Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people.

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 to 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 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 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 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the 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 with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the 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 avenues for deciphering the biological underpinnings of uniquely human traits.

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

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.

A computer-based Pinyin intervention for disadvantaged children in China: Effects on Pinyin skills, phonological awareness, and character reading.

Pinyin is an alphabetic script that denotes pronunciations of Chinese characters. Studies have shown that Pinyin instruction enhances both phonological awareness (e.g., Shu et al., Developmental Science, 2008, 11, 171-181) and character reading (e.g., Lin et al., Psychological Science, 2010, 21, 1117-1122) in Chinese children. In the present study, we provided a 3-week Pinyin intervention with a computer-based Pinyin GraphoGame to disadvantaged migrant children with poor Pinyin skills. A total of 252 first graders who were children of migrant workers in a large Chinese city were assessed to identify poor Pinyin readers. Fifty-six 7-year-old children with poor Pinyin skills were selected and randomly divided into a training group and a control group, with 28 children in each group. The training group played the Pinyin GraphoGame for 3 weeks, while the control group received school instruction only during the same period. Results showed that the children in the training group outperformed their peers in the control group on Pinyin reading accuracy and fluency, onset-rime and phonemic awareness, and character reading. These results suggest that the Pinyin GraphoGame may be a cost-effective method to enhance Pinyin and literacy outcomes for underprivileged children in China.

Paired Associate Learning Tasks and their Contribution to Reading Skills.

Associative learning has been identified as one of several non-linguistic processes involved in reading acquisition. However, it has not been established whether it is an independent process that contributes to reading performance on its own or whether it is a process that is embedded in other linguistic skills (e.g., phonological awareness or phonological memory) and, therefore, contributing to reading performance indirectly. Research has shown that performance on tasks assessing associative learning, e.g., paired-associate learning (PAL) tasks, is lower in children with specific reading difficulties compared to typical readers. We explored the differential associations of two distinct verbal-visual PAL tasks (the Bala Bbala Graphogame, BBG, and a Foreign Language Learning Task, FLLT) with reading skills (word reading and pseudo-word decoding), controlling for phonological awareness, rapid naming, and letter and digit span in children at risk for reading disabilities and their typically developing peers. Our study sample consisted of 110 children living in rural Zambia, ranging in age from 7 to 18 years old (48.1% female). Multivariate analyses of covariance were used to explore the group differences in reading performance. Repeated-measures ANCOVA was used to examine children's learning across the PAL tasks. The differential relationships between both PAL tasks and reading performance were explored via structural equation modeling. The main result was that the children at risk for reading difficulties had lower performance on both PAL tasks. The BBG was a significant predictor for both word reading and pseudo-word decoding, whereas the FLLT-only for word reading. Performance on the FLLT partially mediated the association between phonological awareness and word reading. These results illustrate the partial independence of associative learning from other reading-related skills; the specifics of this relationship vary based on the type of PAL task administered.

Polymorphisms in DCDC2 and S100B associate with developmental dyslexia.

Genetic studies of complex traits have become increasingly successful as progress is made in next-generation sequencing. We aimed at discovering single nucleotide variation present in known and new candidate genes for developmental dyslexia: CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2 (also known as C2orf3), KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B. We used next-generation sequencing to identify single-nucleotide polymorphisms in the exons of these 11 genes in pools of 100 DNA samples of Finnish individuals with developmental dyslexia. Subsequent individual genotyping of those 100 individuals, and additional cases and controls from the Finnish and German populations, validated 92 out of 111 different single-nucleotide variants. A nonsynonymous polymorphism in DCDC2 (corrected P = 0.002) and a noncoding variant in S100B (corrected P = 0.016) showed a significant association with spelling performance in families of German origin. No significant association was found for the variants neither in the Finnish case-control sample set nor in the Finnish family sample set. Our findings further strengthen the role of DCDC2 and implicate S100B, in the biology of reading and spelling.

Neural systems predicting long-term outcome in dyslexia.

Individuals with developmental dyslexia vary in their ability to improve reading skills, but the brain basis for improvement remains largely unknown. We performed a prospective, longitudinal study over 2.5 y in children with dyslexia (n = 25) or without dyslexia (n = 20) to discover whether initial behavioral or brain measures, including functional MRI (fMRI) and diffusion tensor imaging (DTI), can predict future long-term reading gains in dyslexia. No behavioral measure, including widely used and standardized reading and language tests, reliably predicted future reading gains in dyslexia. Greater right prefrontal activation during a reading task that demanded phonological awareness and right superior longitudinal fasciculus (including arcuate fasciculus) white-matter organization significantly predicted future reading gains in dyslexia. Multivariate pattern analysis (MVPA) of these two brain measures, using linear support vector machine (SVM) and cross-validation, predicted significantly above chance (72% accuracy) which particular child would or would not improve reading skills (behavioral measures were at chance). MVPA of whole-brain activation pattern during phonological processing predicted which children with dyslexia would improve reading skills 2.5 y later with >90% accuracy. These findings identify right prefrontal brain mechanisms that may be critical for reading improvement in dyslexia and that may differ from typical reading development. Brain measures that predict future behavioral outcomes (neuroprognosis) may be more accurate, in some cases, than available behavioral measures.

Predictors of developmental dyslexia in European orthographies with varying complexity.

BACKGROUND: The relationship between phoneme awareness, rapid automatized naming (RAN), verbal short-term/working memory (ST/WM) and diagnostic category is investigated in control and dyslexic children, and the extent to which this depends on orthographic complexity. METHODS: General cognitive, phonological and literacy skills were tested in 1,138 control and 1,114 dyslexic children speaking six different languages spanning a large range of orthographic complexity (Finnish, Hungarian, German, Dutch, French, English). RESULTS: Phoneme deletion and RAN were strong concurrent predictors of developmental dyslexia, while verbal ST/WM and general verbal abilities played a comparatively minor role. In logistic regression models, more participants were classified correctly when orthography was more complex. The impact of phoneme deletion and RAN-digits was stronger in complex than in less complex orthographies. CONCLUSIONS: Findings are largely consistent with the literature on predictors of dyslexia and literacy skills, while uniquely demonstrating how orthographic complexity exacerbates some symptoms of dyslexia.

Predicting reading disability: early cognitive risk and protective factors.

This longitudinal study examined early cognitive risk and protective factors for Grade 2 reading disability (RD). We first examined the reading outcome of 198 children in four developmental cognitive subgroups that were identified in our previous analysis: dysfluent trajectory, declining trajectory, unexpected trajectory and typical trajectory. We found that RD was unevenly distributed among the subgroups, although children with RD were found in all subgroups. A majority of the children with RD had familial risk for dyslexia. Second, we examined in what respect children with similar early cognitive development but different RD outcome differ from each other in cognitive skills, task-focused behaviour and print exposure. The comparison of the groups with high cognitive risk but different RD outcome showed significant differences in phonological skills, in the amount of shared reading and in task-focused behaviour. Children who ended up with RD despite low early cognitive risk had poorer cognitive skills, more task avoidance and they were reading less than children without RD and low cognitive risk. In summary, lack of task avoidance seemed to act as a protective factor, which underlines the importance of keeping children interested in school work and reading.

Brain sensitivity to print emerges when children learn letter-speech sound correspondences.

The acquisition of reading skills is a major landmark process in a human's cognitive development. On the neural level, a new functional network develops during this time, as children typically learn to associate the well-known sounds of their spoken language with unfamiliar characters in alphabetic languages and finally access the meaning of written words, allowing for later reading. A critical component of the mature reading network located in the left occipito-temporal cortex, termed the "visual word-form system" (VWFS), exhibits print-sensitive activation in readers. When and how the sensitivity of the VWFS to print comes about remains an open question. In this study, we demonstrate the initiation of occipito-temporal cortex sensitivity to print using functional MRI (fMRI) (n = 16) and event-related potentials (ERP) (n = 32) in a controlled, longitudinal training study. Print sensitivity of fast (<250 ms) processes in posterior occipito-temporal brain regions accompanied basic associative learning of letter-speech sound correspondences in young (mean age 6.4 +/- 0.08 y) nonreading kindergarten children, as shown by concordant ERP and fMRI results. The occipito-temporal print sensitivity thus is established during the earliest phase of reading acquisition in childhood, suggesting that a crucial part of the later reading network first adopts a role in mapping print and sound.

In search of finalizing and validating digital learning tools supporting all in acquiring full literacy.

Unlike many believe, accurate and fluent basic reading skill (ie. to decode text) is not enough for learning knowledge via reading. More than 10 years ago a digital learning game supporting the first step towards full literacy, i.e., GraphoGame (GG) was developed by the first author with his colleagues in the University of Jyväskylä, Finland. It trains the acquisition of basic reading skills, i.e., learning to sound out written language. Nowadays, when almost everyone in the world has an opportunity to use this GG, it is time to start supporting the acquisition of full literacy (FL). FL is necessary for efficient learning in school, where reading the schoolbooks successfully is essential. The present plan aims to help globally almost all who read whatever orthography to start from the earliest possible grade during which children have learned the mastery of the basic reading skill to immediately continue taking the next step to reach FL. Unlike common beliefs, support of FL is mostly needed among those who read transparent orthographies (reading by the majority of readers of alphabetic writings) which are easier to sound out due to consistency between spoken and written units at grapheme-phoneme level. This makes readers able to sound any written item which is pronounceable with only a little help of knowing what it means. Therefore, children tend to become inclined to not pay enough attention to the meaning but concentrate on decoding the text letter-by-letter. They had to learn from the beginning to approach the goal of reading, mediation of the meaning of the text. Readers of nontransparent English need to attend morphology for correct sounding. The continuing fall of OECD's Program for International Student Assessment (PISA) results, e.g., in Finland reveals that especially boys are not any more interested in reading outside school which would be natural way to reach the main goal of reading, FL. What could be a better way to help boys towards FL than motivating them to play computer games which requires reading comprehension. The new digital ComprehensionGame designed by the first author motivates pupils to read in effective way by concurrently elevating their school achievements by connecting the training to daily reading lessons. This article describes our efforts to elaborate and validate this new digital tool by starting from populations of learners who need it most in Africa and in Finland.

Brain-Related Research as a Support Mechanism to Help Learners to Acquire Full Literacy.

Possibly some of the most important skills that one can have are those needed to become fully literate. We all wish our children to reach such a goal. Unfortunately, the focus of attention in reading research has been on acquiring readiness to sound out written language, i.e., the basic reading skills. Full literacy is the readiness to learn knowledge by reading. Thus, one has to be able to take two steps to reach full literacy. Indications related to both of these steps can be observe in the brain. This may be easiest when we observe the brain activity of a learner who faces difficulties in taking these steps. In fact, the serious difficulty of taking the first step can be observed soon after birth, shown below as a summary of relevant details from the paper published earlier in this journal. The step from a basic reading skill to reading comprehension requires that one must learn to read for the mediating meanings of the text, i.e., its morphological information, on top of the phonological one. This can also be approached using brain-related observations, as we show here, too. Taking these steps varies between orthographies. Here, we illustrate the learning of these steps in the context of transparently written alphabetic writings by choosing it as our concrete example because its readers form the majority of readers of alphabetic writings. After learning these facts, we had to be able to help those who face difficulties in these steps to overcome her/his bottlenecks. We summarize how we have tried to do that. Each step can be taken using a digital game-like training environment, which, happily, is now open to be distributed for the use of (almost) all in the world. How we have already tried that concerning the first step is illustrated below. Additionally, how we plan to do that concerning the second step, the final goal, completes our present story.

Maternal history of reading difficulty is associated with reduced language-related gray matter in beginning readers.

Family history and poor preliteracy skills (referred to here as familial and behavioral risk, respectively) are critical predictors of developmental dyslexia. This study systematically investigated the independent contribution of familial and behavioral risks on brain structures, which had not been explored in past studies. We also examined the differential effects of maternal versus paternal history on brain morphometry, and familial risk dimensionally versus categorically, which were also novel aspects of the study. We assessed 51 children (5 to 6 years of age) with varying degrees of familial and behavioral risks for developmental dyslexia and examined associations with brain morphometry. We found that greater maternal history of reading disability was associated with smaller bilateral prefrontal and parieto-temporal gray, but not white matter volumes. Regressing out behavioral risk, socioeconomic status, and maternal education and other confounds did not change the results. No such relationship was observed for paternal reading history and behavioral risk. Results of cortical surface area and thickness further showed that there was a significant negative relationship between cortical surface area (but not thickness) and greater severity of maternal history, in particular within the left inferior parietal lobule, suggesting prenatal influence of maternal history on children's brain morphometry. The results suggested greater maternal, possibly prenatal, influence on language-related brain structures. These results help to guide future neuroimaging research focusing on environmental and genetic influences and provide new information that may help predict which child will develop dyslexia in the future.

The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language.

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

SNP variations in the 7q33 region containing DGKI are associated with dyslexia in the Finnish and German populations.

Four genes, DYX1C1, ROBO1, DCDC2 and KIAA0319 have been studied both genetically and functionally as candidate genes for developmental dyslexia, a common learning disability in children. The identification of novel genes is crucial to better understand the molecular pathways affected in dyslectic individuals. Here, we report results from a fine-mapping approach involving linkage and association analysis in Finnish and German dyslexic cohorts. We restrict a candidate region to 0.3 Mb on chromosome 7q33. This region harbours the gene diacylglycerol kinase, iota (DGKI) which contains overlapping haplotypes associated with dyslexia in both Finnish and German sample sets.

Computer-assisted remedial reading intervention for school beginners at risk for reading disability.

The aim of the longitudinal study was to investigate whether a computer application designed for remedial reading training can enhance letter knowledge, reading accuracy, fluency, and spelling of at-risk children. The participants, 7-year-old Finnish school beginners (N=166), were assigned to 1 of 3 groups: (a) regular remedial reading intervention (n=25), (b) computer-assessed reading intervention (n=25), and (c) mainstream reading instruction (n=116). Based on the results, computer-assisted remedial reading intervention was highly beneficial, whereas regular type of intervention was less successful. The results indicated that at-risk children require computer-based letter-name and letter-sound training to acquire adequate decoding and spelling skills, and to reach the level of their non-at-risk peers.

Parental literacy predicts children's literacy: a longitudinal family-risk study.

This family-risk (FR) study examined whether the literacy skills of parents with dyslexia are predictive of the literacy skills of their offspring. We report data from 31 child-parent dyads where both had dyslexia (FR-D) and 68 dyads where the child did not have dyslexia (FR-ND). Findings supported the differences in liability of FR children with and without dyslexia: the parents of the FR-D children had more severe difficulties in pseudoword reading and spelling accuracy, in rapid word recognition, and in text reading fluency than the parents of the FR-ND children. Finally, parental skills were found to be significant predictors of children's Grade 3 reading and spelling. Parental skills predicted children's reading and spelling accuracy even after controlling for children's preschool skills. Our findings suggest that the literacy skills of a parent with dyslexia might be valuable in assessing early on their child's liability to dyslexia.

Supporting Acquisition of Spelling Skills in Different Orthographies Using an Empirically Validated Digital Learning Environment.

This paper discusses how the association learning principle works for supporting acquisition of basic spelling and reading skills using digital game-based learning environment with the Finland-based GraphoLearn (GL) technology. This program has been designed and validated to work with early readers of different alphabetic writing systems using repetition and reinforcing connections between spoken and written units. Initially GL was developed and found effective in training children at risk of reading disorders in Finland. Today GL training has been shown to support learning decoding skills among children independent of whether they face difficulties resulting from educational, social, or biological reasons.

Unveiling the Mysteries of Dyslexia-Lessons Learned from the Prospective Jyväskylä Longitudinal Study of Dyslexia.

This paper reviews the observations of the Jyväskylä Longitudinal Study of Dyslexia (JLD). The JLD is a prospective family risk study in which the development of children with familial risk for dyslexia (N = 108) due to parental dyslexia and controls without dyslexia risk (N = 92) were followed from birth to adulthood. The JLD revealed that the likelihood of at-risk children performing poorly in reading and spelling tasks was fourfold compared to the controls. Auditory insensitivity of newborns observed during the first week of life using brain event-related potentials (ERPs) was shown to be the first precursor of dyslexia. ERPs measured at six months of age related to phoneme length identification differentiated the family risk group from the control group and predicted reading speed until the age of 14 years. Early oral language skills, phonological processing skills, rapid automatized naming, and letter knowledge differentiated the groups from ages 2.5-3.5 years onwards and predicted dyslexia and reading development, including reading comprehension, until adolescence. The home environment, a child's interest in reading, and task avoidance were not different in the risk group but were found to be additional predictors of reading development. Based on the JLD findings, preventive and intervention methods utilizing the association learning approach have been developed.

Orthographic depth and its impact on universal predictors of reading: a cross-language investigation.

Alphabetic orthographies differ in the transparency of their letter-sound mappings, with English orthography being less transparent than other alphabetic scripts. The outlier status of English has led scientists to question the generality of findings based on English-language studies. We investigated the role of phonological awareness, memory, vocabulary, rapid naming, and nonverbal intelligence in reading performance across five languages lying at differing positions along a transparency continuum (Finnish, Hungarian, Dutch, Portuguese, and French). Results from a sample of 1,265 children in Grade 2 showed that phonological awareness was the main factor associated with reading performance in each language. However, its impact was modulated by the transparency of the orthography, being stronger in less transparent orthographies. The influence of rapid naming was rather weak and limited to reading and decoding speed. Most predictors of reading performance were relatively universal across these alphabetic languages, although their precise weight varied systematically as a function of script transparency.

Effects of multidomain risk accumulation on cognitive, academic, and behavioural outcomes.

This longitudinal study examined the predictive associations between cumulative multidomain risk factors and cognitive (IQ), academic (reading fluency), and social adaptive outcomes at 8 to 9 years among 190 children with or without familial risk for dyslexia. Other risk factors included parental and neurocognitive risks assessed when the children were 1 to 6 years of age. Risks accumulated more among children with familial risk for dyslexia than among children without familial risk. A higher number of risks was associated with poorer performance in all outcome measures as postulated by the cumulative risk model. However, when the effects of individual risk variables were controlled for at the outset, the cumulative risk indices did not have incremental effects beyond those of individual risks. This suggests that the detrimental effect of several risks was due to the content-specific effect of individual risks. Children with familial risk were not differentially affected by the number of risks.