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.

Transcoding counts: Longitudinal contribution of number writing to arithmetic in different languages.

Number writing involves transcoding from number words (e.g., "thirty-two") to written digit strings (32) and is an important unique predictor of arithmetic. The existing longitudinal evidence about the relation between transcoding and arithmetic is mostly language specific. In languages with number word inversion (e.g., German), the order of tens and units is transposed in spoken number words compared with Arabic numbers. This makes transcoding more challenging than in languages without number word inversion (e.g., English). In the current study, we aimed to understand whether the contribution of number writing to the development of arithmetic is similar in languages with and without number word inversion. German-speaking children (n = 166) and English-speaking children (n = 201) were followed over the first 3 years of primary school. In a series of multiple linear regressions, we tested whether number writing of multi-digit numbers was a significant unique predictor of arithmetic after controlling for well-known non-numerical predictors (nonverbal reasoning and working memory) and numerical predictors (symbolic and nonsymbolic magnitude comparison). Number writing in Grade 1 predicted arithmetic in Grades 1, 2, and 3 over and above the other predictors. Crucially, number writing performance was of comparable importance for arithmetic development in German- and English-speaking children. Our findings extend previous evidence by showing that transcoding predicts the development of arithmetic skills during the first 3 years of primary school in languages with and without number word inversion.

Twenty-four or four-and-twenty: Language modulates cross-modal matching for multidigit numbers in children and adults.

Does number-word structure have a long-lasting impact on transcoding? Contrary to English, German number words comprise decade-unit inversion (e.g., vierundzwanzig is literally translated as four-and-twenty). To investigate the mental representation of numbers, we tested the effect of visual and linguistic-morphological characteristics on the development of verbal-visual transcoding. In a longitudinal cross-linguistic design, response times (RTs) in a number-matching experiment were analyzed in Grade 2 (119 German-speaking and 179 English-speaking children) and in Grade 3 (131 German-speaking and 160 English-speaking children). To test for long-term effects, the same experiment was given to 38 German-speaking and 42 English-speaking adults. Participants needed to decide whether a spoken number matched a subsequent visual Arabic number. Systematic variation of digits in the nonmatching distractors allowed comparison of three different transcoding accounts (lexicalization, visual, and linguistic-morphological). German speakers were generally slower in rejecting inverted number distractors than English speakers. Across age groups, German speakers were more distracted by Arabic numbers that included the correct unit digit, whereas English speakers showed stronger distraction when the correct decade digit was included. These RT patterns reflect differences in number-word morphology. The individual cost of rejecting an inverted distractor (inversion effect) predicted arithmetic skills in German-speaking second-graders only. The moderate relationship between the efficiency to identify a matching number and arithmetic performance could be observed cross-linguistically in all age groups but was not significant in German-speaking adults. Thus, findings provide consistent evidence of a persistent impact of number-word structure on number processing, whereas the relationship with arithmetic performance was particularly pronounced in young children.

Reading and Spelling Development Across Languages Varying in Orthographic Consistency: Do Their Paths Cross?

We examined the cross-lagged relations between reading and spelling in five alphabetic orthographies varying in consistency (English, French, Dutch, German, and Greek). Nine hundred and forty-one children were followed from Grade 1 to Grade 2 and were tested on word and pseudoword reading fluency and on spelling to dictation. Results indicated that the relations across languages were unidirectional: Earlier reading predicted subsequent spelling. However, we also found significant differences between languages in the strength of the effects of earlier reading on subsequent spelling. These findings suggest that, once children master decoding, the observed differences between languages are not related to the direction of the effects but to the strength of the effects from reading to spelling. Theoretical and practical implications are discussed.

Stability of Deficits in Reading Fluency and/or Spelling.

Deficits in reading fluency and in spelling can dissociate during development, resulting in groups with reading deficit only (RD), spelling deficit only (SD) and combined reading and spelling deficit (RSD). The current study investigated the one-to-two-year longitudinal stability of these subgroups in 167 German-speaking children. Reading fluency deficits (irrespective of spelling skills) were stable over time, while spelling deficits were stable in the RSD-group but not in the SD-group. Lower stability in the SD-group resulted from the fact that many children improved their spelling skills over time. Improvement in spelling was associated with good performance in phoneme awareness together with intact RAN and decoding skills.

White matter alterations and tract lateralization in children with dyslexia and isolated spelling deficits.

The present study investigated whether children with a typical dyslexia profile and children with isolated spelling deficits show a distinct pattern of white matter alteration compared with typically developing peers. Relevant studies on the topic are scarce, rely on small samples, and often suffer from the limitations of conventional tensor-based methods. The present Constrained Spherical Deconvolution study includes 27 children with typical reading and spelling skills, 21 children with dyslexia and 21 children with isolated spelling deficits. Group differences along major white matter tracts were quantified utilizing the Automated Fiber Quantification software and a lateralization index was calculated in order to investigate the structural asymmetry of the tracts. The two deficit groups mostly displayed different patterns of white matter alterations, located in the bilateral inferior longitudinal fasciculi, right superior longitudinal fasciculus, and cingulum for the group with dyslexia and in the left arcuate fasciculus for the group with isolated spelling deficits. The two deficit groups differed also with respect to structural asymmetry. Children with dyslexia did not show the typical leftward asymmetry of the arcuate fasciculus, whereas the group with isolated spelling deficits showed absent rightward asymmetry of the inferior fronto-occipital fasciculus. This study adds evidence to the notion that different profiles of combined or isolated reading and spelling deficits are associated with different neural signatures.

Understanding comorbidity of learning disorders: task-dependent estimates of prevalence.

BACKGROUND: Reading disorder (RD) and mathematics disorder (MD) frequently co-occur. However, the exact comorbidity rates differ largely between studies. Given that MD is characterised by high heterogeneity on the symptom level, differences in comorbidity rates may result from different mathematical subskills used to define MD. Comorbidity rates with RD are likely to be higher when MD is measured by mathematical subskills that do not only build on number processing, but also require language (i.e. arithmetic fluency), than when measured by magnitude processing skills. METHODS: The association between literacy, arithmetic fluency and magnitude processing as well as the overlap between deficits in these domains were assessed in a representative sample of 1,454 third Graders. RESULTS: Associations were significantly higher between literacy and arithmetic, than between literacy and magnitude processing. This was also reflected in comorbidity rates: comorbidity rates between literacy and arithmetic deficits were four times higher than expected by chance, whereas comorbidity rates between literacy and magnitude processing deficits did not exceed chance rate. Deficits in the two mathematical subskills showed some overlap, but also revealed dissociations, corroborating the high heterogeneity of MD. Results are interpreted within a multiple-deficit framework and implications for diagnosis and intervention are discussed. CONCLUSIONS: The overlap between RD and MD depends on the subskills used to define MD. Due to shared domain-general factors mathematical subskills that draw on language skills are more strongly associated with literacy than those that do not require language. The findings further indicate that the same symptom, such as deficits in arithmetic, can be associated with different cognitive deficits, a deficit in language skills or a deficit in number processing.

Reading strategies of good and poor readers of German with different spelling abilities.

Reading and spelling abilities are thought to be highly correlated during development, and orthographic knowledge is assumed to underpin both literacy skills. Interestingly, recent studies showed that reading and spelling skills can also dissociate. The current study investigated whether spelling skills (indicating orthographic knowledge) are associated with the application of orthographic strategies during reading. We examined eye movements of 137 third- and fourth-graders who were either good or poor readers with or without a spelling deficit: 43 children with typical reading and spelling skills, 28 with isolated spelling deficits, 28 with isolated reading deficits, and 38 with combined reading and spelling deficits. Although we expected to find reduced reliance on orthographic reading processes among poor spellers, this was evident for the group with combined deficits only. Both isolated deficit groups applied sublexical and lexical processes in a similar amount to typically developing children. Our findings suggest that reading rests on orthographic strategies even if lexical representations are poor as indicated by a deficit in spelling skills. Findings also show that dysfluent reading does not result only from overreliance on decoding.

Lexical Reading in Dysfluent Readers of German.

Dyslexia in consistent orthographies like German is characterized by dysfluent reading, which is often assumed to result from failure to build up an orthographic lexicon and overreliance on decoding. However, earlier evidence indicates effects of lexical processing at least in some German dyslexic readers. We investigated variations in reading style in an eye-tracking paradigm with German dysfluent 3rd and 4th graders. Twenty-six TypFix-readers (fixation counts within the range of 47 age-matched typical readers) were compared with 42 HighFix-readers (increased fixation counts). Both groups showed lexical access: Words were read more efficiently than nonwords and pseudohomophones. TypFix-readers showed stronger reliance on lexical reading than HighFix-readers (smaller length effects for number of fixations and total reading time, stronger lexicality effects for gaze duration, stronger word-pseudohomophone effects for mean saccade amplitude). We conclude that in both groups, sublexical and lexical reading processes were impaired due to inefficient visual-verbal integration.

Speaking two languages with different number naming systems: What implications for magnitude judgments in bilinguals at different stages of language acquisition?

Differences between languages in terms of number naming systems may lead to performance differences in number processing. The current study focused on differences concerning the order of decades and units in two-digit number words (i.e., unit-decade order in German but decade-unit order in French) and how they affect number magnitude judgments. Participants performed basic numerical tasks, namely two-digit number magnitude judgments, and we used the compatibility effect (Nuerk et al. in Cognition 82(1):B25-B33, 2001) as a hallmark of language influence on numbers. In the first part we aimed to understand the influence of language on compatibility effects in adults coming from German or French monolingual and German-French bilingual groups (Experiment 1). The second part examined how this language influence develops at different stages of language acquisition in individuals with increasing bilingual proficiency (Experiment 2). Language systematically influenced magnitude judgments such that: (a) The spoken language(s) modulated magnitude judgments presented as Arabic digits, and (b) bilinguals' progressive language mastery impacted magnitude judgments presented as number words. Taken together, the current results suggest that the order of decades and units in verbal numbers may qualitatively influence magnitude judgments in bilinguals and monolinguals, providing new insights into how number processing can be influenced by language(s).

Effects of orthographic consistency on eye movement behavior: German and English children and adults process the same words differently.

The current study investigated the time course of cross-linguistic differences in word recognition. We recorded eye movements of German and English children and adults while reading closely matched sentences, each including a target word manipulated for length and frequency. Results showed differential word recognition processes for both developing and skilled readers. Children of the two orthographies did not differ in terms of total word processing time, but this equal outcome was achieved quite differently. Whereas German children relied on small-unit processing early in word recognition, English children applied small-unit decoding only upon rereading-possibly when experiencing difficulties in integrating an unfamiliar word into the sentence context. Rather unexpectedly, cross-linguistic differences were also found in adults in that English adults showed longer processing times than German adults for nonwords. Thus, although orthographic consistency does play a major role in reading development, cross-linguistic differences are detectable even in skilled adult readers.

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.

A-B-3-Associations and dissociations of reading and arithmetic: Is domain-specific prediction outdated?

Reading and arithmetic are core domains of academic achievement with marked impact on career opportunities and socioeconomic status. While associations between reading and arithmetic are well established, evidence on underlying mechanisms is inconclusive. The main goal of this study was to reevaluate the domain-specificity of established predictors and to enhance our understanding of the (co-)development of reading and arithmetic. In a sample of 885 German-speaking children, standard domain-specific predictors of reading and arithmetic were assessed before and/or at the onset of formal schooling. Reading and arithmetic skills were measured at the beginning and end of second grade. Latent variables were extracted for all relevant constructs: Grapheme-phoneme processing (phonological awareness, letter identification), RAN (RAN-objects, RAN-digits), number system knowledge (number identification, successor knowledge), and magnitude processing (non-symbolic and symbolic magnitude comparison), as well as the criterion measures reading and arithmetic. Four structural equation models tested distinct research questions. Grapheme-phoneme processing was a specific predictor of reading, and magnitude processing explained variance specific to arithmetic. RAN explained variance in both domains, and it explained variance in reading even after controlling for arithmetic. RAN and number system knowledge further explained variance in skills shared between reading and arithmetic. Reading and arithmetic entail domain-specific cognitive components, and they both require tight networks of visual, verbal, and semantic information, as reflected by RAN. This perspective provides a useful background to explain associations and dissociations between reading and arithmetic performance.

Subitizing and counting in typical and atypical development.

Enumeration performance in standard dot counting paradigms was investigated for different age groups with typical and atypically poor development of arithmetic skills. Experiment 1 showed a high correspondence between response times and saccadic frequencies for four age groups with typical development. Age differences were more marked for the counting than the subitizing range. In Experiment 2 we found a discontinuity between subitizing and counting for dyscalculic children; however, their subitizing slopes were steeper than those of typically developing control groups, indicating a dysfunctional subitizing mechanism. Across both experiments a number of factors could be identified that affect enumeration in the subitizing and the counting range differentially. These differential patterns further support the assumption of two qualitatively different enumeration processes.

Phonology-independent general orthographic knowledge.

While reading is among the most important and well-researched topics of developmental psychology, sublexical regularities and how these regularities relate to reading skills have attracted less interest so far. This study tested general orthographic knowledge (GOK) using an indirect reaction time (RT)-based task, in which participants had to detect letters appearing within frequent and infrequent letter clusters. The aim of the method was to minimise the roles of phonological activation and metalinguistic decision. Three different age-groups of German-speaking individuals were tested: first graders (N = 60), third graders (N = 68), and adults (N = 44). Orthographic regularity affected RTs in all three groups, with significantly lower RTs for frequent than for infrequent clusters. The indirect measure of GOK did not show an association with reading measures in first graders and adults, but in the case of third graders it explained variance over and above age and phonological skills. This study provides evidence for phonology-independent GOK, at least in third graders.

Common and distinct predictors of non-symbolic and symbolic ordinal number processing across the early primary school years.

What are the cognitive mechanisms supporting non-symbolic and symbolic order processing? Preliminary evidence suggests that non-symbolic and symbolic order processing are partly distinct constructs. The precise mechanisms supporting these skills, however, are still unclear. Moreover, predictive patterns may undergo dynamic developmental changes during the first years of formal schooling. This study investigates the contribution of theoretically relevant constructs (non-symbolic and symbolic magnitude comparison, counting and storage and manipulation components of verbal and visuo-spatial working memory) to performance and developmental change in non-symbolic and symbolic numerical order processing. We followed 157 children longitudinally from Grade 1 to 3. In the order judgement tasks, children decided whether or not triplets of dots or digits were arranged in numerically ascending order. Non-symbolic magnitude comparison and visuo-spatial manipulation were significant predictors of initial performance in both non-symbolic and symbolic ordering. In line with our expectations, counting skills contributed additional variance to the prediction of symbolic, but not of non-symbolic ordering. Developmental change in ordering performance from Grade 1 to 2 was predicted by symbolic comparison skills and visuo-spatial manipulation. None of the predictors explained variance in developmental change from Grade 2 to 3. Taken together, the present results provide robust evidence for a general involvement of pair-wise magnitude comparison and visuo-spatial manipulation in numerical ordering, irrespective of the number format. Importantly, counting-based mechanisms appear to be a unique predictor of symbolic ordering. We thus conclude that there is only a partial overlap of the cognitive mechanisms underlying non-symbolic and symbolic order processing.

Neural patterns of word processing differ in children with dyslexia and isolated spelling deficit.

There is an ongoing debate concerning the extent to which deficits in reading and spelling share cognitive components and whether they rely, in a similar fashion, on sublexical and lexical pathways of word processing. The present study investigates whether the neural substrates of word processing differ in children with various patterns of reading and spelling deficits. Using functional magnetic resonance imaging, we compared written and auditory processing in three groups of 9-13-year olds (N = 104): (1) with age-adequate reading and spelling skills; (2) with reading and spelling deficits (i.e., dyslexia); (3) with isolated spelling deficits but without reading deficits. In visual word processing, both deficit groups showed hypoactivations in the posterior superior temporal cortex compared to typical readers and spellers. Only children with dyslexia exhibited hypoactivations in the ventral occipito-temporal cortex compared to the two groups of typical readers. This is the result of an atypical pattern of higher activity in the occipito-temporal cortex for non-linguistic visual stimuli than for words, indicating lower selectivity. The print-speech convergence was reduced in the two deficit groups. Impairments in lexico-orthographic regions in a reading-based task were associated primarily with reading deficits, whereas alterations in the sublexical word processing route could be considered common for both reading and spelling deficits. These findings highlight the partly distinct alterations of the language network related to reading and spelling deficits.

Cross-Format Integration of Auditory Number Words and Visual-Arabic Digits: An ERP Study.

Converting visual-Arabic digits to auditory number words and vice versa is seemingly effortless for adults. However, it is still unclear whether this process takes place automatically and whether accessing the underlying magnitude representation is necessary during this process. In two event-related potential (ERP) experiments, adults were presented with identical (e.g., "one" and 1) or non-identical (e.g., "one" and 9) number pairs, either unimodally (two visual-Arabic digits) or cross-format (an auditory number word and a visual-Arabic digit). In Experiment 1 (N=17), active task demands required numerical judgments, whereas this was not the case in Experiment 2 (N=19). We found pronounced early ERP markers of numerical identity unimodally in both experiments. In the cross-format conditions, however, we only observed late neural correlates of identity and only if the task required semantic number processing (Experiment 1). These findings suggest that unimodal pairs of digits are automatically integrated, whereas cross-format integration of numerical information occurs more slowly and involves semantic access.

Comorbidity of learning disorders: prevalence and familial transmission.

BACKGROUND: In order to fully specify the profiles of risk and protective factors of developmental disorders, a better understanding of the conditions under which they co-occur is required. So far, empirical evidence on comorbidities of specific learning disorders in arithmetic, reading and spelling is scarce. METHODS: Prevalence and gender ratios of specific learning disorders in arithmetic (AD), reading (RD), and spelling (SD) and their co-occurrence were assessed in a large (N = 2586) population-based sample of elementary school children and in a subsample of 293 children with at least one learning disorder (LD-sample). A questionnaire on familial transmission was given to a subsample of 256 parents of children with a learning disorder and 146 typically developing children. RESULTS: The rates of deficits in arithmetic, reading, or spelling were four to five times higher in samples already experiencing marked problems in one academic domain compared to the full population. Thus, comorbidity of learning disorders was confirmed in a fairly standard school population. Rates of co-occurrence decreased for AD and RD, but not isolated SD when more stringent cutoff criteria were applied, suggesting that the comorbidity of arithmetic and spelling disorder may be more strongly biologically mediated than the comorbidity of arithmetic and reading disorder. We found a preponderance of girls with AD and boys with SD. These imbalanced gender ratios were especially marked for isolated problems, while for comorbid problems gender ratios were mostly balanced with the exception of deficits in arithmetic and reading (but not spelling) which were more typical for girls. The parental questionnaire provided evidence for disorder-specific familial transmission and co-segregation of arithmetic and literacy deficits. CONCLUSIONS: Comorbidities of learning disorders are not artificial. They are the result of a complex interplay between both general and disorder-specific aetiological factors.