Biomedical subjects

Philip Asherson

Publications and source records attributed to Philip Asherson.

36 records · Page 2Linked to original sources

PubMed2005

Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B.

It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.

Alleles↗

PubMed2005

Transient expression analysis of allelic variants of a VNTR in the dopamine transporter gene (DAT1).

BACKGROUND: The 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT1) has been associated with a range of psychiatric phenotypes, most notably attention-deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study we have characterised the genomic structure of the 9- and 10-repeat VNTR alleles, and directly examined the role of the polymorphism in mediating gene expression by measuring comparative in vitro cellular expression using a reporter-gene assay system. RESULTS: Differences in the sequence of the 9- and 10- repeat alleles were confirmed but no polymorphic differences were observed between individuals. There was no difference in expression of reporter gene constructs containing the two alleles. CONCLUSIONS: Our data suggests that this VNTR polymorphism may not have a direct effect on DAT1 expression and that the associations observed with psychiatric phenotypes may be mediated via linkage disequilibrium with other functional polymorphisms.

Alleles↗

PubMed2005

Continuity and change in preschool ADHD symptoms: longitudinal genetic analysis with contrast effects.

The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78-0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Unravelling the complexity of attention-deficit hyperactivity disorder: a behavioural genomic approach.

International research has established that there is a strong genetically inherited contribution to attention-deficit hyperactivity disorder (ADHD) and the genetic mechanisms involved are being sought with considerable success. It is now established that certain alleles of the genes coding for the dopamine D4 receptor and the dopamine transporter occur more frequently in children with ADHD than in healthy controls, and we are finding other DNA changes associated with ADHD. A major challenge for the field now is to clarify how genetic susceptibility is translated into disorder by integrating the fields of quantitative and molecular genetics, neuropsychology and environmental risks.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Clinical assessment and treatment of attention deficit hyperactivity disorder in adults.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder that frequently persists into adulthood, with significant levels of inattentive, hyperactive and impulsive behavior. Impairments associated with adult ADHD include distress from the symptoms, impaired ability to function in work and academic settings, and problems sustaining stable relationships. The disorder is commonly associated with volatile moods, antisocial behavior, and drug and alcohol misuse. There is an increased risk of developing comorbid anxiety, depression, personality disorders, and drug and alcohol dependence. Despite the proven effectiveness of drugs such as methylphenidate, dexamphetamine and atomoxetine, few cases of ADHD are recognized and treated in the UK. The reasons for this are unclear, since most psychiatrists working with children and adolescents are aware that ADHD commonly persists into adult life and they also see the disorder affecting parents of children with ADHD. Issues of transition from the care of child to adult psychiatry and the need to refer adult relatives of children with ADHD to suitable psychiatric services are a major concern. Furthermore, many cases of adult ADHD go unrecognized or are seen by mental health teams that are not familiar with the subtleties of the adult presentation. As a result, misdiagnosis and treatment for conditions such as atypical depression, mixed affective disorder, cyclothymia, and borderline and unstable emotional personality disorders is not uncommon. There is therefore a requirement for further training in this area. This review will describe the common clinical presentation and provide guidelines for the diagnosis and treatment of ADHD in adults. Any psychiatrically trained physician using standard psychiatric assessment procedures can perform clinical evaluations for adult ADHD. As with other psychiatric disorders in adulthood, ADHD has its own characteristic onset, course and psychopathology. Symptoms of ADHD are trait-like, being stable characteristics from early childhood, and commonly co-occur with affective instability. Stimulants are the mainstay of treatment and are effective in around 70% of cases. Psychotherapeutic interventions also have an important role. These guidelines will assist psychiatrists and other adult mental health workers in identifying and treating individuals with adult ADHD.

Adult↗

PubMed2004

Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships.

There is considerable evidence to suggest that the genetic vulnerabilities to depression and anxiety substantially overlap and quantitatively act to alter risk to both disorders. Continuous scales can be used to index this shared liability and are a complementary approach to the use of clinical phenotypes in the genetic analysis of depression and anxiety. The aim of this study (Genetic and Environmental Nature of Emotional States in Siblings) was to identify genetic variants for the liability to depression and anxiety after the application of quantitative genetic methodology to a large community-based sample (n = 34,371), using four well-validated questionnaires of depression and anxiety. Genetic model fitting was performed on 2658 unselected sibships, which provided evidence for a single common familial factor that accounted for a substantial proportion of the genetic variances and covariances of the four scales. Using the parameter estimates from this model, a composite index of liability (G) was constructed. This index was then used to select a smaller--but statistically powerful--sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. After the data were checked and cleaned, linkage analysis was performed on G and the personality scale of neuroticism using the regression-based linkage program MERLIN-REGRESS. The results indicated two potential quantitative trait loci (QTL): one on chromosome 1p (LOD 2.2) around 64 cM (43-70 cM) near marker D1S2892 and another on chromosome 6p (LOD 2.7) around 47 cM (34-63 cM) near marker D6S1610. Further exploratory sex-specific analyses suggested that these QTLs might have sex-limited effects.

Adolescent↗

PubMed2004

Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD.

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A microsatellite located near the dopamine D5 receptor (DRD5) gene has been associated with ADHD in a number of studies, but other polymorphisms within the vicinity of this gene have not been examined. In this study we genotyped three microsatellites spanning the DRD5 region in a large clinical sample. Overall, we found little evidence to support a role for DRD5 in ADHD. We found no evidence of association with either the previously associated DRD5 marker, or a repeat in the promoter region of the gene. We did, however, find significant association for an allele of D4S615, a dinucleotide repeat located 131 kb 3' of DRD5 that has been previously associated with schizophrenia. A global test incorporating all alleles of this marker, however, was not significant and thus this finding needs replication before any conclusions can be made.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2004

European clinical guidelines for hyperkinetic disorder -- first upgrade.

BACKGROUND: The validity of clinical guidelines changes over time, because new evidence-based knowledge and experience develop. OBJECTIVE: Hence, the European clinical guidelines on hyperkinetic disorder from 1998 had to be evaluated and modified. METHOD: Discussions at the European Network for Hyperkinetic Disorders (EUNETHYDIS) and iterative critique of each clinical analysis. Guided by evidence-based information and based on evaluation (rather than metaanalysis) of the scientific evidence a group of child psychiatrists and psychologists from several European countries updated the guidelines of 1998. When reliable information is lacking the group gives a clinical consensus when it could be found among themselves. RESULTS: The group presents here a set of recommendations for the conceptualization and management of hyperkinetic disorder and attention deficit/hyperactivity disorder (ADHD). CONCLUSION: A general scheme for practice in Europe could be provided, on behalf of the European Society for Child and Adolescent Psychiatry (ESCAP).

Alleles↗

PubMed2004

Attention-Deficit Hyperactivity Disorder in the post-genomic era.

BACKGROUND: ADHD is a common and complex genetic disorder. Genetic risk factors are expected to be multiple, have small effect sizes when considered individually and to interact with each other and with environmental factors. OBJECTIVE: To describe the difficulties involved in the genetic investigation of such a complex disorder and give a prospective for the future. METHODS: Review based on empirical literature and project description. RESULTS: Considerable progress has been achieved through the association analysis of candidate gene loci. Linkage scans using affected sibling pairs have identified a number of potential loci that may lead to the identification of novel genes of moderate effect size. Quantitative trait locus (QTL) approaches provide powerful complementary strategies that have the potential to link the categorical disorder to continuously distributed traits associated more closely with underlying genetic liability in the general population. Success in identifying some associated genes has been complemented by functional studies that seek to understand the mode of action of such genes. CONCLUSION: Progress in understanding the mechanisms involved has not been straightforward and many inconsistencies have arisen. In order to take advantage of the potential for progress that stems from the genetic findings it will be important to draw upon a variety of approaches and experimental paradigms. A functional genomic approach to ADHD means that investigation of gene function is carried out at various levels of analysis, not only at the level of molecular and cellular function but also at the level of psychological processes, neuronal networks, environmental interactions and behavioural outcomes.

Attention Deficit Disorder with Hyperactivity↗

PubMed2003

Polymorphisms in the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A 48 bp repeat in exon three of the dopamine D4 receptor gene has been widely studied in clinical ADHD samples, and a meta-analysis of published studies suggests it is associated with ADHD. A number of other polymorphisms across this gene have been characterised but not so thoroughly investigated in relation to ADHD. In this study we have genotyped five polymorphisms (a 120 bp promoter-region duplication, the -616 C/G substitution, the -521 C/T substitution, a poly-G repeat in intron 1, and the 48 bp exon 3 repeat) across the gene in a large clinical sample (n = 188) and their families. We found that none of the markers is individually associated with ADHD, although there is evidence to suggest that a haplotype of markers in the 5' promoter region of the gene (allele 2 of the 120 bp duplication, the C allele of the -616 substitution, and the C allele of the -521 substitution) may confer susceptibility.

Alleles↗

PubMed2003

CHIP: Defining a dimension of the vulnerability to attention deficit hyperactivity disorder (ADHD) using sibling and individual data of children in a community-based sample.

We are taking a quantitative trait approach to the molecular genetic study of attention deficit hyperactivity disorder (ADHD) using a truncated case-control association design. An epidemiological sample of children aged 5 to 15 years was evaluated for symptoms of ADHD using a parent rating scale. Individuals scoring high or low on this scale were selected for further investigation with additional questionnaires and DNA analysis. Data in studies like this are typically complicated. In the study reported on here, individuals have from 1 to 4 questionnaires completed on them and the sample is composed of a mixture of singletons and siblings. In this paper, we describe how we used a genetic hierarchical model to fit our data, together with a twin dataset, in order to estimate genetic factor loadings. Correlation matrices were estimated for our data using a maximum likelihood approach to account for missing data. We describe how we used these results to create a composite score, the heritability of which was estimated to be acceptably high using the twin dataset. This score measures a quantitative dimension onto which molecular genetic data will be mapped.

Adolescent↗

PubMed2002

Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR.

Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (beta-actin, GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.

3' Untranslated Regions↗

PubMed2002

Association study of a SNAP-25 microsatellite and attention deficit hyperactivity disorder.

Several lines of evidence implicate synaptosomal-associated protein of 25 kDa (SNAP-25) in the etiology of attention deficit hyperactivity disorder (ADHD). Most notably, the coloboma mouse mutant, considered to be a good animal model of hyperactivity, has a deletion spanning this gene. Introducing a SNAP-25 transgene into these animals alleviates hyperlocomotion. We have identified a novel microsatellite repeat in SNAP-25 located between the 5'UTR and the first coding exon, and tested for association with ADHD. Case-control analyses suggest there may be a role of this polymorphism in ADHD, with one allele over-represented in controls and another over-represented in probands. Within-family tests of linkage and association confirmed these findings. Further work is needed to ascertain the role of SNAP-25 in ADHD and assess the functional significance of this polymorphism.

Alleles↗

PubMed2002

Association of DRD4 in children with ADHD and comorbid conduct problems.

Recent family and twin study findings suggest that ADHD when comorbid with conduct problems may represent a particularly familial and heritable form of ADHD. Although several independent groups have shown association between the DRD4 7 repeat allele and ADHD, others have failed to replicate this finding. Previous TDT analyses of UK and Eire samples had also been negative. We set out to further examine the role of DRD4 but selecting a subgroup of children with ADHD and comorbid conduct problems. Families were recruited from Manchester, Ireland, Birmingham and London clinics. From these, 67 children who fulfilled diagnostic criteria for ADHD and who displayed conduct disorder symptoms were selected. TDT analysis, which had previously yielded negative results for the total sample, showed evidence of association between DRD4 and "ADHD with conduct problems" (7 repeat allele-24 transmissions, 13 non-transmissions; one-tailed P=0.05). These results provide further support for the role of DRD4 in ADHD. Furthermore, these results when considered together with family and twin study findings, suggest that those children with ADHD and comorbid conduct problems may be particularly informative for molecular genetic studies of ADHD. Further work is needed to examine these phenotype issues.

Adolescent↗

PubMed2002

Haplotype and linkage disequilibrium analysis to characterise a region in the calcium channel gene CACNA1A associated with idiopathic generalised epilepsy.

Idiopathic generalised epilepsy (IGE) is a common form of epilepsy, including several defined and overlapping syndromes, and likely to be due to the combined actions of mutations in several genes. In a recent study we investigated the calcium channel gene CACNA1A for involvement in IGE, unselected for syndrome, by means of association studies using several polymorphisms within the gene. We reported a highly significant case/control association with a silent single nucleotide polymorphism (SNP) in exon 8 that we confirmed by within-family analyses. In this present study we screened the gene for novel SNPs within 25 kb of exon 8, which have enabled us to define the critical region of CACNA1A in predisposing to IGE. Several intronic SNPs were identified and three, within 1.5 kb of exon 8 and in strong linkage disequilibrium with each other and with the original SNP, were significantly associated with IGE (P=0.00029, P=0.0015 and P=0.010). The associations were not limited to an IGE syndrome or other subgroup. Another SNP, 25 kb away, in intron 6 was also significantly associated with IGE (P=0.0057) but is not in linkage disequilibrium with the SNPs around exon 8. Haplotype predictions revealed even more significant associations (3-marker haplotype: P<10(-6)). Logistic regression showed that all the data can be explained by two of the SNPs, which is consistent with two functionally significant variants being responsible for all five associations, although a single variant cannot be excluded. The functionally significant variant(s) are unlikely to be exonic and suggests an effect on expression or alternative splicing.

Adolescent↗

PubMed2002

Validation of single nucleotide polymorphism quantification in pooled DNA samples with SNaPIT. A glycosylase-mediated methods for polymorphism detection method.

Association studies using genome scans to identify quantitative trait loci for multifactorial disorders, with anything approaching reasonable power, have been compromised by the need for a very dense array of genetic markers and large numbers of affected individuals. These requirements impose enormous burdens on the genotyping capacity for most laboratories. DNA pooling has been proposed as a possible approach to reduce genotyping costs and effort. We report on the application of the SNaPIT technology to evaluate allele frequencies in pooled DNA samples and conclude that it offers a cost effective, efficient and accurate estimator and provides several advantages over competing technologies in this regard.

Chromosome Mapping↗

PubMedDate not supplied

Familiality of clinical characteristics in schizophrenia.

Few studies have assessed the familiality of clinical characteristics in schizophrenia. Therefore, we set out to investigate the familiality of the following characteristics; age of onset, course of disorder, employment status at onset, impairment during disorder, marital status at onset, mode of onset and premorbid functioning. Clinical characteristics were recorded using the Operational Criteria Checklist for Psychotic Illness for 155 subjects with an RDC diagnosis of schizophrenia, schizoaffective disorder, or psychosis of unknown origin, from 61 families multiply affected by schizophrenia. Age of onset, course of disorder, impairment during disorder, mode of onset, and premorbid functioning were shown to be familial. The familiality of these clinical characteristics supports their use in the delineation of homogeneous subsets for future genetic studies.

Adult↗