Biomedical subjects

Bruce F Pennington

Publications and source records attributed to Bruce F Pennington.

30 records · Page 2Linked to original sources

PubMed2004

Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: linkage and association analyses.

Reading disability (RD), or dyslexia, is the most common learning disability with a prevalence rate of ~5%-10% in school-age children. RD is highly heritable with evidence of a neurobiological origin. Linkage studies have identified several quantitative trait loci (QTLs) for RD. The QTL on chromosome 6p21.3 has been independently replicated by several groups and spans a 16.4-Mb (13.8 cM) interval from D6S109 to D6S291. In this study, we performed sib-pair linkage analyses with Haseman-Elston and DeFries-Fulker methods to define more accurately the QTL interval. Linkage was assessed by using five quantitative phenotypes, including a composite measure of reading performance and four component phenotypes. When probands were selected for severe scores, single- and multi-point analyses showed significant linkage with all five phenotypes, converging over an interval of ~3.24 Mb spanning D6S1597 to D6S1571. Maximal linkage converged at marker D6S1554 across phenotypes. Out of 12 genes in the linkage interval, ten clustered within ~680 kb and were selected for association analysis based on central nervous system expression and putative function. Marker-trait associations were assessed by using QTDT (a general test of association for quantitative traits) and the family-based association test (FBAT), and haplotype analysis was performed by using FBAT and the GeneHunter Transmission/Disequilibrium Test TDT. Marker associations were detected in five of the ten genes, results that were corroborated by our haplotype TDT analysis. The results of the association study have thereby allowed us to significantly reduce the number of possible candidate genes and to prioritize genes for further mutation screening.

Adolescent↗

PubMed2004

The relation between sluggish cognitive tempo and DSM-IV ADHD.

To test the relation between sluggish cognitive tempo (SCT) and DSM-IV ADHD symptoms, parent and teacher ratings of the 18 DSM-IV ADHD items and five potential SCT items were obtained in a community sample of 8-18 year-old twins that was overselected for ADHD and learning disabilities (n = 296). Confirmatory factor analyses revealed that a three-factor model provided the best fit to the data for both parent and teacher ratings. DSM-IV inattention and hyperactivity-impulsivity symptoms loaded on two factors consistent with the DSM-IV model, and five SCT symptoms loaded primarily on a third factor. The SCT and inattention factors were highly correlated, whereas SCT and hyperactivity-impulsivity were weakly related. Both raters indicated that children meeting symptom criteria for the combined and inattentive subtypes exhibited significantly more SCT symptoms than those meeting symptom criteria for hyperactive-impulsive type and the comparison group without ADHD. Children meeting symptom criteria for the inattentive type exhibited significantly more SCT symptoms than those meeting criteria for the combined type, based on teacher ratings. These results suggest that SCT is an internally consistent construct that is significantly associated with DSM-IV inattention.

Attention↗

PubMed2004

Performance on Cambridge Neuropsychological Test Automated Battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the Collaborative Programs of Excellence in Autism network.

Recent structural and functional imaging work, as well as neuropathology and neuropsychology studies, provide strong empirical support for the involvement of frontal cortex in autism. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer-administered set of neuropsychological tests developed to examine specific components of cognition. Previous studies document the role of frontal cortex in performance of two CANTAB subtests: the Stockings of Cambridge, a planning task, and the Intradimensional/Extradimensional Shift task, a measure of cognitive set shifting. To examine the integrity of frontal functions, these subtests were administered to 79 participants with autism and 70 typical controls recruited from seven universities who are part of the Collaborative Programs of Excellence in Autism network. The two groups were matched on age, sex, and full-scale IQ. Significant group differences were found in performance on both subtests, with the autism group showing deficits in planning efficiency and extradimensional shifting relative to controls. Deficits were found in both lower- and higher-IQ individuals with autism across the age range of 6 to 47 years. Impairment on the CANTAB executive function subtests did not predict autism severity or specific autism symptoms (as measured by the ADI-R and ADOS), but it was correlated with adaptive behavior. If these CANTAB subtests do indeed measure prefrontal function, as suggested by previous research with animals and lesion patients, this adds to the accumulating evidence of frontal involvement in autism and indicates that this brain region should remain an active area of investigation.

Adolescent↗

PubMed2004

Pre-literacy skills of subgroups of children with speech sound disorders.

BACKGROUND: The existing literature has conflicting findings about the literacy outcome of children with speech sound disorders (SSD), which may be due to the heterogeneity within SSD. Previous studies have documented that two important dimensions of heterogeneity are the presence of a comorbid language impairment (LI) and the persistence of SSD, but these factors have not been examined separately. METHOD: The current study used a 2 x 2 MANOVA design (with follow-up MANCOVAs) to examine how a comorbid language impairment (LI) and the persistence of SSD relate to pre-literacy skills in a sample of 5- to 6-year-old children with SSD. RESULTS: Significant main effects for persistent SSD and LI were obtained, such that each factor was associated with worse performance on pre-literacy tasks, particularly those assessing phonological awareness (even with nonverbal IQ covaried). In addition, even SSD children with normalized speech without LI were found to have deficits on phonological awareness tasks relative to control participants. CONCLUSIONS: These results suggest that a history of SSD and comorbid LI are strong correlates of pre-literacy deficits.

Child↗

PubMed2003

Etiology of the comorbidity between RD and ADHD: exploration of the non-random mating hypothesis.

The present research sought to test the validity of the non-random mating hypothesis in a community sample in order to determine whether it contributes significantly to the comorbidity between attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) and to test whether the two disorders segregate independently. Data were gathered from 394 twin participants of the Colorado Learning Disabilities Research Center (CLDRC) and their biological parents. Parents were asked to complete retrospective questionnaires regarding their own ADHD and RD symptomatology as children, as well as rate their children on DSM-IV ADHD symptomatology before age 12. Twin RD was assessed by a composite score consisting of several reading measures. Chi-square and correlational analyses assessed the presence of non-random mating, as well as whether the two disorders were transmitted independently. Non-random mating between those with ADHD and those with RD did not significantly contribute to the comorbidity of the two disorders. Furthermore, there was some evidence that these two disorders did not segregate independently in this sample. These results are consistent with recent evidence that ADHD and RD are often comorbid because of significant genetic overlap. There was little evidence to support that non-random mating also contributes to this comorbidity in the present sample.

Adolescent↗

PubMed2002

Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder.

Comorbidity is pervasive among both adult and child psychiatric disorders; however, the etiological mechanisms underlying the majority of comorbidities are unknown. This study used genetic linkage analysis to assess the etiology of comorbidity between reading disability (RD) and attention-deficit hyperactivity disorder (ADHD), two common childhood disorders that frequently co-occur. Sibling pairs (N = 85) were ascertained initially because at least one individual in each pair exhibited a history of reading difficulties. Univariate linkage analyses in sibling pairs selected for ADHD from within this RD-ascertained sample suggested that a quantitative trait locus (QTL) on chromosome 6p is a susceptibility locus for ADHD. Because this QTL is in the same region as a well-replicated QTL for reading disability, subsequent bivariate analyses were conducted to test if this QTL contributed to comorbidity between the two disorders. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and three measures of reading difficulty, indicating that comorbidity between RD and ADHD may be due at least in part to pleiotropic effects of a QTL on chromosome 6p.

Analysis of Variance↗

PubMed2002

Interrelations among social-cognitive skills in young children with autism.

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.

Autistic Disorder↗

PubMed2002

Eye movement abnormality suggestive of a spatial working memory deficit is present in parents of autistic probands.

Autistic probands exhibit impaired spatial accuracy and impaired response suppression errors during a delayed oculomotor response task. Family members of autistic probands, and thus the possible familial nature of these deficits, have not been assessed. Eleven parents of autistic probands and 17 adults from unaffected families, ages 25-50 years, completed oculomotor delayed-response tasks. Parents of autistic probands demonstrated poorer spatial accuracy than the comparison group (p = .002), with no significant differences between groups on percentage of premature saccades or latency of remembered saccades. Spatial working memory deficits, as measured by the delayed oculomotor response task, appear to be familial in families with an autistic proband. These deficits deserve further evaluation as a potential endophenotypic marker for genetic risk for autism.

Adult↗

PubMed2002

Fine mapping of the chromosome 2p12-16 dyslexia susceptibility locus: quantitative association analysis and positional candidate genes SEMA4F and OTX1.

A locus on chromosome 2p12-16 has been implicated in dyslexia susceptibility by two independent linkage studies, including our own study of 119 nuclear twin-based families, each with at least one reading-disabled child. Nonetheless, no variant of any gene has been reported to show association with dyslexia, and no consistent clinical evidence exists to identify candidate genes with any strong a priori logic. We used 21 microsatellite markers spanning 2p12-16 to refine our 1-LOD unit linkage support interval to 12cM between D2S337 and D2S286. Then, in quantitative association analysis, two microsatellites yielded P values<0.05 across a range of reading-related measures (D2S2378 and D2S2114). The exon/intron borders of two positional candidate genes within the region were characterized, and the exons were screened for polymorphisms. The genes were Semaphorin4F (SEMA4F), which encodes a protein involved in axonal growth cone guidance, and OTX1, encoding a homeodomain transcription factor involved in forebrain development. Two non-synonymous single nucleotide polymorphisms were found in SEMA4F, each with a heterozygosity of 0.03. One intronic single nucleotide polymorphism between exons 12 and 13 of SEMA4F was tested for quantitative association, but no significant association was found. Only one single nucleotide polymorphism was found in OTX1, which was exonic but silent. Our data therefore suggest that linkage with reading disability at 2p12-16 is not caused by coding variants of SEMA4F or OTX1. Our study outlines the approach necessary for the identification of genetic variants causing dyslexia susceptibility in an epidemiological population of dyslexics.

Chromosome Mapping↗

PubMed2001

Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia.

Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait.

Child↗

PubMed1998

A neuropsychological examination of the underlying deficit in attention deficit hyperactivity disorder: frontal lobe versus right parietal lobe theories.

A neuropsychological approach was used to examine the frontal lobe and right parietal lobe theories of attention deficit hyperactivity disorder (ADHD). Considerable attempts were made to select as pure a group of ADHD boys as possible. The performance of 10-14-year-old ADHD boys (n = 22), both on and off stimulant medication, was compared with the performance of non-ADHD control boys (n = 22) on tasks purported to assess frontal lobe functioning (Stopping Task, Antisaccade Task, Tower of Hanoi) and right parietal lobe functioning (Visual-Spatial Cuing Task, Turning Task, Spatial Relations). Three important findings emerged: (a) unmedicated ADHD boys exhibited performance deficits on tasks in both frontal and parietal domains compared with control boys, (b) unmedicated ADHD boys appeared to be more severely impaired on the frontal tasks than on the parietal tasks, and (c) medicated ADHD boys performed better in both task domains compared with unmedicated ADHD boys. Several alternative interpretations of the results are discussed.

Adolescent↗

PubMedDate not supplied

The neuropsychology of Down syndrome: evidence for hippocampal dysfunction.

This study tested prefrontal and hippocampal functions in a sample of 28 school-aged (M = 14.7 years, SD = 2.7) individuals with Down syndrome (DS) compared with 28 (M = 4.9 years, SD = .75) typically developing children individually matched on mental age (MA). Both neuropsychological domains were tested with multiple behavioral measures. Benchmark measures of verbal and spatial function demonstrated that this DS sample was similar to others in the literature. The main finding was a significant Group x Domain interaction effect indicating differential hippocampal dysfunction in the group with DS. However, there was a moderate partial correlation (r = .54, controlling for chronological age) between hippocampal and prefrontal composite scores in the DS group, and both composites contributed unique variance to the prediction of MA and adaptive behavior in that group. In sum, these results indicate a particular weakness in hippocampal functions in DS in the context of overall cognitive dysfunction. It is interesting that these results are similar to what has been found in a mouse model of DS. Such a model will make it easier to understand the neurobiological mechanisms that lead to the development of hippocampal dysfunction in DS.

Adolescent↗