser over en overflate eller en trykt side. Så lenge det stilles krav til fonologisk gjenfinning og seriebehandling til en viss grad, eksisterer dette RAN-leseforholdet. This study examines the well-established relation between rapid naming and reading. Rapid Automatized Naming has a long reputation for being a strong predictor of reading abilities. Despite extensive research spanning over 4 decades, this robust relationship and their underlying causes remain a subject of inquiry. In our study, we are particularly interested in the role of eye movements and semantic processing as the two potential components that contribute to the RAN-reading relationship. Our original sample consists of 42 undergraduate students at a British university. The participants speak English as their L1 and have neither reading nor spelling difficulties, together with neither auditory nor visual impairments. The materials used in the study included a word reading task, two conventional rapid naming tasks (object and digit), and two RAN-like categorization tasks. Results obtained from paired t-test suggested that semantic processing is not a component that rapid naming taps upon, which implies that semantic deficits in dyslexia are a consequence of phonological deficits, rather than difficulties with semantic processing itself. Besides, hierarchical multiple regression analyses revealed that oculomotor control remains an integral part that accounts for variance in RAN and reading performances, after other factors have been controlled. Taken together, this suggests that RAN and reading are correlated because both require rapid and accurate retrieval of phonological representations of the visual stimuli or symbols and stable coordination of eye movements across a surface or a printed page. As long as there are demands for phonological retrieval and serial processing to a certain extent, this RAN-reading relationship is existent.