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Philip Asherson

Publications and source records attributed to Philip Asherson.

At least 19 recordsLinked to original sources
PubMed2007

Family-based association study between brain-derived neurotrophic factor gene polymorphisms and attention deficit hyperactivity disorder in UK and Taiwanese samples.

Brain-derived neurotrophic factor (BDNF) plays an important role in normal neuronal development. Several lines of evidence implicate the involvement of BDNF in attention-deficit hyperactivity disorder (ADHD). This study investigated the role of two common BDNF variants (Val66Met, C270T) in two samples of ADHD probands from the United Kingdom (n = 180) and Taiwan (n = 212). We found evidence of increased transmission of the C allele of the C270T in Taiwanese samples (TDT: chi(2) = 6.78, P = 0.009) and the two samples pooled together (TDT: chi(2) = 7.24, P = 0.007). No association was found between the Val66Met polymorphism and ADHD in either of the two populations. Analysis of haplotypes demonstrated a significant decreased transmission of haplotypes containing the Val66 allele and the 270T allele in the Taiwanese samples (TDT: chi(2) = 4.57, P = 0.032) and the pooled sample set (TDT: chi(2) = 5.82, P = 0.016). This study provides evidence for the possible involvement of BDNF in susceptibility to ADHD.

Adolescent↗
PubMed2007

Adult attention-deficit hyperactivity disorder: recognition and treatment in general adult psychiatry.

Attention-deficit hyperactivity disorder (ADHD) is a common disorder affecting children and adults. Many young people treated with stimulants, as well as those in whom ADHD went unrecognised in childhood, need treatment as adults. Stimulants and atomoxetine effectively reduce ADHD symptoms at all ages and should be a standard treatment in general adult psychiatric practice.

Adolescent↗
PubMed2007

Gene-environment interplay in attention-deficit hyperactivity disorder and the importance of a developmental perspective.

Attention-deficit hyperactivity disorder (ADHD) varies in its clinical presentation and course. Susceptibility gene variants for ADHD and associated antisocial behaviour are being identified with emerging evidence of gene-environment interaction. Genes and environmental factors that influence the origins of disorder are not necessarily the same as those that contribute to its course and outcome.

Adolescent↗
PubMed2006

Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.

BACKGROUND: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. METHODS: We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. RESULTS: We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. CONCLUSIONS: Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.

Alleles↗
PubMed2006

Association of fatty acid desaturase genes with attention-deficit/hyperactivity disorder.

BACKGROUND: Fatty acids, in particular omega-3 fatty acids, have been found to affect behavior and cognition both directly and indirectly. Evidence to suggest a link with attention-deficit/hyperactivity disorder (ADHD) derives from three key areas: 1) animal dietary restriction studies observed increased locomotive hyperactivity and reduced cognitive ability in offspring; 2) animal dietary studies indicate alterations in the dopamine pathway; and 3) human studies report reduced plasma omega-3 fatty acids in ADHD subjects. METHODS: We investigated three genes that encode essential enzymes (desaturases) for the metabolism of fatty acids by scanning for genetic association between 45 single nucleotide polymorphisms (SNPs) and ADHD. RESULTS: Our findings suggest a significant association of ADHD with SNP rs498793 (case-control p = .004, odds ratio [OR] 1.6, 95% confidence interval [CI] 1.15-2.23; transmission disequilibrium test [TDT] p = .014, OR 1.69) in the fatty acid desaturase 2 (FADS2) gene. As alcohol is known to decrease the activities of these desaturase enzymes, we also tested for interactions between ADHD subjects' genotypes and maternal use of alcohol during pregnancy. Two SNPs in the fatty acid desaturase 1 (FADS1) gene were nominally associated with ADHD only in the prenatal alcohol-exposed group of children; formal test for interaction was not significant. CONCLUSIONS: These preliminary findings are suggestive of an association between FADS2 and ADHD.

Adolescent↗
PubMed2006

The IMAGE project: methodological issues for the molecular genetic analysis of ADHD.

The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions. With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality--the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD. The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.

Journal Article↗
PubMed2006

Reaction time, inhibition, working memory and 'delay aversion' performance: genetic influences and their interpretation.

BACKGROUND: For candidate endophenotypes to be useful for psychiatric genetic research, they first of all need to show significant genetic influences. To address the relative lack of previous data, we set to investigate the extent of genetic and environmental influences on performance in a set of theoretically driven cognitive-experimental tasks in a large twin sample. We further aimed to illustrate how test-retest reliability of the measures affects the estimates. METHOD: Four-hundred 7- to 9-year-old twin pairs were assessed individually on tasks measuring reaction time, inhibition, working memory and 'delay aversion' performance. Test-retest reliability data on some of the key measures were available from a previous study. RESULTS: Several key measures of reaction time, inhibition and working-memory performance indicated a moderate degree of genetic influence. Combining data across theoretically related tasks increased the heritability estimates, as illustrated by the heritability estimates of 60% for mean reaction time and 50% for reaction-time variability. Psychometric properties (reliability or ceiling effects) had a substantial influence on the estimates for some measures. CONCLUSIONS: The data support the usefulness of several of the variables for endophenotype studies that aim to link genes to cognitive and motivational processes. Importantly, the data also illustrate specific conditions under which the true extent of genetic influences may be underestimated and hence the usefulness for genetic mapping studies compromised, and suggest ways to address this.

Child↗
PubMed2006

Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline.

A systematic review of published and unpublished data on the use of long-acting medications in ADHD and hyperkinetic disorder is reported, giving effect sizes and numbers-to-treat for extended-release stimulant preparations and atomoxetine (ATX). A panel of experts from several European countries used the review to make recommendations about the use of these drugs in practice, and conclusions are reported: (1) Long-acting preparations should be available and used; (2) They should not replace short-acting drugs (which will be the initial treatment for many children for reasons of cost and flexibility of dosing). Individual clinical choice is needed. (3) Both ATX and extended-release preparations of stimulants should be available. The choice will depend upon the circumstances, and detailed recommendations are made.

Atomoxetine Hydrochloride↗
PubMed2006

A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood behavioral disorder. Identifying risk factors for ADHD may lead to improved intervention and prevention. The dopamine transporter gene (DAT1) is associated with ADHD in several studies, with an average 1.2 odds ratio and evidence of heterogeneity across data sets. OBJECTIVE: To investigate sources of heterogeneity by refining the DAT1 association using additional markers and investigating gene-environment interaction between DAT1 and maternal use of alcohol and tobacco during pregnancy. DESIGN: Prospective study. SETTING AND PATIENTS: Children with ADHD from child behavior clinics in the southeast of England and in the Taipei area of Taiwan. INTERVENTIONS: Within-family tests of association using 2 repeat polymorphisms in the 3' untranslated region and intron 8 plus additional markers in the English sample. MAIN OUTCOME MEASURES: Transmission ratios of risk alleles from heterozygote parents to affected offspring and comparison of the transmission ratios in high- and low-exposure groups for the environmental variables. RESULTS: A novel association was identified between ADHD, the intron 8 polymorphism, and a specific risk haplotype in both English and Taiwanese samples. The risk haplotype showed significant interactions with maternal use of alcohol during pregnancy. CONCLUSIONS: The identification of a common haplotype in 2 independent populations is an important step toward identifying functionally significant regions of DAT1. Interaction between DAT1 genotypes and maternal use of alcohol during pregnancy suggests that DAT1 moderates the environmental risk and has implications for the prevention of ADHD. Further studies are required to delineate the precise causal risk factor involved in this interaction.

Alcohol Drinking↗
PubMed2006

No association of single nucleotide polymorphisms in the micro-opioid receptor subunit gene with idiopathic generalized epilepsy.

We have investigated the reported association (p = 0.019) between the A118G single nucleotide polymorphism (SNP) of the opioid receptor micro subunit gene (OPRM1) and idiopathic absence epilepsy (IAE). Five SNPs, including A118G, were investigated by association studies in a sample of 240 probands with idiopathic generalized epilepsy (IGE), including 110 with IAE, and 257 controls. No significant association was found for A118G with IGE or IAE. The difference between the two studies was in the control samples that had significantly different allele frequencies (p = 0.00005), suggesting that population stratification may explain the earlier significant association with IAE. In the current study, none of the other four SNPs was significantly associated with IGE or IAE. Our results provide no support for association of A118G with either IAE or IGE and also exclude association in our sample of a small-to-moderate gene effect with IGE from a large part of OPRM1.

Chromatography, High Pressure Liquid↗
PubMed2006

Attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a behavioral diagnosis based on the presence of developmentally inappropriate levels of impulsivity, overactivity, and inattentiveness. It is a familial condition with a complex pattern of inheritance. Variation of several genes involved in the regulation of dopamine, norepinephrine, and serotonin neurotransmission is associated with ADHD. We highlight the two most prominent findings with the dopamine D4 receptor (DRD4) gene and the dopamine transporter (DAT1) gene, and their implications for the understanding of the cellular and neurobiological basis for ADHD. Cognitive and functional studies using electrophysiology and brain imaging frequently indicate altered processing in ADHD during performance on cognitive tasks hypothesized to measure a "core" deficit, such as response inhibition. Yet, children with ADHD appear to suffer from a more general deficit, including impairment in attentional alerting, orienting, response preparation, and control. Reward processes are also altered and, further, a strong association emerges with intraindividual variability, with several causal hypotheses being proposed. Task performance correlates with underactivation of, especially, frontostriatal areas of the brain, but an extended network of brain regions is also implicated. Electroencephalography studies indicate abnormalities in ADHD in relation to slow-wave activity, linked to underarousal. These advances in the areas of genetics, cognitive function, neurophysiology, and neuroanatomy of ADHD give important leads for interdisciplinary research that aims to delineate the causal pathways. Such research is only at its beginning, but is illustrated by recent findings of an association between DAT1 and increased response variability in ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains.

BACKGROUND: The Spontaneously Hypertensive Rat (SHR) shows a number of behaviours that closely parallel those seen in children with attention-deficit hyperactivity disorder. These include motor hyperactivity, excessive responses under a fixed-interval/extinction schedule, difficulty in acquiring operant tasks and increased sensitivity to immediate behavioural reinforcement. As in children with ADHD, the behavioural and cognitive deficits in the SHR are responsive to stimulants, including d-amphetamine and d,l-methylphenidate. The non-hyperactive Wistar Kyoto (WKY) rat strain is often used as a control in behavioural studies of the SHR, and WKY itself has been suggested to be a useful animal model of depression. Numerous studies have shown that dopaminergic neurotransmission is altered between the two strains. Human genetic studies have found associations between several dopaminergic genes and both ADHD and depression. METHODS: We sequenced three candidate dopaminergic genes (Drd2, Drd4, and Dat1) in the SHR and WKY to identify between-strain sequence differences. RESULTS: No between-strain sequence differences were found in either Drd2 or Drd4, but several variations were found in the Dat1 gene that encodes the dopamine transporter. CONCLUSION: It is plausible that DNA sequence changes in the Dat1 gene account for some of the behavioural differences observed between the SHR and WKY strains. Future work will focus on elucidating the functional effects of the observed polymorphisms.

Journal Article↗
PubMed2005

Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: no evidence for association in UK and Taiwanese samples.

Five independent studies have reported associations between serotonin transporter gene (5-HTT) polymorphisms and attention deficit hyperactivity disorder (ADHD). Four studies found evidence for association between the long-allele of a 44-base pair insertion/deletion polymorphism (5-HTTLPR), one of the studies found association to a variable number tandem repeat within intron 2, another to the T-allele of a single base pair substitution in the 3'-untranslated regions and another reported preferential transmission of a haplotype of the three markers (long-allele/10-repeat-allele/T-allele). One further study found no evidence for these associations. We investigated the association of these three markers in two samples of ADHD patients from the United Kingdom (n = 197) and Taiwan (n = 212), using within-family tests of association. No association was found between any of the three markers in either of the two populations. Although we found some evidence for the preferential transmission of a rare haplotype (long-allele/9-repeat-allele/T-allele; chi2 = 4.5, P = 0.034), we concluded that this most likely occurred by chance factors alone.

Adolescent↗
PubMed2005

No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent and highly heritable childhood disorder. The dopamine D4 receptor (DRD4) gene has shown a genetic association with ADHD in Caucasian populations with meta-analysis indicating a small but significant effect across datasets. It remains uncertain whether this association can be generalised to non-Caucasian ethnic groups. Here we investigate two markers within the DRD4 gene in a Taiwanese population, the exon 3 variable number tandem repeat (VNTR) and a 5' 120 base-pair duplication. METHODS: Within-family transmission disequilibrium tests of association of the 5' 120 base-pair duplication, and exon 3 VNTR in a Taiwanese population. RESULTS: No evidence of association of ADHD with either polymorphism in this population was observed. CONCLUSION: The DRD4 gene markers investigated were not found to be associated with ADHD in this Taiwanese sample. Further work in Taiwanese and other Asian populations will therefore be required to establish whether the reports of association of DRD4 genetic variants in Caucasian samples can be generalised to Asian populations.

Adolescent↗
PubMed2005

The serotonin transporter gene as a QTL for ADHD.

Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.

Adolescent↗
PubMed2005

DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association.

The norepinephrine system is known to play a role in attentional and cognitive-energetic mechanisms and is thought to be important in attention deficit hyperactivity disorder (ADHD). Stimulant medications are known to alter the activity of norepinephrine as well as dopamine in the synapse and the highly selective norepinephrine reuptake inhibitor, atomoxetine, is an effective treatment for ADHD symptoms. This study set out to investigate whether common polymorphisms within the norepinephrine transporter gene (NET1) are associated with DSM-IV ADHD combined subtype, using a sample that has previously shown association with genes that affect the synaptic release and uptake of neurotransmitters; DAT1 and SNAP-25. We identified 21 single nucleotide polymorphisms (SNPs) from publicly available databases that had minor allele frequencies > or =5% and span the NET1 genomic region, including those analyzed in previous studies of ADHD. DNA pooling was used to screen for associations using two case pools (n = 180 cases) and four control pools (n = 334 controls). We identified three SNPs that showed suggestive evidence for association using either case-control or within family tests of association, however, none of these were significant after adjustment for the number of markers analyzed. We conclude that none of the markers show significant evidence of association with ADHD although we cannot rule out small genetic effects.

Algorithms↗
PubMed2005

Genetic influences on the stability of attention-deficit/hyperactivity disorder symptoms from early to middle childhood.

BACKGROUND: The high heritability of the core symptoms of attention-deficit/hyperactivity disorder (ADHD) has been repeatedly demonstrated, but few studies to date have investigated the extent to which the same genetic influences operate across development or new genes emerge at different developmental periods. METHODS: We report data from a large, population-based study of approximately 4,000 twin pairs, who have been followed up from early to middle childhood. RESULTS: Parents' ratings of ADHD symptoms showed moderate stability across the ages, which was mainly due to shared genetic influences. There was also evidence of additional genetic influences, which were not shared with those acting earlier on, emerging at later age periods. The contribution of environmental influences to the stability of the ADHD symptoms over time was small. Parents' ratings on the Conners' DSM-IV ADHD subscale at the last assessment point, at an average age of 8 years, did not show the rater contrast effects that were observed in the parents' ratings at earlier ages with briefer measures. Similar estimates of genetic and environmental influences were obtained for girls and boys. CONCLUSIONS: We discuss the implications of the findings for molecular genetic studies on ADHD symptomatology.

Age Factors↗