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P Sham

Publications and source records attributed to P Sham.

At least 37 records · Page 2Linked to original sources
PubMed2001

Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach.

Adolescent↗
PubMed2001

No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients.

Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. One possible explanation for such discrepancy is disease heterogeneity due to the current limitations in the diagnosis of schizophrenia. We conducted a case-control study of the T102C polymorphism with detailed characterisation of the clinical phenotypes to investigate the possible association with schizophrenia not only at the diagnostic level, but also with reference to other clinical phenotypes potentially related to serotonin dysfunction. Four hundred and seventy-one biologically unrelated schizophrenic patients and 523 unrelated healthy controls of Han Chinese descent in Hong Kong were compared for genotypes and allele frequencies of the T102C polymorphism by PCR amplification and restriction analysis. No evidence of association was detected at the diagnostic level and various clinical phenotypes. However, we found a trend association with small effect size between genotype 102T/102C and patients with better verbal fluency and less motor co-ordination soft neurological signs. There is a need for future large-scale studies on the possible associations between genetic polymorphisms and neurocognitive function impairments in schizophrenia.

Adolescent↗
PubMed2001

QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms.

Current developments in molecular genetics have led to a rapid increase in research aimed at the identification of genetic variation that influences complex human phenotypes. One phenotype that has aroused a great deal of interest is the behavioral trait hyperactivity and the related clinical disorder attention-deficit hyperactivity disorder (ADHD). The driving force behind the molecular genetic research in this area is the overwhelming evidence from quantitative genetic studies that show high heritablility (h(2) = 0.7-0.9) for the behaviors characterizing the diagnosis of ADHD, whether the disorder is viewed as a categorical entity or a continuous trait. To date, molecular studies have aimed at identifying susceptibility genes for ADHD, defined using operational diagnostic criteria, and have focused on variation within genes that regulate dopamine neurotransmission. Several studies report ADHD to be associated with the 7-repeat allele of a 48 bp repeat polymorphism (DRD4-7) in exon 3 of the dopamine D4 receptor gene (DRD4). In this study, we take a dimensional perspective of ADHD and examine the relationship of this DRD4 polymorphism in a sample of children selected from the general population on the basis of high and low scores on the five ADHD items of the Strengths and Difficulties Questionnaire (SDQ) as rated by their parents. We found a significant relationship between DRD4-7 and high-scoring individuals [chi-square = 8.63; P = 0.003; OR = 2.09 (95% CI 1.24 < OR < 3.54), F-statistic = 7.245; P = 0.008].

Adolescent↗
PubMed2001

Familiality of symptom dimensions in schizophrenia.

The division of schizophrenic symptoms into three core dimensions - psychomotor poverty, reality distortion, and disorganisation - is well established. When factor analytic studies have included affective symptoms they have identified two additional dimensions - manic and depressive. Whether these five dimensions represent underlying psychopathology of a genetic or environmental aetiology remains unclear. The aims of this study were to perform factor analysis of symptoms in a group of familial schizophrenic patients and to investigate the familiality of the symptom dimensions identified, and their relationship to clinical characteristics. Symptoms were recorded, using the Operational Criteria Checklist for Psychotic Illness, for 155 Caucasian subjects with an RDC diagnosis of schizophrenia, schizoaffective disorder, or psychosis of unknown origin, from 61 families multiply affected with schizophrenia. Factor analysis indicated five symptom dimensions: depressive, manic, reality distortion, disorganisation, and psychomotor poverty. The psychomotor poverty, disorganisation, and manic dimensions were shown to be familial. Psychomotor poverty, disorganisation, and reality distortion were all associated with deterioration from premorbid functioning and chronic course of the disorder. In addition, psychomotor poverty was significantly related to poor premorbid functioning, as well as to single marital status and unemployment at onset. Disorganisation was significantly related to single marital status and unemployment at onset. The familiality of the psychomotor poverty, disorganisation, and manic dimensions supports their use in the delineation of homogeneous subsets for genetic studies.

Adult↗
PubMed2001

Individual-specific risk factors for anorexia nervosa: a pilot study using a discordant sister-pair design.

BACKGROUND: The aim of this pilot study was to examine which unique factors (genetic and environmental) increase the risk for developing anorexia nervosa by using a case-control design of discordant sister pairs. METHODS: Forty-five sister-pairs, one of whom had anorexia nervosa and the other did not, were recruited. Both sisters completed the Oxford Risk Factor Interview for Eating Disorders and measures for eating disorder traits, and sib-pair differences. Blood or cheek cell samples were taken for genetic analysis. Statistical power of the genetic analysis of discordant same-sex siblings was calculated using a specially written program, DISCORD. RESULTS: The sisters with anorexia nervosa differed from their healthy sisters in terms of personal vulnerability traits and exposure to high parental expectations and sexual abuse. Factors within the dieting risk domain did not differ. However, there was evidence of poor feeding in childhood. No difference in the distribution of genotypes or alleles of the DRD4, COMT, the 5HT2A and 5HT2C receptor genes was detected. These results are preliminary because our calculations indicate that there is insufficient power to detect the expected effect on risk with this sample size. CONCLUSIONS: A combination of intrinsic and extrinsic factors increases the risk of developing anorexia nervosa. It would, therefore, be informative to undertake a larger study to examine in more detail the unique genetic and environmental factors that are associated with various forms of eating disorders.

Adolescent↗
PubMed2001

Verbal fluency in patients with schizophrenia and affective psychoses and their first-degree relatives.

BACKGROUND: Schizophrenic patients are known to have neuropsychological deficits including impaired verbal fluency, but it is not clear whether this latter deficit is: (a) a consequence of overall intellectual deficit; (b) shared with affective psychotic patients; or (c) shared by the relatives of schizophrenic patients; and (d) shared by the relatives of affective psychotic patients. METHODS: We administered Thurstone's Verbal Fluency Test to 45 schizophrenic patients and 72 of their relatives, and 30 affective psychotic patients and 53 of their relatives. Subjects were asked to generate as many words as possible beginning with the letters 'C' and 'S' and the total was taken as the dependent variable. Subjects also completed the National Adult Reading Test (NART) to provide a measure of (pre-morbid) IQ. RESULTS: Schizophrenic patients generated significantly fewer words than affective psychotic patients, however adjusting for NART this became non-significant. Schizophrenic (but not affective psychotic) patients generated significantly fewer words than their relatives; again adjusting for NART this became non-significant. Patients who had been exposed to obstetric complications (OC+) and those who had not (OC-) had similarly poor verbal fluency scores. Relatives of OC+ schizophrenic patients had superior verbal fluency than relatives of OC- schizophrenic patients and this remained significant after adjustment for NART. CONCLUSIONS: The results suggest that some families transmit impairment in verbal fluency as part of a pattern of lower overall IQ. However, in other families, relatives show largely normal neuropsychological function, and the poorer verbal performance of the schizophrenic member appears to have arisen secondary to his/her exposure to OCs.

Adult↗
PubMed2001

Prodromes, coping strategies and course of illness in bipolar affective disorder--a naturalistic study.

BACKGROUND: Psychosocial interventions for bipolar patients often include teaching patients to recognize prodromal symptoms and tackle them early. This prospective study set out to investigate which bipolar prodromal symptoms were reported frequently and reliably over a period of 18 months. Furthermore, we have also investigated which types of coping strategies were related to good outcome. METHOD: Forty bipolar patients were interviewed for their bipolar prodromal symptoms and their coping strategies at recruitment and 18 months later. Patients were also assessed as to whether they had experienced relapses. RESULTS: Bipolar patients were able to report bipolar prodromal symptoms reliably. Mania prodromal symptoms tended to be behavioural symptoms. A quarter of patients reported difficulties in detecting depression prodromes, which tended to be more diverse and consisted of a mix of behavioural, cognitive and somatic symptoms. Significantly fewer patients who reported the use of behavioural coping strategies to curb excessive behaviour during the mania prodromal stage experienced a manic episode. Similarly, significantly fewer patients who reported the use of behavioural coping strategies experienced depression relapses. How well patients coped with mania prodromes predicted bipolar episodes significantly when the mood levels at baseline were controlled. Ratings of how well subjects coped with mania prodromal symptoms also predicted manic symptoms significantly at T2 when manic symptom at T1 was controlled. CONCLUSION: Our study suggests that bipolar patients are able to report prodromal symptoms reliably. It is advisable to teach patients to monitor their moods systematically and to promote good coping strategies.

Adaptation, Psychological↗
PubMed2001

A genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: a five-stage design using DNA pooling and extreme selected groups.

All measures of cognitive processes correlate moderately at the phenotypic level and correlate substantially at the genetic level. General cognitive ability (g) refers to what diverse cognitive processes have in common. Our goal is to identify quantitative trait loci (QTLs) associated with high g compared with average g. In order to detect QTLs of small effect size, we used extreme selected samples and a five-stage design with nominal alpha levels that permit false positive results in early stages but remove false positives in later stages. As a first step toward a systematic genome scan for allelic association, we used DNA pooling to screen 1842 simple sequence repeat (SSR) markers approximately evenly spaced at 2 cM throughout the genome in a five-stage design: (1) case-control DNA pooling (101 cases with mean IQ of 136 and 101 controls with mean IQ of 100), (2) case-control DNA pooling (96 cases with IQ > 160 and 100 controls with mean IQ of 102), (3) individual genotyping of Stage 1 sample, (4) individual genotyping of Stage 2 sample, (5) transmission disequilibrium test (TDT; 196 parent-child trios for offspring with IQ > 160). The over all Type I error rate is 0.000125, which robustly protects against false positive results. The numbers of markers surviving each stage using a conservative allele-specific directional test were 108, 6, 4, 2, and 0, respectively, for the five stages. A genomic control test using DNA pooling suggested that the failure to replicate the positive case-control results in the TDT analysis was not due to ethnic stratification. Several markers that were close to significance at all stages are being investigated further. Relying on indirect association based on linkage disequilibrium between markers and QTLs means that 100,000 markers may be needed to exclude QTL associations. Because power drops off precipitously for indirect association approaches when a marker is not close to the QTL, we are not planning to genotype additional SSR markers. Instead we are using the same design to screen markers such as cSNPs and SNPs in regulatory regions that are likely to include functional polymorphisms in which the marker can be presumed to be the QTL.

Adolescent↗
PubMed2001

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). 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 (chi(2) = 6.17, 1 df, P = 0.01, OR = 1.73, 95% CI = 1.11--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, chi(2) = 0.69). Analysis of the entire sample of 132 probands using TRANSMIT 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.

Alleles↗
PubMed2001

Association and linkage studies between bipolar affective disorder and the polymorphic CAG/CTG repeat loci ERDA1, SEF2-1B, MAB21L and KCNN3.

Several reports have suggested the presence of anticipation in bipolar affective disorder (BPAD). In addition, independent studies using the RED (repeat expansion detection) have shown association between BPAD and longer CAG/CTG repeats. Therefore loci with large CAG/CTG repeats are plausible candidates in the inheritance of BPAD. The present study assesses the length of the repeats in four loci: the ERDA-1 locus which is known to account for most of the long CAG repeats detected by RED, the SEF2-1b locus which is placed in a region where positive linkage results have been reported and the loci MAB21L and KCNN3 as functional candidate genes. A Brazilian case-control sample with 115 unrelated BPAD patients and 196 healthy control subjects and 14 multiply affected bipolar families was investigated. With the case-control design the distribution of alleles between the two groups did not approach statistical significance. The extended transmission disequilibrium test (ETDT) performed in our families did not show evidence for linkage disequilibrium. Parametric and non-parametric linkage analysis also did not provide support for linkage between any of the four loci and BPAD. Our data do not support the hypothesis that variation at the polymorphic CAG/CTG repeat loci ERDA-1, SEF2-1b, MAB21L or KCNN3 influence susceptibility to BPAD in our sample.

Adolescent↗
PubMed2001

A SNP resource for human chromosome 22: extracting dense clusters of SNPs from the genomic sequence.

The recent publication of the complete sequence of human chromosome 22 provides a platform from which to investigate genomic sequence variation. We report the identification and characterization of 12,267 potential variants (SNPs and other small insertions/deletions) of human chromosome 22, discovered in the overlaps of 460 clones used for the chromosome sequencing. We found, on average, 1 potential variant every 1.07 kb and approximately 18% of the potential variants involve insertions/deletions. The SNPs have been positioned both relative to each other, and to genes, predicted genes, repeat sequences, other genetic markers, and the 2730 SNPs previously identified on the chromosome. A subset of the SNPs were verified experimentally using either PCR-RFLP or genomic Invader assays. These experiments confirmed 92% of the potential variants in a panel of 92 individuals. [Details of the SNPs and RFLP assays can be found at http://www.sanger.ac.uk and in dbSNP.]

Base Composition↗
PubMed2001

Shifting paradigms in gene-mapping methodology for complex traits.

The analysis of genetic linkage has been highly successful in the mapping of the genes responsible for Mendelian diseases. In the past decade, attempts have been made to extend this approach to multifactorial disorders and other health-related traits. It has proved difficult, however, to obtain strong and replicable linkage findings for the common forms of heritable diseases. This, together with the rapid pace of development of molecular technology and expansion of genome sequence information, has resulted in significant shifts in research paradigm. There is an increasing recognition of the need to understand the population genetics and biometrical properties of clinically relevant traits so that phenotypes can be defined in such a way that maximises the chances of successful gene mapping. There is a trend towards systematic association analysis with increasing sophistication in the analysis of pooled DNA samples and multi-locus haplotypes, and in the use of unlinked background markers to protect against spurious associations. We can expect increasing integration between genetics, epidemiology and clinical trials leading to genetically informative designs that will not only identify susceptibility genes but also clarify how the environment influences their effects and how they may modify the response to therapeutic interventions.

Animals↗
PubMed2000

Allele association studies with SSR and SNP markers at known physical distances within a 1 Mb region embracing the ALDH2 locus in the Japanese, demonstrates linkage disequilibrium extending up to 400 kb.

There has been considerable recent debate concerning the distances over which levels of allelic association useful for genomic quantitative trait locus (QTL) scans can be detected. We have examined simple sequence repeat (SSR) polymorphisms and two single nucleotide polymorphisms (SNPs) in the region flanking the aldehyde dehydrogenase 2 locus, ALDH2, in populations of Japanese alcoholics and controls. These groups differ significantly in the allele frequencies for the functional SNP in exon XII of this gene located on chromosome 12. The results obtained with SSR markers complement recent investigations with SNPs over similar distances at the TCR alpha/delta locus. Significant allelic association with this marker could be detected for SSRs over distances up to 400 kb and over 37 kb for the SNP thereby extending the distance over which LD at this locus could be detected by an order of magnitude. Furthermore, as a proof of principle, we show that comparisons of allele frequency differences for the SSR markers in the case (alcoholics) and control populations would have detected the ALDH2 marker as a putative QTL. Extending the tests to include alleles at two or three flanking loci suggests that the power to detect QTLs through association can be enhanced significantly.

Alcohol Dehydrogenase↗
PubMed2000

Pharmacogenetic prediction of clozapine response.

We did association studies in multiple candidate genes to find the combination of polymorphisms that give the best predictive value of response to clozapine in schizophrenic patients. A combination of six polymorphisms in neurotransmitter-receptor-related genes resulted in 76.7% success in the prediction of clozapine response (p=0.0001) and a sensitivity of 95% (+/- 0.04) for satisfactory response. These results will form the basis for a simple test to enhance the usefulness of clozapine in psychiatric treatment.

Alleles↗
PubMed2000

Familial influence on variation in age of onset and behavioural phenotype in Alzheimer's disease.

BACKGROUND: Alzheimer's disease manifests considerable heterogeneity, the cause of which is unknown. AIMS: To determine the familial (genotypic) influence on phenomenology (phenotype) in Alzheimer's disease. METHOD: Affected sibling pairs with Alzheimer's disease were assessed for a range of cognitive and non-cognitive symptoms. Resemblance for phenotypic characteristics was estimated using intraclass correlations for continuous traits and by pairwise concordance for dichotomous traits. The relationship between age of onset and APOE genotype was examined using linear regression analysis. RESULTS: Significant familial effects on age of onset (intraclass correlation 0.41) and mood state (intraclass correlation 0.26), and a relatively high pairwise concordance for agitation (excess concordance 0.1) were found. The APOE locus was found to account for 4% of the variance in age of onset. CONCLUSIONS: Substantial familial influence on age of onset, depression and agitation suggests that genotype does influence phenotype in Alzheimer's disease. Establishing the molecular basis for this phenotypic variation may prove relevant to other neuropsychiatric disorders.

Affect↗