Lindsey Kent

Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT 1B receptor gene in 273 nuclear families from a multi-centre sample

Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR1B and HTR2A (which encode the serotonin receptors 5-HT1B and 5-HT2A respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR1B in the total sample (for HHRR; χ2 = 7.4, P = 0.0065 and TDT; (χ2 = 6.4, P = 0.014). Analysis of HTR2A failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (χ2 = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings.

Association study of a dopamine transporter polymorphism and attention deficit hyperactivity disorder in UK and Turkish samples.

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder.1 Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein.2,3 To date, there have been eight published association studies of ADHD with a 480 base-pair allele of a variable number tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the gene, five4–8 that support an association and three9–11 against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT).12 Results from the UK (χ2 = 8.97, P = 0.001, OR = 1.95), but not the Turkish sample (χ2 = 0.93, P = 0.34) support association and linkage between genetic variation at the DAT1 locus and ADHD. When considered alongside evidence from other published reports, there is only modest evidence for the association, consistent with a very small main effect for the 480-bp allele (χ2 = 3.45, P = 0.06, OR = 1.15), however we find significant evidence of heterogeneity between the combined dataset (χ2 = 22.64, df = 8, P = 0.004).

Comorbidity of autistic spectrum disorders in children with Down syndrome.

The aim of the study was to identify the comorbidity of autistic spectrum disorders in a population of children with Down syndrome (DS). All children with DS within a defined population of South Birmingham were identified. The Asperger Syndrome Screening Questionnaire and the Child Autism Rating Scale were completed and diagnosis made according to ICD‐10 criteria following interview and observation. Thirty‐three of 58 identified children completed the measures, four of whom received a diagnosis of an autistic spectrum disorder. This is equivalent to a minimum comorbid rate of 7%. The questionnaire items concerning social withdrawal, restricted or repetitive interests, clumsiness, and unusual eye contact were associated with an autistic disorder. Of the remaining 29 participating children, 11 also displayed marked obsessional and ritualistic behaviours. The comorbid occurrence of autism and DS is at least 7%. It is important that these children are identified and receive appropriate education and support. A full assessment of social, language, and communication skills and behaviour is crucial, particularly in children with DS who appear different from other children with DS. Potential mechanisms accounting for this comorbidity are discussed.

Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis.

Reduced central serotonergic activity has been implicated in poor impulse regulation and aggressive behaviour in animals, adults and also young children.1,2 Two recently published studies have implicated variation at a polymorphism in the promoter of the serotonin transporter (5HTT; hSERT) in influencing susceptibility to ADHD.3,4 Consistent with these results we have also found a trend for the long allele of the promoter polymorphism to influence susceptibility to ADHD in a sample of 113 ADHD parent proband trios (65 transmissions vs 49 non-transmissions, χ2u2009=u20092.25, Pu2009=u20090.13). A pooled analysis of our, and these published results demonstrated a significant over representation of the long allele of the promoter in ADHD probands compared to controls (χ2u2009=u20097.14, Pu2009=u20090.008). We have also examined two other 5HTT polymorphisms (the VNTR in intron 2 and the 3′ UTR SNP). TDT analysis demonstrated preferential transmission of the T allele of the 3′ UTR SNP (χ2u2009=u20094.06, Pu2009=u20090.04). In addition, ETDT analysis of haplotypes demonstrated significant preferential transmission of haplotypes containing the T allele of the 3′ UTR SNP with the long allele of the promoter polymorphism (χ2u2009=u200913.18, 3u2009df, Pu2009=u20090.004) and the 10 repeat of the VNTR (χ2u2009=u20098.77, 3u2009df, Pu2009=u20090.03). This study provides further evidence for the possible involvement of the serotonin transporter in susceptibility to ADHD.

Is there a relationship between attention deficit hyperactivity disorder and bipolar disorder

With the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults and psychotic disorders in children and adolescents, the possibility of a relationship between bipolar disorder (BP) and ADHD has attracted growing interest. This paper critically reviews the scientific literature concerning this postulated relationship by examining evidence from clinico-epidemiological, follow up, family and laboratory studies, including neuroimaging, neuropsychology and genetic studies. The evidence suggests that although the diagnostic categories of BP and ADHD appear to be unrelated, there is support for a possible relationship between some ADHD and manic-like symptoms. However, several fundamental methodological issues require rectification in future research in order to further elucidate the relationship between these disorders.

Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample

Recent studies report association and linkage between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a 48 base-pair repeat in the dopamine D4 receptor gene (DRD4).1 We examined the frequency of this allele in a sample of probands with DSM-IV ADHD using a case-control design, as well as the transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk (HHRR) in the subset of probands with DNA available from both parents. One hundred and thirty-two ADHD probands were compared with 189 controls (χ2u2009=u20096.17, 1 df, Pu2009=u20090.01, ORu2009=u20091.73, 95% CIu2009=u20091.11–2.71). A total of 85 complete trios were available for within-family tests of association and linkage. Fifty-two heterozygous parents carrying one copy of the 7-repeat were informative for the TDT (29 transmitted vs 23 non-transmitted, χ2u2009=u20090.69). Analysis of the entire sample of 132 probands using TRANSMIT2 provided no additional evidence for excess transmission of the 7-repeat allele (58 transmitted vs 54 non-transmitted). HHRR gave similar results. We conclude that the case-control findings are likely to be falsely positive, resulting from genetic stratification. However we can not rule out alternative explanations of low statistical power and gene–environment correlation.

Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 × 10−6). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (χ2=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

Exploring selective attention in ADHD: visual search through space and time

BACKGROUNDnIn order to examine the mechanisms mediating selective attention in Attention Deficit Hyperactivity Disorder (ADHD), this study compared the performance of children diagnosed with ADHD to non-clinical controls on a visual search task in three conditions.nnnMETHODnIn the single feature condition, the target differed from distractors in terms of shape only, whilst in the conjunction baseline, the target was defined by shape and colour relative to distractors. In the preview condition, the conjunction stimuli were segmented over time, so that one set of distractors appeared first, followed 1000 ms later by the second set with the target.nnnRESULTSnAlthough children with ADHD were slower overall than controls, RTs revealed no difference in search mechanisms between groups; for all children, search was more efficient in the single feature and preview conditions than in the conjunction baseline. However, children with ADHD made more errors, especially in the conjunction and preview conditions.nnnCONCLUSIONSnChildren with ADHD were not impaired in their mechanisms of visual search relative to controls, but their error patterns implied the adoption of a premature response deadline in the conjunction search condition, and an occasional failure to inhibit old items in the preview condition.

Maternal and child psychological sequelae in paediatric burn injuries

It is a commonly held belief that many children suffer psychological sequelae following burn injury. This six month controlled, prospective, follow up study was designed to investigate psychological sequelae in children and their mothers following paediatric burn injury. The study employed a sample of 40 children with burn injuries, and their mothers with three control groups, each of 40 children and their mothers: an acutely ill group, a fracture group and a non ill/injured group. Measures at initial contact and 6 month follow up included the Child Behaviour Checklist and the Hospital Anxiety and Depression Scale. The results demonstrated higher initial maternal anxiety scores in the burn, compared to the fracture and non ill/injured groups, which remained comparatively high 6 months later even though they decreased over time. Children with burn injuries, of the type included in this study, did not appear to develop significant psychological or behavioural sequelae. Following paediatric burn injury mothers appear to be at higher risk than children for developing psychological sequelae, which may have longer term implications for the childs outcome such as affecting compliance with treatment.

Visual search, singleton capture, and the control of attentional set in ADHD

We report the data on effects on visual search of (1) preview displays and (2) singleton targets and distractors in IQ‐matched ADHD and control children. All children showed interference from singleton distractors even when targets never carried singleton values. This interference from singleton distractors increased under preview conditions, indicating that the children then had fewer resources available to control attention. There was also one selective deficit for ADHD children; they showed marked problems in responding to singleton targets following preview displays. This suggests that, in ADHD, there is either a selective delay or an impairment in switching attentional sets (from a negative set to the preview to a positive set to a singleton target). We discuss the implications for understanding both ADHD and the development of selective attention.