Biomedical subjects

R Tannock

Publications and source records attributed to R Tannock.

At least 19 recordsLinked to original sources

PubMed2006

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Adult↗

PubMed2005

The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.

The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD.

Animals↗

PubMed2005

Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a childhood-onset disorder characterized by marked inattention, hyperactivity and impulsivity. The dopaminergic system has been hypothesized to be involved in the development of ADHD. Positive associations have been found for the dopamine receptors D1 and D5 genes, suggesting that other genes involved in D1/D5 signalling may also contribute to ADHD. In this study, we tested the calcyon gene (DRD1IP), which encodes a brain-specific D1-interacting protein involved in D1/D5 receptors calcium signalling, for association with ADHD. The inheritance of nine polymorphisms in the calcyon gene was examined in a sample of 215 nuclear families, with 260 affected children, using the transmission/disequilibrium test. The most common haplotype, designated C1, demonstrated significant evidence for excess transmission. Quantitative trait analyses of this haplotype showed significant relationships with both the inattentive (parent's rating, P=0.006; teacher's rating, P=0.003) and hyperactive/impulsive (parent's rating, P=0.004) dimensions of the disorder. Two of the nine marker alleles included in haplotype C1, rs4838721A located approximately 10 kb 5' of the gene and rs2275723C located 10 bp upstream of the exon 5 acceptor splice site, also showed significant evidence for association when analysed individually. As these two variants are not predicted to alter calcyon function, we screened the gene exons by sequencing. No variation in the coding region was identified, suggesting that a causal variant allele resides elsewhere in a regulatory sequence of the gene. These findings support the proposed involvement of the calcyon gene in ADHD and implicate haplotype C1 as containing a risk allele.

Adolescent↗

PubMed2005

Tapping and anticipation performance in attention deficit hyperactivity disorder.

The objective of this study was to examine the precise timing of a motor response in a sample of adolescents with ADHD and comparison participants. 46 participants with ADHD (M age=15.6, SD=1.4; 40 boys) and 44 control participants (M age=15.3, SD=1.4; 40 boys) were recruited through a metropolitan hospital. Participants were administered a tapping task and an anticipation task. Adolescents with ADHD displayed significantly more intra-individual variability on the visual 1000-msec. frequency interval of the tapping task and displayed lower accuracy on the cued and uncued trials of the anticipation task than comparison participants. Intra-individual variability on the tapping task was correlated with intra-individual variability on the anticipation task within both the ADHD and control groups. These findings suggest that adolescents with ADHD have impairments in both the cognitive representation and motor production of the precise timing of a motor response.

Acoustic Stimulation↗

PubMed2004

Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.

Adolescent↗

PubMed2004

Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.

The glutamate system may be involved in the development of attention-deficit/hyperactivity disorder (ADHD) based on animal models and the role of N-methyl-D-aspartate receptors (NMDAR) in cognition and motor processes. A follow-up study of the first genome scan for ADHD identified significant evidence for linkage to the 16p13 region. The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the NMDA receptor, resides in this region and a recent study has reported an association between this gene and ADHD. We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children. In contrast to previous findings, we did not identify any evidence for a relationship of these markers and ADHD. Owing to the role of GRIN2A in aspects of cognition, we investigated the relationship of this gene to the cognitive phenotypes of inhibitory control, verbal short-term memory and verbal working memory. There was no significant evidence of linkage between GRIN2A and these phenotypes. While the results were not significant in our sample, the previous association finding suggests that further study of this gene is warranted.

Adolescent↗

PubMed2004

Support for EKN1 as the susceptibility locus for dyslexia on 15q21.

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.

Child↗

PubMed2003

The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder.

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (chi(2) = 2.91, P = 0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (chi(2) = 4.80, P = 0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.

Adolescent↗

PubMed2003

Time perception deficits in attention-deficit/ hyperactivity disorder and comorbid reading difficulties in child and adolescent samples.

BACKGROUND: Our objective was to investigate time perception in Attention-Deficit/Hyperactivity Disorder (ADHD) with and without comorbid reading difficulties (RD) in child and adolescent participants. METHOD: In study 1, 50 children with ADHD (31 ADHD, 19 ADHD+RD) and age-matched healthy controls (n = 50) completed three psychophysical tasks: duration discrimination (target duration of 400 ms versus a foil duration), frequency discrimination (a control condition to evaluate general perceptual ability), and a duration estimation task using the method of reproduction for intervals of 400 ms, 2000 ms, and 6000 ms. Study 2 used the same tasks with an adolescent sample (35 ADHD, 24 ADHD+RD, 39 controls). RESULTS: In both studies, children and adolescents with ADHD and ADHD+RD displayed some impairments in duration discrimination and the precision with which they reproduced the intervals on the estimation task, particularly the shorter 400 ms interval. The most severe impairments tended to occur in the comorbid ADHD+RD group. No impairments were found on the frequency discrimination task. ADHD participants also displayed significant intra-individual variability in their performance on the estimation task. Finally, short-term and working memory, estimated full-scale IQ, and teacher report of hyperactivity/impulsivity were found to differentially predict performance on the time perception measures in the adolescent clinical sample. CONCLUSIONS: Deficits in duration discrimination, duration estimation, and intra-individual performance variability may have cascaded effects on the temporal organisation of behaviour in children and adolescents with ADHD and ADHD+RD.

Adolescent↗

PubMed2003

The attributions of children with Attention-Deficit/ Hyperactivity Disorder for their problem behaviors.

This study investigated the attributions children with ADHD make about their most problematic symptoms. Children were interviewed to determine the degree to which they felt their behavior was controllable, stable, global, and stigmatizing; and about the locus of the cause of their behavior. Participants were 16 children with ADHD (10 boys, 6 girls), and 16 children without ADHD (9 boys, 7 girls), ages 7 to 13. The present study demonstrated that children with ADHD viewed their most problematic behaviors as less within their control and more global across situations than children without ADHD. Children with ADHD were more likely than children without ADHD to view their most problematic behavior as always having been present, but were no more likely to view their most problematic behavior as persisting into the future. No significant group differences emerged on the locus of causality dimension. With regards to stigmatization, girls without ADHD reported that their behaviors can bother their teachers, parents, and peers, whereas girls and boys with ADHD did not perceive their behavior as bothersome.

Adolescent↗

PubMed2002

Validity of the Brown ADD scales: an investigation in a predominantly inattentive ADHD adolescent sample with and without reading disabilities.

The Brown ADD Scale for Adolescents is widely used in clinical settings, yet, no published studies have investigated divergent and concurrent validity and specificity and sensitivity to inattentive ADHD symptomatology. Ninety-eight participants (13 to 16 years) were classified as ADHD/I and/or reading disabled (RD) using Kiddie Schedule for Affective Disorder and Schizophrenia (K-SADS), Conners' Rating Scales (CRS-R), and Ontario Child Health Study Scales (OCHSS), WRAT3, and WRMT-R. The results were: 29 ADHD/I; 12 RD, 16 ADHD/I with RD; and, 41 controls. The RD group was included to evaluate specificity. The Brown was administered but not used in classification. The ADHD groups scored higher on the Brown subscales compared with the other two groups. The recommended cutoffs resulted in high rates of false negatives but few false positives; this suggests good specificity but poor sensitivity. There were moderate correlations among the Brown, CRS-R, and OCHSS. The Brown can be useful in screening out ADHD; however, its low sensitivity precludes its usefulness in diagnosing ADHD.

Adolescent↗

PubMed2001

Actigraphy and parental ratings of sleep in children with attention-deficit/hyperactivity disorder (ADHD).

STUDY OBJECTIVES: To assess various sleep parameters in latency-aged children with ADHD and their normally developing peers through the use of multiple sleep measures. DESIGN: Six sleep parameters were evaluated for two groups of children, ADHD and normal comparison. Each group consisted of 25 children (20 males, 5 females) who ranged in age from 7 to 11 years. All children underwent rigorous diagnostic procedures and the ADHD subjects were selected only if they displayed pervasiveness in their symptomatology and were medication naive. Parents completed a retrospective questionnaire which evaluated sleep problems over the past six months. Additionally, each child wore an actigraph for seven consecutive nights, and the child's parents completed a sleep diary during this time period. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. RESULTS: Based on the findings from the questionnaire, parents of children with ADHD reported significantly more sleep problems than parents of normally developing children. However, the majority of these sleep differences were not verified through actigraphy or sleep diary data, with the exception of longer sleep duration for children with ADHD and parent reports that describe increased bedtime resistence. It was also found that child-parent interactions during bedtime routines were more challenging in the ADHD group. CONCLUSIONS: Despite the possibility of intrinsic sleep problems such as longer sleep duration, results indicate that many of the sleep problems of children with ADHD may be due to challenging behaviours during bedtime routines. The reason for discrepancies among sleep studies employing objective measures as well as between retrospective and prospective measures are discussed.

Attention Deficit Disorder with Hyperactivity↗

PubMed2001

Linkage study of polymorphisms in the gene for myelin oligodendrocyte glycoprotein located on chromosome 6p and attention deficit hyperactivity disorder.

Family and twin studies have shown that there is a substantial genetic contribution to both reading disabilities (RD) and attention deficit hyperactivity disorder (ADHD), and recent twin studies have suggested that the overlap between these phenotypes is largely due to common genetic influences. Studies using a linkage approach to search for genes for susceptibility to RD and ADHD have identified regions linked to each of these phenotypes separately, with recent studies suggesting that some chromosomal regions may contribute to both. Linkage to the human leukocyte antigen (HLA) region has been targeted in particular for RD and ADHD, as both of these disorders have been suggested to be autoimmune. Linkage to the HLA region of 6p for RD has now been reported by several groups. Alleles at two genes in the HLA (C4B and DRB1) have also been reported to be associated with ADHD, prompting one investigator to suggest a possible connection between the linkage of RD and ADHD to this region. The location of the gene for myelin oligodendrocyte glycoprotein (MOG), in the region of 6p with the strongest evidence for linkage to RD, and its proposed role as a minor component of myelin in the central nervous system suggest that it may be a factor in neuronal functioning and therefore a candidate for RD and ADHD. In this study, we tested the gene for linkage to ADHD by genotyping two polymorphisms in the MOG gene-a dinucleotide repeat located upstream from the MOG transcription start site and a Val145Ile substitution in exon 3-in a sample of 104 nuclear families identified through a proband with ADHD. We examined the transmission of the alleles of the Val145Ile and the dinucleotide repeat polymorphisms using the transmission disequilibrium test. We did not observe biased transmission of the alleles at either polymorphism to ADHD probands or siblings. Our findings using this sample do not support the role of the MOG gene in ADHD.

Amino Acid Substitution↗

PubMed2001

Linkage study of the alpha2A adrenergic receptor in attention-deficit hyperactivity disorder families.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder, characterized by marked and pervasive inattention, hyperactivity, and impulsiveness. An alteration in the expression or function of the adrenergic system has been suggested to be involved in ADHD based on animal models, pharmacological interventions, and the neural circuitry of attentional processes. The efficacy of clonidine in reducing disruptive behaviors in some children with ADHD argues for a causal role of the adrenergic system and more specifically for the alpha2A receptors as clonidine is an alpha2A agonist that inhibits release of noradrenaline into the synapse. In animal studies, alpha2A receptor agonists have also been shown to improve performance on working memory tasks under distracting conditions, indicating that these receptors function in the regulation of attention. We examined the possibility that the gene for the alpha2A adrenergic receptor (ADRA2A) is linked to ADHD by testing a polymorphism located in the promoter region of the ADRA2A gene in a sample of 94 nuclear families with an ADHD proband. We found no evidence for linkage of the ADRA2A gene with ADHD, using the transmission disequilibrium test in this set of families.

Adolescent↗

PubMed2001

Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. METHODS: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. RESULTS: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. CONCLUSIONS: Our results support previous findings of an association between the DAT1 gene and ADHD.

Alleles↗

PubMed2001

5'-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

Recently the molecular genetic basis of attention-deficit hyperactivity disorder (ADHD) has been the focus of a number of studies with the majority of these investigating the role of dopamine system genes. A great deal of attention has been focused on the possible involvement of the dopamine D4 receptor gene (DRD4) following a report of an association of ADHD with the allele containing seven copies of the 48-bp repeat in the third exon. In this paper we extended the search for the molecular explanation for the observed association by testing three polymorphisms in the region 5' to the dopamine receptor D4 gene transcription start site for linkage to ADHD. We specifically targeted polymorphisms in the region 5' to the start site of transcription as DNA variants in this region could alter the transcription level of the gene and hence the phenotype. We did not observe significant evidence for biased transmission of any of the alleles at these three polymorphisms to ADHD probands using the transmission disequilibrium test. We conclude that these three polymorphisms are not related to the ADHD phenotype.

5' Untranslated Regions↗

PubMed2001

Attention-deficit hyperactivity disorder and the adrenergic receptors alpha 1C and alpha 2C.

The adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, alpha 1C (ADRA1C) located on chromosome 8p11.2, and alpha 2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor alpha 1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor alpha 2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families.

Attention Deficit Disorder with Hyperactivity↗

PubMed2001

Methylphenidate selectively improves story retelling in children with attention deficit hyperactivity disorder.

OBJECTIVES: The goal of this study was to determine stimulant effects on story grammar, comprehension, and errors in the narratives of children with attention deficit hyperactivity disorder (ADHD) with and without comorbid language impairment. Previous research has demonstrated impairments in the narrative abilities of children with ADHD, but the effect of the primary treatment modality (methylphenidate) is unknown. METHODS: Fifty children with ADHD (7 to 12 years of age) were stratified for language impairment that might influence performance. In an acute, randomized, placebo-controlled crossover trial with two single doses (10 and 20 mg) of methylphenidate, the children listened to an audiotaped story while viewing a wordless picture book of the study, then retold the story and answered comprehension questions. The narratives were transcribed and coded for story grammar, length, and errors. RESULTS: Methylphenidate only increased children's reporting of the story characters' internal responses and attempts. It had no effect on story length or responses to comprehension questions. Responses to the factual questions were significantly more accurate than the inferential questions, irrespective of medication dose. Comorbid language impairment had no effect on performance or stimulant response. CONCLUSION: Story grammar analysis was sensitive to drug effects, which were subtle but specific and clinically meaningful. Results provide evidence for the theoretical linkage between internal responses and attempts.

Attention Deficit Disorder with Hyperactivity↗