This article has 2 primary goals. First, a brief tutorial on behavioral and molecular genetic methods is provided for readers without extensive training in these areas. To illustrate the application ...of these approaches to developmental disorders, etiologically informative studies of reading disability (RD), math disability (MD), and attention-deficit hyperactivity disorder (ADHD) are then reviewed. Implications of the results for these specific disorders and for developmental disabilities as a whole are discussed, and novel directions for future research are highlighted.
Previous family and twin studies of RD, MD, and ADHD are reviewed systematically, and the extensive molecular genetic literatures on each disorder are summarized. To illustrate 4 novel extensions of these etiologically informative approaches, new data are presented from the Colorado Learning Disabilities Research Center, an ongoing twin study of the etiology of RD, ADHD, MD, and related disorders.
RD, MD, and ADHD are familial and heritable, and co-occur more frequently than expected by chance. Molecular genetic studies suggest that all 3 disorders have complex etiologies, with multiple genetic and environmental risk factors each contributing to overall risk for each disorder. Neuropsychological analyses indicate that the 3 disorders are each associated with multiple neuropsychological weaknesses, and initial evidence suggests that comorbidity between the 3 disorders is due to common genetic risk factors that lead to slow processing speed.
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.
This study
evaluated the internal structure and convergent and discriminant evidence for
the Colorado Learning Difficulties Questionnaire (CLDQ), a 20-item parent-report
rating scale that was ...developed to provide a brief screening measure for
learning difficulties. CLDQ ratings were obtained from parents of children in 2
large community samples and 2 samples from clinics that specialize in the
assessment of learning disabilities and related disorders (total
N = 8,004). Exploratory and confirmatory factor analyses
revealed 5 correlated but separable dimensions that were labeled
reading, math, social
cognition, social anxiety, and spatial
difficulties. Results revealed strong convergent and discriminant
evidence for the CLDQ Reading scale, suggesting that this scale may provide a
useful method to screen for reading difficulties in both research studies and
clinical settings. Results are also promising for the other 4 CLDQ scales, but
additional research is needed to refine each of these measures.
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.
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.
To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach.
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.
Genome-wide significant effects were observed at rs1555839 (p=4.03×10
) 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
in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating
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.
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.
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.
This review includes 1) an explanation of what neuropsychology is, 2) a brief history of how developmental cognitive neuroscience emerged from earlier neuropsychological approaches to understanding ...atypical development, 3) three recent examples that illustrate the benefits of this approach, 4) issues and challenges this approach must face, and 5) a forecast for the future of this approach.
Abstract 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.
In a 3-year longitudinal study, middle- to upper-middle-class preschool children at high family risk (HR group, N = 67) and low family risk (LR group, N = 57) for dyslexia (or reading disability, ...RD), were evaluated yearly from before kindergarten to the end of second grade. Both phonological processing and literacy skills were tested at each of four time points. Consistent with the well-known familiarity of RD, 34% of the HR group compared with 6% of the LR group became RD. Participants who became RD showed deficits in both implicit and explicit phonological processing skills at all four time points, clearly indicating a broader phonological deficit than is often found at older ages. The predictors of literacy skill did not vary by risk group. Both risk groups underwent a similar developmental shift from letter-name knowledge to phoneme awareness as the main predictor of later literacy skill. This shift, however, occurred 2 years later in the HR group. Familial risk was continuous rather than discrete because HR children who did not become RD performed worse than LR non-RD children on some phonological and literacy measures. Finally, later RD could be predicted with moderate accuracy at age 5 years, with the strongest predictor being letter-name knowledge.
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