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.

Identification of brain cell types underlying genetic association with word reading and correlated traits.

Neuroimaging studies implicate multiple cortical regions in reading ability/disability. However, the neural cell types integral to the reading process are unknown. To contribute to this gap in knowledge, we integrated genetic results from genome-wide association studies for word reading (n = 5054) with gene expression datasets from adult/fetal human brain. Linkage disequilibrium score regression (LDSC) suggested that variants associated with word reading were enriched in genes expressed in adult excitatory neurons, specifically layer 5 and 6 FEZF2 expressing neurons and intratelencephalic (IT) neurons, which express the marker genes LINC00507, THEMIS, or RORB. Inhibitory neurons (VIP, SST, and PVALB) were also found. This finding was interesting as neurometabolite studies previously implicated excitatory-inhibitory imbalances in the etiology of reading disabilities (RD). We also tested traits that shared genetic etiology with word reading (previously determined by polygenic risk scores): attention-deficit/hyperactivity disorder (ADHD), educational attainment, and cognitive ability. For ADHD, we identified enrichment in L4 IT adult excitatory neurons. For educational attainment and cognitive ability, we confirmed previous studies identifying multiple subclasses of adult cortical excitatory and inhibitory neurons, as well as astrocytes and oligodendrocytes. For educational attainment and cognitive ability, we also identified enrichment in multiple fetal cortical excitatory and inhibitory neurons, intermediate progenitor cells, and radial glial cells. In summary, this study supports a role of excitatory and inhibitory neurons in reading and excitatory neurons in ADHD and contributes new information on fetal cell types enriched in educational attainment and cognitive ability, thereby improving our understanding of the neurobiological basis of reading/correlated traits.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

How you read affects what you gain: Individual differences in the functional organization of the reading system predict intervention gains in children with reading disabilities.

There is now considerable evidence regarding the types of interventions that are effective at remediating reading disabilities on average. It is generally unclear, however, what predicts the magnitude of individual-level change following a given intervention. We examine new predictors of intervention gains that are theoretically grounded in computational models of reading and focus on individual differences in the functional organization of the reading system. Specifically, we estimate the extent to which children with reading disabilities (n=118 3rd-4th graders) rely on two sources of information during an oral word reading task - print-speech correspondences and semantic imageability - before and after a phonologically-weighted intervention. We show that children who relied more on print-speech regularities and less on imageability pre-intervention had better intervention gains. In parallel, children who over the course of the intervention exhibited greater increases in their reliance on print-speech correspondences and greater decreases in their reliance on imageability had better intervention outcomes. Importantly, these two factors were differentially related to specific reading task outcomes, with greater reliance on print-speech correspondences associated with pseudoword naming, while (lesser) reliance on imageability related to word reading and comprehension. We discuss the implications of these findings for theoretical models of reading acquisition and educational practice.

Resting-state functional connectivity and reading subskills in children.

Individual differences in reading ability have been linked to characteristics of functional connectivity in the brain in both children and adults. However, many previous studies have used single or composite measures of reading, leading to difficulty characterizing the role of functional connectivity in discrete subskills of reading. The present study addresses this issue using resting-state fMRI to examine how resting-state functional connectivity (RSFC) related to individual differences in children's reading subskills, including decoding, sight word reading, reading comprehension, and rapid automatized naming (RAN). Findings showed both positive and negative RSFC-behaviour relationships that diverged across different reading subskills. Positive relationships included increasing RSFC among left dorsal and anterior regions with increasing decoding proficiency, and increasing RSFC between the left thalamus and right fusiform gyrus with increasing sight word reading, RAN, and reading comprehension abilities. In contrast, negative relationships suggested greater functional segregation of attentional and reading networks with improved performance on RAN, decoding, and reading comprehension tasks. Importantly, the results suggest that although reading subskills rely to some extent on shared functional networks, there are also distinct functional connections supporting different components of reading ability in children.

Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African-American youth.

BACKGROUND: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. OBJECTIVE: To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. METHODS: We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African-American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. RESULTS: Genome-wide significant effects were observed at rs1555839 (p=4.03×10-8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. CONCLUSION: This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene-brain-behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Reading-Related Causal Attributions for Success and Failure: Dynamic Links With Reading Skill.

The present study investigated the relation among reading skills and attributions, naming speed, and phonological awareness across a wide range of reading skill. Participants were 1,105 school-age children and youths from two understudied populations: African Americans and Hispanic Americans. Individual assessments of children ranging in age from 8 to 15 years were conducted for reading outcomes, cognitive and linguistic predictors of reading, and attributions for success and failure in reading situations. Quantile regressions were formulated to estimate these relations across the full skill span of each outcome. Reading-related attributions predicted contextual word recognition, sight word and decoding fluency, and comprehension skills. Attributions to ability in success situations were positively related to each outcome across the full span. On three reading outcomes, this relation strengthened at higher skill levels. Attributions to effort in success situations were consistently and negatively related to all reading outcomes. The results provide evidence that the strength of the relation between reading and attributions varies according to reading skill levels, with the strongest evidence for ability-based attributions in situations of reading success.

Achievement attributions are associated with specific rather than general learning delays.

The causal attributions that children make for success and failure have been associated with later reading motivation and ability perceptions, which have the potential to impact future task engagement. Few studies have investigated whether such attributions are domain specific, that is linked with the specific skill in question, or a general motivational set. Even fewer studies have examined these relationships among diverse racial and ethnic subgroups. The present study examined differences in success and failure attributions among children with and without reading delay (RD) and general language impairments (LI), in a predominately Hispanic and African American sample. Participants were 1311 children, 8 to 15 years old. Significant differences in ability attributions were observed between participants with and without RD and LI, with no additive effect for cases with co-occurring reading and language impairments. When reading and vocabulary were evaluated continuously, significant and substantial positive relationships were observed between skill and ability attributions in situations of success, and negative associations observed in situations of failure. Weaker relationships were observed for vocabulary, though vocabulary did function as a moderator in the relationship between reading skill and ability attributions, with stronger associations at higher vocabulary levels. Overall, the findings suggest that ability attributions for reading success and failure are linked with reading skill and/or deficits, and not with general language impairments.

Literacy promotion by health care professionals: A comprehensive biomedical and psychosocial approach.

Literacy is the ability to read, write and understand print. Proficiency in literacy is fundamental to social inclusion and strongly linked to health outcomes. Thus, improving literacy is important for lifelong health promotion. Poverty, inadequate hearing, speech and vision and learning disabilities may challenge literacy development. In our review, we explore these topics and suggest recommendations to: Mitigate the Effects of Poverty, Access Comprehensive Medical Assessments, Promote Early Childhood Education and Advocate for Early Intervention and Remediation Programs.

Early intervention for children at risk for reading disabilities: The impact of grade at intervention and individual differences on intervention outcomes.

Across multiple schools in three sites, the impact of grade-at-intervention was evaluated for children at risk or meeting criteria for reading disabilities. A multiple-component reading intervention with demonstrated efficacy was offered to small groups of children in 1st, 2nd, or 3rd grade. In a quasi-experimental design, 172 children received the Triple-Focus Program (PHAST + RAVE-O), and 47 were control participants. Change during intervention and 1-3 years later (6-8 testing points), and the influence of individual differences in predicting outcomes, were assessed using reading and reading-related repeated measures. Intervention children out-performed control children at posttest on all 14 outcomes, with average effect sizes (Cohen's d) on standardized measures of .80 and on experimental measures of 1.69. On foundational word reading skills (standardized measures), children who received intervention earlier, in 1st and 2nd grade, made gains relative to controls almost twice that of children receiving intervention in 3rd grade. At follow-up, the advantage of 1st grade intervention was even clearer: First graders continued to grow at faster rates over the follow-up years than 2nd graders on six of eight key reading outcomes. For some outcomes with metalinguistic demands beyond the phonological, however, a posttest advantage was revealed for 2nd grade Triple participants and for 3rd grade Triple participants relative to controls. Estimated IQ predicted growth during intervention on seven of eight outcomes. Growth during follow-up was predicted by vocabulary and visual sequential memory. These findings provide evidence on the importance of early intensive evidence-based intervention for reading problems in the primary grades.

Working Toward a More Literate World: Reading Intervention Commentary.

This issue of New Directions for Child and Adolescent Development summarizes recent and ongoing work to establish evidence-based practices in early reading instruction and intervention and to improve access to and quality of literacy programs in low- and middle-income countries. The authors describe projects of varying sizes and goals, conducted in multiple sites in Africa, the Middle East, Asia, and Latin America. What is immediately striking is the commitment to documenting the efficacy and effectiveness of these programs using wherever possible the methodological standards of intervention science and education research. Often thousands of children and hundreds of schools have been included despite the challenges involved. Data from these projects have informed plans for future programming in these countries, and results from large scale-ups have provided insight into the most important factors necessary for scale-up and sustainability. In this article, I present, in the context of an overview of the sum of these articles, my own thoughts on their importance and implications.

Exploring Differential Effects Across Two Decoding Treatments on Item-Level Transfer in Children with Significant Word Reading Difficulties: A New Approach for Testing Intervention Elements.

In English, gains in decoding skill do not map directly onto increases in word reading. However, beyond the Self-Teaching Hypothesis (Share, 1995), little is known about the transfer of decoding skills to word reading. In this study, we offer a new approach to testing specific decoding elements on transfer to word reading. To illustrate, we modeled word-reading gains among children with reading disability (RD) enrolled in Phonological and Strategy Training (PHAST) or Phonics for Reading (PFR). Conditions differed in sublexical training with PHAST stressing multi-level connections and PFR emphasizing simple grapheme-phoneme correspondences. Thirty-seven children with RD, 3rd - 6th grade, were randomly assigned 60 lessons of PHAST or PFR. Crossed random-effects models allowed us to identify specific intervention elements that differentially impacted word-reading performance at posttest, with children in PHAST better able to read words with variant vowel pronunciations. Results suggest that sublexical emphasis influences transfer gains to word reading.

Phonological awareness mediates the relationship between DCDC2 and reading performance with home environment.

Proficient reading requires critical phonological processing skill that interacts with both genetic and environmental factors. However, the precise nature of the relationships between phonological processing and genetic and environmental factors are poorly understood. We analyzed data from the Genes, Reading and Dyslexia (GRaD) Study on 1419 children ages 8-15 years from African-American and Hispanic-American family backgrounds living in North America. The analyses showed that phonological awareness mediated the relationship between DCDC2-READ1 and reading outcomes when parental education and socioeconomic status was low. The association between READ1 and reading performance is complex, whereby mediation by phonological awareness was significantly moderated by both parental education and socioeconomic status. These results show the importance of home environment and phonological skills when determining associations between READ1 and reading outcomes. This will be an important consideration in the development of genetic screening for risk of reading disability.

Empowering Schools to Implement Effective Research-Based Reading Remediation Delivers Long-Lasting Improvements to Children's Reading Trajectories.

There is a wide gap between what research evidence identifies as effective reading intervention and what is currently offered in schools. This effectiveness study reports the results of a long-term research/school system partnership that is implementing reading intervention for children with reading difficulties in community schools. In Study 1, growth-curve analyses revealed significant long-term shifts in the reading trajectories of children (n = 731) from Kindergarten to Grade 5 as a function of receiving the Empower™ Reading: Decoding and Spelling intervention. Long-term outcomes were higher in children who received intervention in Grade 2 than in Grade 3, supporting the benefit of earlier intervention. In Study 2, we compare reading outcomes before and after children participated in school system-led intervention (Empower™ Reading, n = 341) to results from previously reported researcher-led intervention and business-as-usual controls. Children in both school system-led and researcher-led interventions showed greater improvement than controls on standardized measures of decoding and reading comprehension. Among school system participants, greater gains were seen for those with stronger reading skills at pre-test. Findings demonstrate successful school system implementation of research-originated and validated reading intervention. Researcher/school system partnerships may be integral in closing the research-practice gap.

White matter correlates of reading subskills in children with and without reading disability.

Individual differences in reading ability are associated with characteristics of white matter microstructure in the brain. However, previous studies have largely measured reading as a single construct, resulting in difficulty characterizing the role of structural connectivity in discrete subskills of reading. The present study used diffusion tensor imaging to examine how white matter microstructure, measured by fractional anisotropy (FA), relates to individual differences in reading subskills in children aged 8 to 14 (n = 65). Findings showed positive correlations between FA of the left arcuate fasciculus and measures of single word reading and rapid naming abilities. Negative correlations were observed between FA of the right inferior longitudinal fasciculus and bilateral uncinate fasciculi, and reading subskills, particularly reading comprehension. The results suggest that although reading subskills rely to some extent on shared tracts, there are also distinct characteristics of white matter microstructure supporting different components of reading ability in children.

A taxometric investigation of developmental dyslexia subtypes.

Long-standing issues with the conceptualization, identification and subtyping of developmental dyslexia persist. This study takes an alternative approach to examine the heterogeneity of developmental dyslexia using taxometric classification techniques. These methods were used with a large sample of 671 children ages 6-8 who were diagnosed with severe reading disorders. Latent characteristics of the sample are assessed in regard to posited subtypes with phonological deficits and naming speed deficits, thus extending prior work by addressing whether these deficits embody separate classes of individuals. Findings support separate taxa of dyslexia with and without phonological deficits. Different latent structure for naming speed deficits was found depending on the definitional criterion used to define dyslexia. Non-phonologically based forms of dyslexia showed particular difficulty with naming speed and reading fluency.

Evaluating the efficacy of remediation for struggling readers in high school.

Preliminary efficacy data are reported for a research-based reading intervention designed for struggling readers in high school. PHAST PACES teaches (a) word identification strategies, (b) knowledge of text structures, and (c) reading comprehension strategies. In a quasi-experimental design, 268 intervention and 83 waiting list control students meeting criteria for reading disability were assessed before and after their semester. After 60 to 70 hours of PHAST PACES instruction, struggling readers demonstrated significant gains on standardized tests of word attack, word reading, and passage comprehension and on experimental measures of letter-sound knowledge and multisyllabic word identification relative to control students. An average effect size of .68 was revealed across these outcome measures. One year follow-up data on 197 PHAST PACES students revealed an average trend to decelerated growth after the intervention, except for passage comprehension outcomes that demonstrated continued growth over follow-up.

Multiple-component remediation for developmental reading disabilities: IQ, socioeconomic status, and race as factors in remedial outcome.

Results from a controlled evaluation of remedial reading interventions are reported: 279 young disabled readers were randomly assigned to a program according to a 2 × 2 × 2 factorial design (IQ, socioeconomic status [SES], and race). The effectiveness of two multiple-component intervention programs for children with reading disabilities (PHAB + RAVE-O; PHAB + WIST) was evaluated against alternate (CSS, MATH) and phonological control programs. Interventions were taught an hour daily for 70 days on a 1:4 ratio at three different sites. Multiple-component programs showed significant improvements relative to control programs on all basic reading skills after 70 hours and at 1-year follow-up. Equivalent gains were observed for different racial, SES, and IQ groups. These factors did not systematically interact with program. Differential outcomes for word identification, fluency, comprehension, and vocabulary were found between the multidimensional programs, although equivalent long-term outcomes and equal continued growth confirmed that different pathways exist to effective reading remediation.

Language Difficulties in School-Age Children With Developmental Dyslexia.

Developmental dyslexia (DD) is a common reading disability, affecting 5% to 11% of children in North America. Children classified as having DD often have a history of early language delay (ELD) or language impairments. Nevertheless, studies have reported conflicting results as to the association between DD-ELD and the extent of current language difficulties in children with DD. To examine these relationships, we queried the parents of school-age children with reading difficulties on their child's early and current language ability. Siblings were also examined. Children were directly assessed using quantitative tests of language and reading skills. To compare this study with the literature, we divided the sample (N = 674) into three groups: DD, intermediate readers (IR), and skilled readers (SR). We found a significant association between DD and ELD, with parents of children in the DD/IR groups reporting their children put words together later than the SR group. We also found a significant association between DD and language difficulties, with children with low reading skills having low expressive/receptive language abilities. Finally, we identified early language predicted current language, which predicted reading skills. These data contribute to research indicating that children with DD experience language difficulties, suggesting early recognition may help identify reading problems.

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities.

Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.