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Background Efficient memory functions are important to the development of cognitive and functional skills, allowing individuals to manipulate and store information. Theories of memory have suggested the presence of domain-specific (i.e. verbal and spatial) and general processing mechanisms across memory domains, including memory functions dependent on the prefrontal cortex (PFC) and the hippocampus. Comparison of individuals who have syndromes associated with striking contrasts in skills on verbal and spatial tasks [e.g. Down syndrome (DS) and Williams syndrome (WS)] allows us to test whether or not these dissociations may extend across cognitive domains, including PFC and hippocampal memory processes. Methods The profile of memory function, including immediate memory (IM), working memory (WM) and associative memory (AM), was examined in a sample of adolescents and young adults with DS ( n = 27) or WS ( n = 28), from which closely CA- and IQ-matched samples of individuals with DS ( n = 18) or WS ( n = 18) were generated. Relations between memory functions and IQ and adaptive behaviour were also assessed in the larger sample. Results Comparisons of the two matched groups indicated significant differences in verbal IM (DS < WS), spatial IM (DS > WS) and spatial and verbal AM (DS > WS), but no between-syndrome differences in WM. For individuals with DS, verbal IM was the most related to variation in IQ, and spatial AM related to adaptive behaviour. The pattern was clearly different for individuals with WS. Verbal and spatial AM were the most related to variation in IQ, and verbal WM related to adaptive behaviour. Conclusions These results suggest that individuals with these two syndromes have very different patterns of relative strengths and weaknesses on memory measures, which do not fully mirror verbal and spatial dissociations. Furthermore, different patterns of memory dysfunction relate to outcome in individuals with each syndrome. [ABSTRACT FROM AUTHOR]

Typically developing infants show a reliable developmental sequence of emergence of early social-cognitive skills, such as joint attention, communicative gestures, gaze and point following, imitation, and referential language. First infants share others' attention, then they follow others' attention and then behavior, and then they direct others' attention and then behavior. The current study used a series of tests from a study of typically developing infants (Carpenter, Nagell, & Tomasello, 1998) to investigate interrelations among these social-cognitive skills in young children with autism and children with other developmental delays. Tests of object permanence, spatial relations, facial and manual imitation, and executive function also were included. We found that for most children with autism, unlike other children, tests involving others' attention were more difficult than tests involving others' behavior. However, within the domains of attention and behavior, the typical pattern of sharing, then following, and then directing was evident. There were several positive intercorrelations among the social-cognitive skills (as there were for typically developing infants), but there also was some evidence of individual differences in patterns. Implications for theories of social-cognitive and language development are discussed. [ABSTRACT FROM AUTHOR]

This study used a community sample of 494 twins with a reading disability (223 girls, 271 boys) and 373 twins without a reading disability (189 girls, 184 boys) to assess the relation between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD). Symptoms of DSM-III and DSM-IV ADHD were classified into symptoms of inattention and symptoms of hyperactivity-impulsivity (H/I). Results indicated that individuals with RD were more likely than individuals without RD to meet criteria for ADHD and that the association between RD and ADHD was stronger for symptoms of inattention than for symptoms of H/I. Parents and teachers reported similar rates of ADHD, suggesting that ADHD symptoms were pervasive across settings and were not solely attributable to academic frustration. Analyses of possible gender differences revealed that RD was significantly associated with inattention in both girls and boys but associated with H/I only in boys. This difference may provide a partial explanation for the discrepancy between the gender ratio obtained in referred (approximately 4 boys to 1 girl) and nonreferred (1.2 to 1.5 boys to 1 girl) samples of individuals with RD. Specifically, the hyperactive and impulsive behaviors exhibited by boys with RD may be more disruptive than the inattentive behaviors exhibited by girls and may therefore precipitate more frequent referrals for clinical attention. [ABSTRACT FROM AUTHOR]

Although results obtained from recent twin and adoption studies suggest that individual differences in mathematics performance are due in part to heritable influences, no genetic analysis of mathematics disability (MD) has been previously reported. In this article we present data from the first twin sample ascertained for mathematics deficits (40 identical and 23 same-sex fraternal twin pairs in which at least one member had MD). When mathematics performance data from these twin pairs were subjected to a multiple regression analysis, evidence for a significant genetic etiology was obtained. However, tests for the differential etiology of MD as a function of reading performance level were nonsignificant. Results of this first twin study of MD indicate that the condition is significantly heritable, but data from additional twin pairs will be required to test hypotheses of differential etiology more rigorously. [ABSTRACT FROM AUTHOR]

This study examined whether domain-general cognitive weaknesses in processing speed (PS) or executive functioning (EF) moderate the relation between word reading scores and anxiety such that lower word reading scores in combination with lower cognitive scores are associated with higher anxiety symptoms. The sample consisted of 755 youth ages 8-16 who were recruited as part of the Colorado Learning Disabilities Research Center twins study. Lower scores on PS ( R 2 = .007, p = .014), EF ( R 2 = .009, p = .006), and word reading ( R 2 = .006-.008, p = .010-.032) were associated with higher anxiety scores. In addition, the word reading × cognitive interactions were significant such that lower scores on PS ( R 2 = .010, p = .005) or EF ( R 2 = .013, p = .010) combined with lower word reading were associated with higher-than-expected anxiety symptoms. Results suggest that weaknesses in PS, EF, and word reading are modestly associated with higher anxiety symptoms, and these anxiety symptoms may be compounded in youth with both PS or EF weaknesses and word reading difficulties. These findings can guide assessment approaches for identifying youth with word reading challenges who may be at increased risk for anxiety.

The relationship between the p factor and cognition in youth has largely focused on general cognition (IQ) and executive functions (EF). Another cognitive construct, processing speed (PS), is dissociable from IQ and EF, but has received less research attention despite being related to many different mental health symptoms. The present sample included 795 youth, ages 11-16 from the Colorado Learning Disabilities Research Center (CLDRC) sample. Confirmatory factor analyses tested multiple p factor models, with the primary model being a second-order, multi-reporter p factor. We then tested the correlation between the p factor and a latent PS factor. There was a significant, negative correlation between the p factor and PS (r(87) = -0.42, p < .001), indicating that slower processing speed is associated with higher general mental health symptoms. This association is stronger than previously reported associations with IQ or EF. This finding was robust across models that used different raters (youth and caregiver) and modeling approaches (second-order vs. bifactor). Our findings indicate that PS is related to general psychopathology symptoms. This research points to processing speed as an important transdiagnostic construct that warrants further exploration across development., (© 2023. The Author(s).)

This study investigated the relationship between mathematics difficulties and psychopathology in a large community sample ( N = 881) of youth (8-18 years of age) in the United States. The primary aims of the study were to (a) test the associations between mathematics difficulties and specific components of internalizing, externalizing, attention, and social problems; (b) examine potential age and gender differences; and (c) investigate the longitudinal relationship between mathematics and psychopathology using 5-year follow-up data. Results indicated that individuals with mathematics difficulties exhibited elevations in most dimensions of psychopathology, including anxiety, depression, externalizing behaviors, attention problems, and social problems. Furthermore, mathematics impairment was associated with internalizing problems, rule-breaking behaviors, inattention, and social problems even after controlling for comorbid reading difficulties. Results suggested that the associations between mathematics and psychopathology are generally similar in males and females. Finally, preliminary longitudinal evidence suggested that initial mathematics difficulties predicted elevations of conduct disorder, rule-breaking behavior, inattention, hyperactivity, and social problems at follow-up, with several of these associations remaining significant even after controlling for initial reading. In contrast, there was no significant association between initial mathematics ability and internalizing symptoms at follow-up, demonstrating some amelioration of internalizing symptoms over time.

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., (© 2022. The Author(s).)

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.

Purpose: Speech sound disorder (SSD) in conjunction with a language disorder has been associated with poor literacy acquisition; however, no study has evaluated whether articulation, phonological, or sequencing skills are differentially related to reading skills. Therefore, this study examined the relationship between speech error types at ages 5-6 years and literacy at ages 7-9 years. Phonological errors were hypothesized to predict phonological awareness (PA) and literacy even while accounting for other speech error types and language skills., Method: One hundred twenty-three children, 86 with a history of speech impairment, completed a battery of speech, language, and literacy tests at ages 5-6 years and again at ages 7-9 years. Speech production at ages 5-6 years was analyzed, and indices of articulation errors, phonological errors, and sequencing deficits were obtained. The relationships of these error types to concurrent language and preliteracy skills and to later literacy outcomes were assessed., Results: As expected, phonological, but not articulation, errors at ages 5-6 years predicted concurrent PA and letter knowledge, as well as literacy at ages 7-9 years, even while accounting for language skills. Surprisingly, of all the error types, sequencing deficits showed the strongest relationship with PA (ages 5-6 years) and literacy (ages 7-9 years)., Conclusions: These results suggest that some components of SSD uniquely predict preliteracy and literacy skills, even when controlling for language ability. Future investigations should examine further the association between sequencing deficits and literacy skills, test whether observed relationships hold at younger ages, and evaluate the efficacy of integrating literacy interventions into speech therapy to reduce later reading difficulties., Supplemental Material: https://doi.org/10.23641/asha.19624020.

Despite historical emphasis on "specific" learning disabilities (SLDs), academic skills are strongly correlated across the curriculum. Thus, one can ask how specific SLDs truly are. To answer this question, we used bifactor models to identify variance shared across academic domains (academic g ), as well as variance unique to reading, mathematics, and writing. Participants were 686 children ages 8 to 16. Although the sample was overselected for learning disabilities, we intentionally included children across the full range of individual differences in this study in response to growing recognition that a dimensional, quantitative view of SLD is more accurate than a categorical view. Confirmatory factor analysis identified five academic domains (basic reading, reading comprehension, basic math, math problem-solving, and written expression); spelling clustered with basic reading and not writing. In the bifactor model, all measures loaded significantly on academic g . Basic reading and mathematics maintained variance distinct from academic g , consistent with the notion of SLDs in these domains. Writing did not maintain specific variance apart from academic g , and evidence for reading comprehension-specific variance was mixed. Academic g was strongly correlated with cognitive g ( r = .72) but not identical to it. Implications for SLD diagnosis are discussed.

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 p T  = 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., (© 2020. The Author(s).)

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R 2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success., Competing Interests: Conflict of interest statement The authors declare that Lauren M. McGrath and Bruce F. Pennington receive royalties from the textbook, Diagnosing Learning Disorders: From Science into Practice, 3rd Edition from Guilford Press. All other authors declare no conflicts of interest. The findings reported in this manuscript are original, have not been published previously, and have not been simultaneously submitted elsewhere.

The multiple deficit model (MDM) was proposed because the prevailing single-deficit model provided an inadequate account of atypical neuropsychological development. Across methods and levels of analysis, there has been support for the two fundamental tenets of the MDM, that multiple predictors contribute probabilistically to neurodevelopmental disorders and shared risk factors contribute to comorbidity. Diagnostically, the multiplicity of factors means that no single cognitive deficit or combination of deficits can be used to rule in or out most neurodevelopmental disorders. Challenges for the MDM are that the theory is difficult to falsify and that current cross-sectional studies cannot establish causality. Prospects for further development of the MDM include incorporating an explicit focus on promotive and protective factors and pursuing mechanistic connections between multiple factors across levels of analysis.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies within the United States suggest there are cultural and contextual influences on how Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms are perceived. If such influences operate within a single country, they are likely to also occur between countries. In the current study, we tested whether country differences in mean ADHD scores also reflect cultural and contextual differences, as opposed to actual etiological differences. The sample for the present study included 974 participants from four countries tested at two-time points, the end of preschool and the end of 2 nd grade. Consistent with previous research, we found lower mean ADHD scores in Norway and Sweden in comparison to Australia and the United States, and we tested four explanations for these country differences: 1) Genuine etiological differences, 2) Slower introduction to formal academic skills in Norway and Sweden than in the United States and Australia that indicated a context difference, 3) Under-reporting tendency in Norway and Sweden, or 4) Over-reporting tendency in the United States and Australia. Either under-or over-reporting would be examples of cultural differences in the perception of ADHD symptoms. Of these explanations, results of ADHD measurement equivalence tests across countries rejected the first three explanations and supported the fourth explanation: an over-reporting tendency in the United States and Australia. These findings indicate that parental reporting of ADHD symptoms is more accurate in Norway and Sweden than in Australia and the United States, and thus have important clinical and educational implications for how parental reporting informs an ADHD diagnosis in these countries.

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies., (© 2019 Wiley Periodicals, Inc.)

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10 -8 ) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10 -9 ), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10 -8 ). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10 -8 ) and with all the cognitive traits tested (p = 3.07 × 10 -8 ), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10 -5 -10 -7 ]) and negatively associated with ADHD PRS (p ~ [10 -8 -10 -17 ]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.

Previous research has established that learning to read improves children's performance on reading-related phonological tasks, including phoneme awareness (PA) and nonword repetition. Few studies have investigated whether literacy acquisition also promotes children's rapid automatized naming (RAN). We tested the hypothesis that literacy acquisition should influence RAN in an international, longitudinal population sample of twins. Cross-lagged path models evaluated the relationships among literacy, PA, and RAN across four time points from pre-kindergarten through grade 4. Consistent with previous research, literacy showed bidirectional relationships with reading-related oral language skills. We found novel evidence for an effect of earlier literacy on later RAN, which was most evident in children at early phases of literacy development. In contrast, the influence of earlier RAN on later literacy was predominant among older children. These findings imply that the association between these two related skills is moderated by development. Implications for models of reading development and for dyslexia research are discussed., (© 2017 John Wiley & Sons Ltd.)

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.

Approximate number sense (ANS), the ability to rapidly and accurately compare quantities presented non-symbolically, has been proposed as a precursor to mathematics skills. Earlier work reported low heritability of approximate number sense, which was interpreted as evidence that approximate number sense acts as a fitness trait. However, viewing ANS as a fitness trait is discordant with findings suggesting that individual differences in approximate number sense acuity correlate with mathematical performance, a trait with moderate genetic effects. Importantly, the shared etiology of approximate number sense, mathematics, and general cognitive ability has remained unexamined. Thus, the etiology of approximate number sense and its overlap with math and general cognitive ability was assessed in the current study with two independent twin samples (N = 451 pairs). Results suggested that ANS acuity had moderate but significant additive genetic influences. ANS also had overlap with generalist genetic mechanisms accounting for variance and covariance in mathematics and general cognitive ability. Furthermore, ANS may have genetic factors unique to covariance with mathematics beyond overlap with general cognitive ability. Evidence across both samples was consistent with the proposal that the etiology of approximate number sense functions similar to that of mathematics and general cognitive skills.

The current study tested a multiple-cognitive predictor model of word reading, math ability, and attention in a community-based sample of twins ages 8 to 16 years ( N = 636). The objective was to identify cognitive predictors unique to each skill domain as well as cognitive predictors shared among skills that could help explain their overlap and thus help illuminate the basis for comorbidity of related disorders (reading disability, math disability, and attention deficit hyperactivity disorder). Results indicated that processing speed contributes to the overlap between reading and attention as well as math and attention, whereas verbal comprehension contributes to the overlap between reading and math. There was no evidence that executive functioning skills help account for covariation among these skill domains. Instead, specific executive functions differentially related to certain outcomes (i.e., working memory to math and inhibition to attention). We explored whether the model varied in younger versus older children and found only minor differences. Results are interpreted within the context of the multiple deficit framework for neurodevelopmental disorders.

Background: Males are diagnosed with dyslexia more frequently than females, even in epidemiological samples. This may be explained by greater variance in males' reading performance., Methods: We expand on previous research by rigorously testing the variance difference theory, and testing for mediation of the sex difference by cognitive correlates. We developed an analytic framework that can be applied to group differences in any psychiatric disorder., Results: Males' overrepresentation in the low performance tail of the reading distribution was accounted for by mean and variance differences across sex. There was no sex difference at the high performance tail. Processing speed (PS) and inhibitory control partially mediated the sex difference. Verbal reasoning emerged as a strength in males., Conclusions: Our results complement a previous finding that PS partially mediates the sex difference in symptoms of attention deficit/hyperactivity disorder (ADHD), and helps explain the sex difference in both dyslexia and ADHD and their comorbidity., (© 2017 Association for Child and Adolescent Mental Health.)

Because of recent concerns about the replication of published results in the behavioral and biomedical sciences (Ioannidis, PLoS Medicine, Vol. 2, 2005, p. e124; Open Science Collaboration, Science, Vol. 349, 2015, p. 943; Pashler & Wagenmakers, Perspectives on Psychological Science, Vol. 7, 2012, pp. 528-530), we have conducted a replication of our recently published analyses of longitudinal reading performance and attention deficit-hyperactivity disorder data from twin pairs selected for reading difficulties (Wadsworth et al., Twin Research and Human Genetics, Vol. 18, 2015, pp. 755-761). Results obtained from univariate and bivariate (DeFries & Fulker, Behavior Genetics, Vol. 15, 1985, pp. 467-473; Acta Geneticae Medicae et Gemellologiae: Twin Research, Vol. 37, 1988, pp. 205-216) analyses of data from a subset of twin pairs tested in the International Longitudinal Twin Study of Early Reading Development at post-4th grade, and its continuation into high school at post-9th grade, were compared to those from our previous report. Similar measures of reading performance, the same measures of inattention and hyperactivity/impulsivity, and similar selection criteria were used in the two studies. In general, the patterns of results obtained from these two independent studies were highly similar. Thus, these results clearly illustrate the principle that findings from studies in quantitative behavioral genetics often replicate (Plomin et al., Perspectives on Psychological Science, Vol. 11, 2016, pp. 3-23).

Background: Reading and language skills have overlapping genetic bases, most of which are still unknown. Part of the missing heritability may be caused by copy number variants (CNVs)., Methods: In a dataset of children recruited for a history of reading disability (RD, also known as dyslexia) or attention deficit hyperactivity disorder (ADHD) and their siblings, we investigated the effects of CNVs on reading and language performance. First, we called CNVs with PennCNV using signal intensity data from Illumina OmniExpress arrays (~723,000 probes). Then, we computed the correlation between measures of CNV genomic burden and the first principal component (PC) score derived from several continuous reading and language traits, both before and after adjustment for performance IQ. Finally, we screened the genome, probe-by-probe, for association with the PC scores, through two complementary analyses: we tested a binary CNV state assigned for the location of each probe (i.e., CNV+ or CNV-), and we analyzed continuous probe intensity data using FamCNV., Results: No significant correlation was found between measures of CNV burden and PC scores, and no genome-wide significant associations were detected in probe-by-probe screening. Nominally significant associations were detected (p~10(-2)-10(-3)) within CNTN4 (contactin 4) and CTNNA3 (catenin alpha 3). These genes encode cell adhesion molecules with a likely role in neuronal development, and they have been previously implicated in autism and other neurodevelopmental disorders. A further, targeted assessment of candidate CNV regions revealed associations with the PC score (p~0.026-0.045) within CHRNA7 (cholinergic nicotinic receptor alpha 7), which encodes a ligand-gated ion channel and has also been implicated in neurodevelopmental conditions and language impairment. FamCNV analysis detected a region of association (p~10(-2)-10(-4)) within a frequent deletion ~6 kb downstream of ZNF737 (zinc finger protein 737, uncharacterized protein), which was also observed in the association analysis using CNV calls., Conclusions: These data suggest that CNVs do not underlie a substantial proportion of variance in reading and language skills. Analysis of additional, larger datasets is warranted to further assess the potential effects that we found and to increase the power to detect CNV effects on reading and language.

Background: The onset of hyperactivity/impulsivity and attention problems (HAP) is typically younger than that of conduct problems (CP), and some research supports a directional relation wherein HAP precedes CP. Studies have tested this theory using between-person and between-group comparisons, with conflicting results. In contrast, prior research has not examined the effects of within-person fluctuations in HAP on CP., Method: This study tested the hypothesis that within-person variation in HAP would positively predict subsequent within-person variation in CP, in two population samples of youth (N = 620) who participated in identical methods of assessment over the course of 30 months. Three-level, hierarchical models were used to test for within-person, longitudinal associations between HAP and CP, as well as moderating effects of between-person and between-family demographics., Results: We found a small but significant association in the expected direction for older youth, but the opposite effect in younger and non-Caucasian youth. These results were replicated across both samples., Conclusions: The process by which early HAP relates to later CP may vary by age and racial identity., (© 2015 Association for Child and Adolescent Mental Health.)

Background: Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6., Objective: To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319., Methods: We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap., Results and Conclusions: READ1 and KIAHap show interdependence--READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Approximately 60% of children with reading difficulties (RD) meet criteria for at least one co-occurring disorder. The most common of these, attention deficit-hyperactivity disorder (ADHD), occurs in 20-40% of individuals with RD. Recent studies have suggested that genetic influences are responsible. To assess the genetic etiologies of RD and the comorbidity of RD and two ADHD symptom dimensions -- inattention (IN) and hyperactivity/impulsivity (H/I) -- we are conducting the first longitudinal twin study of RD and ADHD. Data from twin pairs in which at least one member of the pair met criteria for proband status for RD at initial assessment, and were reassessed 5 years later, were subjected to DeFries-Fulker (DF) analysis. Analyses of reading composite data indicated that over 60% of the proband deficit at initial assessment was due to genetic influences, and that reading deficits at follow-up were due substantially to the same genetic influences. When a bivariate DF model was fitted to reading performance and IN data, genetic influences accounted for 60% of contemporaneous comorbidity and over 60% of the longitudinal relationship. In contrast, analysis of the comorbidity between reading performance and H/I indicated that common genetic influences accounted for only about 20% of the contemporaneous and about 10% of the longitudinal relationships. Results indicate that (1) genetic influences on RD are substantial and highly stable; (2) the comorbidity between RD and IN is due largely to genetic influences, both contemporaneously and longitudinally; and (3) genetic influences contribute significantly less to the comorbidity between RD and H/I.

Objective: To identify distinct behavioral and cognitive profiles associated with ADHD in Turner syndrome (TS), relative to idiopathic ADHD and neurotypical controls, in order to elucidate X-linked influences contributing to ADHD., Methods: We used a multilevel-model approach to compare 49 girls with TS to 37 neurotypical females, aged 5-12, on established measures of behavior (BASC-2) and neurocognitive function (NEPSY). We further compared girls with TS to BASC-2 and NEPSY age-matched reference data obtained from children with idiopathic ADHD., Results: Within the TS group, 51% scored at or above the "at-risk" range for ADHD-associated behaviors on the BASC-2 (TS/+ADHD). The BASC-2 behavioral profile in this TS/+ADHD-subgroup was comparable to a reference group of boys with ADHD with respect to attentional problems and hyperactivity. However, the TS/+ADHD-subgroup had significantly higher hyperactivity scores relative to a reference sample of girls with ADHD (p = 0.016). The behavioral profile in TS was associated with significantly lower attention and executive function scores on the NEPSY relative to neurotypical controls (p = 0.015); but was comparable to scores from a reference sample of children with idiopathic ADHD. Deficits in attention and executive function were not observed in girls with TS having low levels of ADHD-associated behavior (TS/-ADHD)., Conclusions: ADHD-associated behavioral and cognitive problems in TS are prevalent and comparable in severity to those found in children with idiopathic ADHD. The ADHD phenotype in TS also appears relatively independent of cognitive features typically associated with TS, like visuospatial weaknesses. These findings suggest that X-linked haploinsufficiency and downstream biological effects contribute to increased risk for ADHD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Males show higher rates of attention deficit hyperactivity disorder (ADHD) than do females. Potential explanations include genuine etiological differences or artifact., Methods: 2,332 twin and sibling youth participated in behavioral and cognitive testing. Partially competing models of symptom severity distribution differences, the mean difference, and variance difference models, were tested within a randomly selected subsample. The Delta method was used to test for mediation of sex differences in ADHD symptom severity by processing speed, inhibition and working memory., Results: The combined mean difference and variance difference models fully explained the sex difference in ADHD symptom severity. Cognitive endophenotypes mediated 14% of the sex difference effect., Conclusions: The sex difference in ADHD symptom severity is valid and may be due to differing genetic and cognitive liabilities between the sexes., (© 2014 Association for Child and Adolescent Mental Health.)

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated., (© 2015 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Objective: To advance our understanding of adult ADHD and sluggish cognitive tempo (SCT), the present study investigates their construct validity by exploring the nature of trait- and method-related variance in self- and parent-ratings of ADHD and SCT., Method: Using a multitrait-multimethod (MTMM) design, response variance in college undergraduates' (n = 3,925) and a subset of their parents' (n = 2,242) ratings was decomposed into method, trait, and error-specific variance., Results: Global evidence for convergent and discriminant validity was supported, but parameter-level comparisons suggest that method effects, situational specificity, and ADHD's core feature--inattention--are prominent., Conclusion: This investigation offers two important conclusions: (a) SCT appears to be a related but separate factor from ADHD; and (b) self- and parent-ratings of emerging adult ADHD exhibit low to moderate correlations and support the situational specificity hypothesis, suggesting that multiple raters should be consulted when assessing adult ADHD. Implications of these findings and recommendations for the continued study of SCT are discussed., (© 2014 SAGE Publications.)

This review uses a levels-of-analysis framework to summarize the current understanding of developmental dyslexia's etiology, brain bases, neuropsychology, and social context. Dyslexia is caused by multiple genetic and environmental risk factors as well as their interplay. Several candidate genes have been identified in the past decade. At the brain level, dyslexia is associated with aberrant structure and function, particularly in left hemisphere reading/language networks. The neurocognitive influences on dyslexia are also multifactorial and involve phonological processing deficits as well as weaknesses in other oral language skills and processing speed. We address contextual issues such as how dyslexia manifests across languages and social classes as well as what treatments are best supported. Throughout the review, we highlight exciting new research that cuts across levels of analysis. Such work promises eventually to provide a comprehensive explanation of the disorder as well as its prevention and remediation.

Studies of poor comprehenders vary in the selection criteria and tests that they use to define poor comprehension. Could these differences play a role in determining findings about poor comprehension? This study assessed the extent to which differences in selection methods affect who gets identified as poor comprehenders, and examined how their cognitive profiles differ. Over 1,500 children, ages 8 - 19, took multiple tests of reading comprehension, listening comprehension, single word reading and nonword reading. Poor comprehension was defined by performing in the low-tail and by discrepancies either with word or nonword reading. Odds of any two selection methods identifying the same individuals were generally low, and depended on type of comprehension test more than modality, as well as selection criteria, and comprehender's age. Poor comprehenders selected by the different methods were found to vary in IQ, working memory, but not attention. The findings show that differences across studies in tests and selection criteria used to define poor comprehension are not insignificant and can have substantial consequences for what is meant by poor comprehension and its associated deficits.

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10(-7) for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills., (© 2014 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI-and their associated deficits-are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.

Reversal errors play a prominent role in theories of reading disability. We examined reversal errors in the writing of letters by 5-6-year-old children. Of the 130 children, 92 had a history of difficulty in producing speech sounds, a risk factor for reading problems. Children were more likely to reverse letter forms that face left, such as 〈d〉 and 〈J〉, than forms that face right, such as 〈b〉 and 〈C〉. We propose that this asymmetry reflects statistical learning: Children implicitly learn that the right-facing pattern is more typical of Latin letters. The degree of asymmetry that a child showed was not related to the child's reading skill at Time 2, 2 ¾ years later. Although children who went on to become poorer readers made more errors in the letter writing task than children who went on to become better readers, they were no more likely to make reversal errors.

Studies of subtypes of DSM-IV attention-deficit/hyperactivity disorder (ADHD) have provided inconsistent support for the discriminant validity of the combined type (ADHD-C) and predominantly inattentive type (ADHD-I). A large sample of children and adolescents with ADHD (N = 410) and a comparison group without ADHD (N = 311) were used to test the internal and external validity of sluggish cognitive tempo (SCT), a dimension characterized by low energy and sleepy and sluggish behavior. SCT scores were then incorporated in analyses of ADHD subtypes to test whether the discriminant validity of ADHD-C and ADHD-I could be improved by including SCT symptoms as part of the criteria for ADHD-I. Factor analyses of parent and teacher ratings indicated that six SCT items loaded on a factor separate from symptoms of ADHD and other psychopathology, providing important support for the internal validity of SCT. The external validity of SCT was supported by significant associations between SCT and measures of functional impairment and neuropsychological functioning when symptoms of ADHD and other psychopathology were controlled. However, contrary to initial predictions, high levels of SCT did not identify a subgroup of ADHD-I that was clearly distinct from ADHD-C. Instead, the current results suggest that DSM-IV inattention and SCT are separate but correlated symptom dimensions that are each independently associated with important aspects of functional impairment and neuropsychological functioning.

Limited evidence supports the external validity of the distinction between developmental phonological and surface dyslexia. We previously identified children age 8 to 13 meeting criteria for these subtypes (Peterson, Pennington, & Olson, 2013), and now report on their reading and related skills approximately 5 years later. Longitudinal stability of subtype membership was fair and appeared stronger for phonological than surface dyslexia. Phonological dyslexia was associated with a pronounced phonological awareness deficit, but subgroups otherwise had similar cognitive profiles. Subtype did not inform prognosis. Results provide modest evidence for the validity of the distinction, although not for its clinical utility.

Background: Previous research on the etiology of ADHD symptoms suggests that neuropsychological differences may be present as early as birth; however, the diagnosis is typically not given until school age. This study aimed to (a) identify early behavioral and cognitive markers of later significant parent and/or teacher ratings of ADHD symptomology, (b) examine sex differences in these predictors, and (c) describe the developmental trajectories of comorbid symptoms in school-aged children., Methods: 1,106 children and at least one parent enrolled in the NICHD Study of Early Child Care and Youth Development were followed from 1 month of age through 6th grade. Effect size calculations, discriminant function analysis, and growth curve analyses were conducted to address the three aims., Results: Children with high- versus low-ADHD symptomology at 3rd grade could be distinguished using cognitive and behavioral measures as early as 15 months (females) and 24 months (males). Sensitivity and specificity were modest at 15, 24, and 26 months. Growth curves revealed significant differences between high- and low-ADHD groups in comorbid symptoms at kindergarten and significantly different slopes for externalizing, social skills, and academic skills ratings across elementary school. There were few gender differences on cognitive and behavioral variables within the high-ADHD group., Conclusions: Cognitive and behavioral markers of ADHD symptoms are present in children prior to entry into formal schooling, but current behavioral screeners are not developmentally sensitive to these differences in infancy and toddlerhood., (© 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.)

Reading disability (RD) and math disability (MD) frequently co-occur, but the etiology of this comorbidity is not well understood. Groups with RD only (N = 241), MD only (N = 183), and RD + MD (N = 188) and a control group with neither disorder (N = 411) completed a battery of measures of internalizing and externalizing psychopathology, social and academic functioning, and 10 neuropsychological processes. Groups with RD only, MD only, and RD + MD were significantly impaired versus the control group on nearly all measures, and the group with RD + MD was more impaired than the groups with MD and RD alone on measures of internalizing psychopathology, academic functioning, and 7 of 10 neuropsychological constructs. Multiple regression analyses of the neuropsychological measures indicated that deficits in reading and math were associated with shared weaknesses in working memory, processing speed, and verbal comprehension. In contrast, reading difficulties were uniquely associated with weaknesses in phoneme awareness and naming speed, and math deficits were uniquely associated with weaknesses in set shifting. These results support multiple-deficit neuropsychological models of RD and MD and suggest that RD and MD are distinct but related disorders that co-occur because of shared neuropsychological weaknesses in working memory, processing speed, and verbal comprehension.