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.

The Rosetta Phenotype Harmonization Method Facilitates Finding a Relationship Quantitative Trait Locus for a Complex Cognitive Trait.

Genetics researchers increasingly combine data across many sources to increase power and to conduct analyses that cross multiple individual studies. However, there is often a lack of alignment on outcome measures when the same constructs are examined across studies. This inhibits comparison across individual studies and may impact the findings from meta-analysis. Using a well-characterized genotypic (brain-derived neurotrophic factor: BDNF) and phenotypic constructs (working memory and reading comprehension), we employ an approach called Rosetta, which allows for the simultaneous examination of primary studies that employ related but incompletely overlapping data. We examined four studies of BDNF, working memory, and reading comprehension with a combined sample size of 1711 participants. Although the correlation between working memory and reading comprehension over all participants was high, as expected (ρ = 0.45), the correlation between working memory and reading comprehension was attenuated in the BDNF Met/Met genotype group (ρ = 0.18, n.s.) but not in the Val/Val (ρ = 0.44) or Val/Met (ρ = 0.41) groups. These findings indicate that Met/Met carriers may be a unique and robustly defined subgroup in terms of memory and reading comprehension. This study demonstrates the utility of the Rosetta method when examining complex phenotypes across multiple studies, including psychiatric genetic studies, as shown here, and also for the mega-analysis of cohorts generally.

Orthographic Depth May Influence the Degree of Severity of Maze Learning Performance in Children at Risk for Reading Disorder.

Reading disability (RD), which affects between 5 and 17% of the population worldwide, is the most prevalent form of learning disability, and is associated with underactivation of a universal reading network in children. However, recent research suggests there are differences in learning rates on cognitive predictors of reading performance, as well as differences in activation patterns within the reading neural network, based on orthographic depth (i.e., transparent/shallow vs. deep/opaque orthographies) in children with RD. Recently, we showed that native English-speaking children with RD exhibit impaired performance on a maze learning task that taps into the same neural networks that are activated during reading. In addition, we demonstrated that genetic risk for RD strengthens the relationship between reading impairment and maze learning performance. However, it is unclear whether the results from these studies can be broadly applied to children from other language orthographies. In this study, we examined whether low reading skill was associated with poor maze learning performance in native English-speaking and native German-speaking children, and the influence of genetic risk for RD on cognition and behavior. In addition, we investigated the link between genetic risk and performance on this task in an orthographically diverse sample of children attending an English-speaking international school in Germany. The results from our data suggest that children with low reading skill, or with a genetic risk for reading impairment, exhibit impaired performance on the maze learning task, regardless of orthographic depth. However, these data also suggest that orthographic depth influences the degree of impairment on this task. The maze learning task requires the involvement of various cognitive processes and neural networks that underlie reading, but is not influenced by potential differences in reading experience due to lack of text or oral reporting. As a fully automated tool, it does not require specialized training to administer, and current results suggest it may be a practicable screening tool for early identification of reading impairment across orthographies.

Discovery of 42 genome-wide significant loci associated with dyslexia.

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

Dyslexia associated gene KIAA0319 regulates cell cycle during human neuroepithelial cell development.

Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.

D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia.

D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.

Sex-specific associations between traumatic experiences and resting-state functional connectivity in the Philadelphia Neurodevelopmental Cohort.

BACKGROUND: Traumatic experiences during childhood or adolescence are a significant risk factor for multiple psychiatric disorders and adversely affect multiple cognitive functions. Resting-state functional magnetic resonance imaging has been used to investigate the effects of traumatic experiences on functional connectivity, but the impact of sex differences has not been well documented. This study investigated sex-specific associations between resting-state functional connectivity (rsFC) and traumatic experiences in typically developing youth. METHODS: The sample comprised 1395 participants, aged 8-21 years, from the Philadelphia Neurodevelopmental Cohort. Traumatic experiences were assessed based on the structured psychiatric evaluation. Sex, the number of traumatic events, and their interaction were regressed onto voxel-wise intrinsic connectivity distribution parameter values derived from resting-state functional magnetic resonance imaging. Brain regions that passed cluster correction were used as seeds to define resting-state networks. RESULTS: After quality control, the final sample had 914 participants with mean (SD) age 14.6 (3.3) years; 529 (57.8%) females; 437 (47.8%) experienced at least one kind of traumatic event. Four discrete anatomical clusters showed decreased functional connectivity as the number of traumatic events increased. The resting-state networks defined by using these four clusters as seeds corresponded with the somatomotor network. Sex-specific associations were identified in another three clusters for which males showed increased connectivity, and females showed decreased connectivity as the number of traumatic events increased. The resting-state networks defined by the three sex-specific clusters corresponded with the default mode network (DMN). CONCLUSIONS: In youth without psychiatric diagnoses, traumatic experiences are associated with an alteration of rsFC in brain regions corresponding with the somatomotor network. Associations differ in direction between males and females in brain regions corresponding with the DMN, suggesting sex-specific responses to early exposure to trauma.

Identifying Dyslexia: Link between Maze Learning and Dyslexia Susceptibility Gene, DCDC2, in Young Children.

Dyslexia is a common learning disability that affects processing of written language despite adequate intelligence and educational background. If learning disabilities remain untreated, a child may experience long-term social and emotional problems, which influence future success in all aspects of their life. Dyslexia has a 60% heritability rate, and genetic studies have identified multiple dyslexia susceptibility genes (DSGs). DSGs, such as DCDC2, are consistently associated with the risk and severity of reading disability (RD). Altered neural connectivity within temporoparietal regions of the brain is associated with specific variants of DSGs in individuals with RD. Genetically altering DSG expression in mice results in visual and auditory processing deficits as well as neurophysiological and neuroanatomical disruptions. Previously, we demonstrated that learning deficits associated with RD can be translated across species using virtual environments. In this 2-year longitudinal study, we demonstrate that performance on a virtual Hebb-Williams maze in pre-readers is able to predict future reading impairment, and the genetic risk strengthens, but is not dependent on, this relationship. Due to the lack of oral reporting and use of letters, this easy-to-use tool may be particularly valuable in a remote working environment as well as working with vulnerable populations such as English language learners.

The temporal dynamics of first and second language processing: ERPs to spoken words in Mandarin-English bilinguals.

The dynamics of bilingual spoken word recognition remain poorly characterized, especially for individuals who speak two languages that are highly dissimilar in their phonological and morphological structure. The present study compared first language (L1) and second language (L2) spoken word processing within a group of adult Mandarin-English bilinguals (N = 34; ages 18-25). Event-related potentials (ERPs) were recorded while participants completed the same cross-modal matching task separately in their L1 Mandarin and L2 English. This task consisted of deciding whether spoken words matched pictures of items. Pictures and spoken words either matched (e.g., Mandarin: TANG2-tang2; English: BELL-bell), or differed in word-initial phonemes (e.g., Mandarin: TANG2-lang2; English: BELL-shell), word-final phonemes (e.g., Mandarin: TANG2-tao2; English: BELL-bed), or whole words (e.g., Mandarin: TANG2-xia1: English: BELL-ham). Each mismatch type was associated with a pattern of modulation of the Phonological Mapping Negativity, the N400, and the Late N400 that was distinct from those of the other mismatch types yet similar between the two languages. This was interpreted as evidence of incremental processing with similar temporal dynamics in both languages. These findings support models of spoken word recognition in bilingual individuals that adopt an interactive-activation framework for both L1 and L2 processing.

DCDC2 READ1 regulatory element: how temporal processing differences may shape language.

Classic linguistic theory ascribes language change and diversity to population migrations, conquests, and geographical isolation, with the assumption that human populations have equivalent language processing abilities. We hypothesize that spectral and temporal characteristics make some consonant manners vulnerable to differences in temporal precision associated with specific population allele frequencies. To test this hypothesis, we modelled association between RU1-1 alleles of DCDC2 and manner of articulation in 51 populations spanning five continents, and adjusting for geographical proximity, and genetic and linguistic relatedness. RU1-1 alleles, acting through increased expression of DCDC2, appear to increase auditory processing precision that enhances stop-consonant discrimination, favouring retention in some populations and loss by others. These findings enhance classical linguistic theories by adding a genetic dimension, which until recently, has not been considered to be a significant catalyst for language change.

Effect of READ1 on latent profiles of reading disorder and comorbid attention and language impairment subtypes.

Recent studies of co-occurring reading disorder (RD) and attention deficit/hyperactivity disorder (ADHD), and co-occurring RD and language impairment (LI), support a core disability plus co-occurrence model focused on language and attention. Genetic factors have been associated with poor reading performance. However, little is known about whether different genetic variants independently contribute to RD co-occurrence subtypes. We aimed to identify subgroups of struggling readers using a latent profile analysis (LPA) in a sample of 1,432 Hispanic American and African American youth. RD classes were then tested for association with variants of READ1, a regulatory element within the candidate RD risk gene, DCDC2. Six groups were identified in the LPA using RD designation as a known-class variable. The three RD classes identified groups of subjects with neurocognitive profiles representing RD+ADHD, specific phonological deficit RD, and RD+LI. Genetic associations across RD subtypes were investigated against functional groupings of READ1. The RU1-1 group of READ1 alleles was associated with RD cases that were marked by deficits in both processing speed and attention (RD+ADHD). The DCDC2 microdeletion that encompasses READ1 was associated with RD cases showing a phonological deficit RD profile. These findings provide evidence for differential genetic contribution to RD subtypes, and that previously implicated genetic variants for RD may share an underlying genetic architecture across population groups for reading disorder.

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.

Causal Attribution Profiles as a Function of Reading Skills, Hyperactivity, and Inattention.

The causes that individuals attribute to reading outcomes shape future behaviors, including engagement or persistence with learning tasks. Although previous reading motivation research has examined differences between typical and struggling readers, there may be unique dynamics related to varying levels of reading and attention skills. Using latent profile analysis, we found 4 groups informed by internal attributions to ability and effort. Reading skills, inattention, and hyperactivity/impulsivity were investigated as functional correlates of attribution profiles. Participants were 1,312 youth (8-15 years of age) of predominantly African American and Hispanic racial/ethnic heritage. More adaptive attribution profiles had greater reading performance and lower inattention. The reverse was found for the least adaptive profile with associations to greater reading and attention difficulties. Distinct attribution profiles also existed across similar-achieving groups. Understanding reading-related attributions may inform instructional efforts in reading. Promoting adaptive attributions may foster engagement with texts despite learning difficulties and, in turn, support reading achievement.

Worldwide distribution of the DCDC2 READ1 regulatory element and its relationship with phoneme variation across languages.

DCDC2 is a gene strongly associated with components of the phonological processing system in animal models and in multiple independent studies of populations and languages. We propose that it may also influence population-level variation in language component usage. To test this hypothesis, we investigated the evolution and worldwide distribution of the READ1 regulatory element within DCDC2, and compared its distribution with variation in different language properties. The mutational history of READ1 was estimated by examining primate and archaic hominin sequences. This identified duplication and expansion events, which created a large number of polymorphic alleles based on internal repeat units (RU1 and RU2). Association of READ1 alleles was studied with respect to the numbers of consonants and vowels for languages in 43 human populations distributed across five continents. Using population-based approaches with multivariate ANCOVA and linear mixed effects analyses, we found that the RU1-1 allele group of READ1 is significantly associated with the number of consonants within languages independent of genetic relatedness, geographic proximity, and language family. We propose that allelic variation in READ1 helped create a subtle cognitive bias that was amplified by cultural transmission, and ultimately shaped consonant use by different populations over time.

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.

A molecular-genetic and imaging-genetic approach to specific comprehension difficulties in children.

Children with poor reading comprehension despite typical word reading skills were examined using neuropsychological, genetic, and neuroimaging data collected from the Genes, Reading and Dyslexia Study of 1432 Hispanic American and African American children. This unexpected poor comprehension was associated with profound deficits in vocabulary, when compared to children with comprehension skills consistent with their word reading. Those with specific comprehension difficulties were also more likely to have RU2Short alleles of READ1 regulatory variants of DCDC2, strongly associated with reading and language difficulties. Subjects with RU2Short alleles showed stronger resting state functional connectivity between the right insula/inferior frontal gyrus and the right supramarginal gyrus, even after controlling for potentially confounding variables including genetic ancestry and socioeconomic status. This multi-disciplinary approach advances the current understanding of specific reading comprehension difficulties, and suggests the need for interventions that are more appropriately tailored to the specific comprehension deficits of this group of children.

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.

Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNC.

Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability.