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.

Disentangling genetic and environmental influences on early language development: The interplay of genetic propensity for negative emotionality and surgency, and parenting behavior effects on early language skills in an adoption study.

Parenting and children's temperament are important influences on language development. However, temperament may reflect prior parenting, and parenting effects may reflect genes common to parents and children. In 561 U.S. adoptees (57% male) and their birth and rearing parents (70% and 92% White, 13% and 4% African American, and 7% and 2% Latinx, respectively), this study demonstrated how genetic propensity for temperament affects language development, and how this relates to parenting. Genetic propensity for negative emotionality inversely predicted language at 27 months (ß = -.15) and evoked greater maternal warmth (ß = .12), whereas propensity for surgency positively predicted language at 4.5 years (ß = .20), especially when warmth was low. Parental warmth (ß = .15) and sensitivity (ß = .19) further contributed to language development, controlling for common gene effects.

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

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

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.

Breadth versus depth: Cumulative risk model and continuous measure prediction of poor language and reading outcomes at 12.

This study examines whether, and how, multiple risks in early childhood are associated with an increased likelihood of a poor language or literacy outcome in early adolescence. Using data from 210 participants in the longitudinal Twins Early Developmental Study, we focus on the following risk factors at age 4: family risk, and poor language, speech, emergent literacy and nonverbal skills. The outcomes of interest at age 12 are language, reading fluency and reading comprehension. We contrast a 'cumulative risk' model, counting the presence or absence of each risk factor (breadth), with a model that also considers the severity of the early deficits (depth). A 'cumulative risk index' correlated modestly but significantly with outcome (r = 0.32-0.40). Odds ratios confirmed that having many risk factors (3-6) confers a higher probability of a poor outcome (OR 7.86-17.71) than having one or two (OR 3.65-7.28). Logistic regression models showed that predictive validity is not improved by including information about the severity of each deficit. Even with rich information on children's risk status at age 4, we can make only a moderately accurate prediction of the likelihood of a language or literacy disorder 8 years later (Area Under the Curve = 0.74-0.84; Positive Predictive Value = 0.33-0.55, Negative Predictive Value = 0.86-0.91). Taken together, and consistent with the idea of 'cumulative risk', these results suggest that the breadth of risk is a core predictor of outcome, and furthermore, that the severity of early deficits does not add significantly to this prediction.

Dyslexia and Developmental Language Disorder: comorbid disorders with distinct effects on reading comprehension.

BACKGROUND: Reading comprehension draws on both decoding and linguistic comprehension, and poor reading comprehension can be the consequence of a deficit in either of these skills. METHODS: Using outcome data from the longitudinal Wellcome Language and Reading Project, we identified three groups of children at age 8 years: children with dyslexia (N = 21) who had deficits in decoding but not oral language, children with Developmental Language Disorder (DLD; N = 38) whose decoding skills were in the normal range, and children who met criteria for both dyslexia and DLD (N = 29). RESULTS: All three groups had reading comprehension difficulties at the ages of 8 and 9 years relative to TD controls though those of the children with dyslexia were mild (relative to TD controls, d = 0.51 at age 8, d = 0.60 at age 8); while the most severe problems were found in the comorbid dyslexia + DLD group (d = 1.79 at age 8, d = 2.06 at age 9) those with DLD also had significant difficulties (d = 1.56 at age 8, d = 1.56 at age 9). CONCLUSIONS: These findings confirm that children with dyslexia or DLD are at-risk for reading comprehension difficulties but for different reasons, because of weak decoding in the case of dyslexia or weak oral language skills in the case of DLD. Different forms of intervention are required for these groups of children, targeted to their particular area(s) of weakness.

Developmental Outcomes for Children at High Risk of Dyslexia and Children With Developmental Language Disorder.

We followed children at family risk of dyslexia and children with preschool language difficulties from age 3½, comparing them with controls (N = 234). At age 8, children were classified as having dyslexia or Developmental Language Disorder (DLD) and compared at earlier time points with controls. Children with dyslexia have specific difficulties with phonology and emergent reading skills in the preschool period, whereas children with DLD, with or without dyslexia, show a wider range of impairments including significant problems with executive and motor tasks. For children with both dyslexia and DLD, difficulties with phonology are generally more severe than those observed in children with dyslexia or DLD alone. Findings confirm that poor phonology is the major cognitive risk factor for dyslexia.

When does speech sound disorder matter for literacy? The role of disordered speech errors, co-occurring language impairment and family risk of dyslexia.

BACKGROUND: This study considers the role of early speech difficulties in literacy development, in the context of additional risk factors. METHOD: Children were identified with speech sound disorder (SSD) at the age of 3½ years, on the basis of performance on the Diagnostic Evaluation of Articulation and Phonology. Their literacy skills were assessed at the start of formal reading instruction (age 5½), using measures of phoneme awareness, word-level reading and spelling; and 3 years later (age 8), using measures of word-level reading, spelling and reading comprehension. RESULTS: The presence of early SSD conferred a small but significant risk of poor phonemic skills and spelling at the age of 5½ and of poor word reading at the age of 8. Furthermore, within the group with SSD, the persistence of speech difficulties to the point of school entry was associated with poorer emergent literacy skills, and children with 'disordered' speech errors had poorer word reading skills than children whose speech errors indicated 'delay'. In contrast, the initial severity of SSD was not a significant predictor of reading development. Beyond the domain of speech, the presence of a co-occurring language impairment was strongly predictive of literacy skills and having a family risk of dyslexia predicted additional variance in literacy at both time-points. CONCLUSIONS: Early SSD alone has only modest effects on literacy development but when additional risk factors are present, these can have serious negative consequences, consistent with the view that multiple risks accumulate to predict reading disorders.

The Home Literacy Environment as a Predictor of the Early Literacy Development of Children at Family-Risk of Dyslexia.

The home literacy environment (HLE) predicts language and reading development in typically developing children; relatively little is known about its association with literacy development in children at family-risk of dyslexia. We assessed the HLE at age 4 years, precursor literacy skills at age 5, and literacy outcomes at age 6, in a sample of children at family-risk of dyslexia (n = 116) and children with no known risk (n = 72). Developmental relationships between the HLE and literacy were comparable between the groups; an additional effect of storybook exposure on phoneme awareness was observed in the family-risk group only. The effects of socioeconomic status on literacy were partially mediated by variations in the HLE; in turn, effects of the HLE on literacy were mediated by precursor skills (oral language, phoneme awareness, and emergent decoding) in both groups. Findings are discussed in terms of possible gene-environment correlation mechanisms underpinning atypical literacy development.

Language and traits of autism spectrum conditions: evidence of limited phenotypic and etiological overlap.

Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by ~3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation = -0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation = 0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier.

Reliability of the serial reaction time task: If at first you don't succeed, try, try, try again.

Procedural memory is involved in the acquisition and control of skills and habits that underlie rule and procedural learning, including the acquisition of grammar and phonology. The serial reaction time task (SRTT), commonly used to assess procedural learning, has been shown to have poor stability (test-retest reliability). We investigated factors that may affect the stability of the SRTT in adults. Experiment 1 examined whether the similarity of sequences learned in two sessions would impact stability: test-retest correlations were low regardless of sequence similarity (r < .31). Experiment 2 added a third session to examine whether individual differences in learning would stabilise with further training. There was a small (but nonsignificant) improvement in stability for later sessions (Sessions 1 and 2: r = .42; Sessions 2 and 3: r = .60). Stability of procedural learning on the SRTT remained suboptimal in all conditions, posing a serious obstacle to the use of this task as a sensitive predictor of individual differences and ultimately theoretical advance.

The reliability of the serial reaction time task: meta-analysis of test-retest correlations.

The Serial Reaction Time task, one of the most widely used tasks to index procedural memory, has been increasingly employed in individual differences research examining the role of procedural memory in language and other cognitive abilities. Yet, despite consistently producing robust procedural learning effects at the group level (i.e. faster responses to sequenced/probable trials versus random/improbable trials), these effects have recently been found to have poor reliability. In this meta-analysis (N = 7), comprising 719 participants (M = 20.81, s.d. = 7.13), we confirm this 'reliability paradox'. The overall retest reliability of the robust procedural learning effect elicited by the SRTT was found to be well below acceptable psychometric standards (r < 0.40). However, split-half reliability within a session is better, with an overall estimate of 0.66. There were no significant effects of sampling (participants' age), methodology (e.g. number of trials, sequence type) and analytical decisions (whether all trials were included when computing the procedural learning scores; using different indexes of procedural learning). Thus, despite producing robust effects at the group-level, until we have a better understanding of the factors that improve the reliability of this task using the SRTT for individual differences research should be done with caution.

Limited Evidence of an Association Between Language, Literacy, and Procedural Learning in Typical and Atypical Development: A Meta-Analysis.

The ability to extract patterns from sensory input across time and space is thought to underlie the development and acquisition of language and literacy skills, particularly the subdomains marked by the learning of probabilistic knowledge. Thus, impairments in procedural learning are hypothesized to underlie neurodevelopmental disorders, such as dyslexia and developmental language disorder. In the present meta-analysis, comprising 2396 participants from 39 independent studies, the continuous relationship between language, literacy, and procedural learning on the Serial Reaction Time task (SRTT) was assessed across children and adults with typical development (TD), dyslexia, and Developmental Language Disorder (DLD). Despite a significant, but very small, relationship between procedural learning and overall language and literacy measures, this pattern was not observed at the group-level when examining TD, dyslexic, and DLD groups separately. Based on the procedural/declarative model, a positive relationship was expected between procedural learning and language and literacy measures for the typically developing group; however, no such relationship was observed. This was also the case for the disordered groups (ps > .05). Also counter to expectations, the magnitude of the relationship between procedural learning and grammar and phonology did not differ between TD and DLD (ps > .05), nor between the TD and dyslexic group on reading, spelling, and phonology (ps > .05). While lending little support to the procedural/declarative model, we consider that these results may be the consequence of poor psychometric properties of the SRTT as a measure of procedural learning.

The etiology of variation in language skills changes with development: a longitudinal twin study of language from 2 to 12 years.

The present study is the first long-term longitudinal examination of the etiology of individual differences in language from early childhood through to adolescence. We applied a multivariate latent factor genetic model to longitudinal data from the Twins Early Development Study in order to (a) compare the magnitude of genetic and environmental influences on language skills in early childhood (2, 3 and 4 years), middle childhood (7, 9 and 10 years), and early adolescence (12 years); and (b) determine to what extent the same genetic and environmental factors underlie variation in language skills at these three stages of language development. We found that while shared environmental influences appear to be dominant (latent factor c² = .74) in early language, with a smaller though significant role for genetic factors (latent factor a² = .24), the pattern is reversed by middle childhood such that genetic influences are substantially more important (latent factor a² = .57-.63 at 7, 9 and 10 years and .47-.57 at 12 years) and shared environmental influences less so (latent factor c² = .31-.37 at 7, 9 and 10 years and .31-.32 at 12 years). The increase in the heritability of language skills between early and middle childhood appears to be due to new genetic factors that come into play at that transition. In contrast, genetic factors remain stable from middle childhood through to early adolescence, and account for the phenotypic continuity in language skills across these two stages.

Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals.

Language impairments are a characteristic feature of autism and related autism spectrum disorders (ASDs). Autism is also highly heritable and one of the most promising candidate genes implicated in its pathogenesis is contactin-associated protein-like 2 (CNTNAP2), a gene also associated with language impairment. In the current study we investigated the functional effects of variants of CNTNAP2 associated with autism and language impairment (rs7794745 and rs2710102; presumed risk alleles T and C, respectively) in healthy individuals using functional magnetic resonance imaging (fMRI) during performance of a language task (n = 66). Against a background of normal performance and lack of behavioral abnormalities, healthy individuals with the putative risk allele versus those without demonstrated significant increases in activation in the right inferior frontal gyrus (Broca's area homologue) and right lateral temporal cortex. These findings demonstrate that risk associated variation in the CNTNAP2 gene impacts on brain activation in healthy non-autistic individuals during a language processing task providing evidence of the effect of genetic variation in CNTNAP2 on a core feature of ASDs.

Shared storybook reading with children at family risk of dyslexia.

Background: Shared storybook reading is an important context for language learning and often constitutes young children's first encounter with the printed word. The quality of early shared reading interactions is a known predictor of language and reading development, but few studies have examined these interactions in children at family risk of dyslexia. Methods: This exploratory study describes the quality of shared storybook reading between mothers and their 3- to 4-year-old children at family risk of dyslexia (FR; n = 18) in comparison with dyads with no known risk (no-FR; n = 13). Mother-child interactions while sharing a familiar and an unfamiliar storybook were coded for type of extra-textual talk (meaning-related talk at the concrete and abstract levels; print-related talk) and affective quality. Maternal and child language and literacy skills were considered as potential correlates of shared reading quality. Results: The linguistic and affective quality of shared reading was broadly comparable across FR and no-FR dyads, particularly when sharing a book they knew well, with large within-group variation. Mothers contributed more concrete meaning-related talk when introducing an unfamiliar book to their children; children contributed more extra-textual talk overall when sharing a familiar book. Maternal language, but not reading, skills were related to the linguistic quality of shared reading. The affective quality of reading interactions was rated more highly in dyads where mothers and children had stronger language skills. Conclusions: These results suggest that the quality of shared reading does not vary systematically as a function of children's risk of dyslexia but is related to maternal language skills. This finding needs to be replicated in a larger sample in order to better understand the risk and protective factors associated with dyslexia. Highlights: What is already known about this topic The quality of extra-textual talk during shared reading between parents and preschoolers predicts later language and literacy outcomes in typically developing children.The affective quality of early shared reading predicts children's motivation to read independently in later childhood.Children at family risk of dyslexia are more likely than their peers with no family risk to have difficulty learning to read and may show weaknesses in oral language skills. What this paper adds The linguistic and affective quality of shared reading between mothers and preschool children is broadly similar when children are at family risk of dyslexia compared with no family risk.The type and quantity of extra-textual talk contributed by mothers and children appears to differ according to the familiarity of the storybook, but replication of the findings in a larger sample is required.The linguistic and affective quality of shared reading is related to maternal language skills. Implications for theory, policy or practice Shared storybook reading offers rich language learning opportunities for children at family risk of dyslexia.Maternal language skills may be an important determinant of the interactional quality of shared reading.The linguistic and affective quality of shared reading is not clearly associated with maternal reading difficulties.

Mind-Mindedness and Stress in Parents of Children with Developmental Disorders.

Relations between mind-mindedness (assessed using the describe-your-child interview) and stress were investigated in parents of children with developmental disorders (ADHD, n = 51, ASD, n = 23, Down's Syndrome, n = 38, and 22q11.2 Deletion Syndrome, 22q11.2DS, n = 32) and typically-developing children (n = 89). Mind-mindedness did not differ across diagnostic groups, and mind-mindedness predicted parenting stress across groups. Parenting stress was lowest in the typically-developing and Down's Syndrome groups. Across all groups, mind-minded and positive descriptions predicted lower parenting stress, and negative descriptions predicted higher stress. In the developmental disorder groups, describing the children with reference to their disorder was negatively correlated with mind-mindedness. Results are discussed with regard to interventions for families where children have developmental disorders.

Does the Inclusion of a Genome-Wide Polygenic Score Improve Early Risk Prediction for Later Language and Literacy Delay?

Purpose The ability to identify children early in development who are at substantial risk for language/literacy difficulties would have great benefit both for the children and for the educational and therapeutic institutions that serve them. Information that is relatively easily available prior to the age of 3 years, such as late talking, family history of language/literacy difficulties, and socioeconomic status, have some but very limited predictive power. Here, we examine whether the inclusion of a DNA-based genome-wide polygenic score that has been shown to capture children's genetic propensity for educational attainment (EA3) adds enough prediction to yield a clinically useful score. Method Data are longitudinal scores of 1,420 children from the Twins Early Development Study, who were assessed at ages 2 and 3 years on language and nonverbal ability and at 12 years of age on oral language, word decoding, and reading comprehension. Five risk factors were examined: expressive vocabulary, nonverbal ability (these two from parent report), family history, mothers' education, and EA3. Analyses were conducted both for continuous and categorically defined measures of risk and outcome. Results Language and literacy abilities at 12 years of age were significantly but modestly predicted by the risk factors, with a small but significant added prediction from EA3. Indices of diagnostic validity for poor outcomes, such as sensitivity and area under the curve statistics, were poor in all cases. Conclusions We conclude that, at present, clinically useful prediction from toddlerhood remains an unattained goal. Supplemental Material https://doi.org/10.23641/asha.12170331.

Generalist genes and learning disabilities: a multivariate genetic analysis of low performance in reading, mathematics, language and general cognitive ability in a sample of 8000 12-year-old twins.

BACKGROUND: Our previous investigation found that the same genes influence poor reading and mathematics performance in 10-year-olds. Here we assess whether this finding extends to language and general cognitive disabilities, as well as replicating the earlier finding for reading and mathematics in an older and larger sample. METHODS: Using a representative sample of 4000 pairs of 12-year-old twins from the UK Twins Early Development Study, we investigated the genetic and environmental overlap between internet-based batteries of language and general cognitive ability tests in addition to tests of reading and mathematics for the bottom 15% of the distribution using DeFries-Fulker extremes analysis. We compared these results to those for the entire distribution. RESULTS: All four traits were highly correlated at the low extreme (average group phenotypic correlation = .58). and in the entire distribution (average phenotypic correlation = .59). Genetic correlations for the low extreme were consistently high (average = .67), and non-shared environmental correlations were modest (average = .23). These results are similar to those seen across the entire distribution (.68 and .23, respectively). CONCLUSIONS: The 'Generalist Genes Hypothesis' holds for language and general cognitive disabilities, as well as reading and mathematics disabilities. Genetic correlations were high, indicating a strong degree of overlap in genetic influences on these diverse traits. In contrast, non-shared environmental influences were largely specific to each trait, causing phenotypic differentiation of traits.

Children who read words accurately despite language impairment: who are they and how do they do it?

Some children learn to read accurately despite language impairments (LI). Nine- to 10-year-olds were categorized as having LI only (n = 35), dyslexia (DX) only (n = 73), LI + DX (n = 54), or as typically developing (TD; n = 176). The LI-only group had mild to moderate deficits in reading comprehension. They were similar to the LI + DX group on most language measures, but rapid serial naming was superior to the LI + DX group and comparable to the TD. For a subset of children seen at 4 and 6 years, early phonological skills were equally poor in those later classified as LI or LI + DX. Poor language need not hinder acquisition of decoding, so long as rapid serial naming is intact; reading comprehension, however, is constrained by LI.