No abstract

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 HTR 1B and HTR 2A (which encode the serotonin receptors 5-HT 1B and 5-HT 2A 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 HTR 1B in the total sample (for HHRR; 2 = 7.4, P = 0.0065 and TDT; ( 2 = 6.4, P = 0.014). Analysis of HTR 2A 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 ( 2 = 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.

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 basepair allele of a variable number tandem repeat (VNTR) polymorphism in the 3Ј-untranslated region of the gene, five 4-8 that support an association and three 9-11 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 ( In this study, we have taken a family-based association design to investigate the DAT1 VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children. Cases were included if they had a diagnosis of ADHD under DSM-IV criteria and DNA from both parents available for genotyping. They were excluded if they had neurological disease or damage or congenital disorders known to cause hyperactivity. The UK sample consisted of 59 cases with the combined subtype, six the hyperactive/impulsive subtype and one the inattentive subtype of ADHD. Axis 1 co-morbidity other than oppositional defiant disorder and conduct disorder (ODD/CD) consisted of two cases with an affective disorder. The Turkish sample consisted of 111 complete trios with DSM-IV-ADHD combined type. Comorbid diagnoses other than ODD/CD were Tourette's syndrome and/or tics (TS/tics) in 34% and anxiety/depression in 8% of probands.Analysis was performed using the transmission disequilibrium test (TDT) of linkage in the presence of association.12 In order to further evaluate the evidence, we included data from other published reports and performed a combined analysis. The results of this study are shown in Table 1. When considered alone, data from the UK sample ( 2 = 6.12, P = 0.0.01, OR = 1.95), but not the Turkish sample ( 2 = 0.93, P = 0.335), support association and linkage between the DAT1 locus and ADHD.We are not alone in finding differences between datasets. Among previous published reports there have been five providing evidence for the association and three against. The reasons for this are unclear and require further investigation, but may relate to the statistical power of individual samples. To address this issue we combined available published data on the VNTR polymorphism and applied the TDT. Because the TDT is primarily a test of linkage, it is valid to analyse the combined data by adding the number of transmitted and non-transmitted alleles across different studies. As shown in Table 1, combined analysis provides evidence for association and linkage at an alphalevel of 0.06 and odds ratio of 1.15. Although diagnostic differences...

Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained.

Background:It has been suggested that cancer registries in England are too dependent on processing of information from death certificates, and consequently that cancer survival statistics reported for England are systematically biased and too low.Methods:We have linked routine cancer registration records for colorectal, lung, and breast cancer patients with information from the Hospital Episode Statistics (HES) database for the period 2001–2007. Based on record linkage with the HES database, records missing in the cancer register were identified, and dates of diagnosis were revised. The effects of those revisions on the estimated survival time and proportion of patients surviving for 1 year or more were studied. Cases that were absent in the cancer register and present in the HES data with a relevant diagnosis code and a relevant surgery code were used to estimate (a) the completeness of the cancer register. Differences in survival times calculated from the two data sources were used to estimate (b) the possible extent of error in the recorded survival time in the cancer register. Finally, we combined (a) and (b) to estimate (c) the resulting differences in 1-year cumulative survival estimates.Results:Completeness of case ascertainment in English cancer registries is high, around 98–99%. Using HES data added 1.9%, 0.4% and 2.0% to the number of colorectal, lung, and breast cancer registrations, respectively. Around 5–6% of rapidly fatal cancer registrations had survival time extended by more than a month, and almost 3% of rapidly fatal breast cancer records were extended by more than a year. The resulting impact on estimates of 1-year survival was small, amounting to 1.0, 0.8, and 0.4 percentage points for colorectal, lung, and breast cancer, respectively.Interpretation:English cancer registration data cannot be dismissed as unfit for the purpose of cancer survival analysis. However, investigators should retain a critical attitude to data quality and sources of error in international cancer survival studies.