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P Sham

Publications and source records attributed to P Sham.

At least 55 records · Page 3Linked to original sources
PubMed2000

Pooled genotyping of microsatellite markers in parent-offspring trios.

We studied the extent to which genotyping of simple sequence repeat polymorphisms (SSRs) in pooled DNA samples can be used to predict differences in allele frequencies between parents and their affected offspring. We also developed a simple method of correction for the effects of stutter and differential amplification on the analysis of SSRs in pooled DNA samples based on widely available software. We genotyped individually eight polymorphic microsatellite markers in 110 parent-offspring trios affected with bipolar affective disorder (BP). Analysis of pooled DNA samples predicted very accurately the differences in individual allele frequency distributions between children and their parents. The mean error was <1% (range 0%-3.2%) when marker-specific corrections for stutter and differential amplification were performed. We show that if an individual allele is significantly preferentially transmitted from parents to affected offspring, the difference in the frequency of that allele would be sufficiently large to be detected with pooling in most situations. We propose recommendations for disequilibrium mapping with pooling in which both case-control samples and trios are used in an initial screen and markers are genotyped individually only if they satisfy very relaxed criteria for statistical significance. The use of case-control samples should reduce the false-negative rate as the differences in allele frequencies between cases and controls are twice as high in the presence of the same genetic effect. The use of trios will confirm or reject any suggested differences, thus reducing the false-positive rate that can be created by hidden population stratification.

Bipolar Disorder↗
PubMed1999

102T/C polymorphism of serotonin receptor type 2A gene is not associated with schizophrenia in either Chinese or British populations.

Several pieces of evidence implicate serotonin receptors in the aetiology of schizophrenia, and recently a number of studies have reported a genetic association between the 102T/C polymorphism of serotonin receptor type 2A gene and schizophrenia. Unfortunately a number of failures to replicate these positive associations in both Caucasian and Chinese populations have also been reported. We have examined the 102T/C polymorphism by PCR amplification and restriction analysis of DNA from: 202 schizophrenics and 202 controls from Shanghai; 112 schizophrenics and 224 parents from Chengdu, Cina; and 253 schizophrenics and 244 controls from the the UK. We find no evidence of association or transmission disequilibrium between the 102T/C polymorphism and schizophrenia in any of the groups we have examined. We conclude that either the original positive reports occurred by chance or any effect must be minimal, and urge caution in interpreting small positive results derived using data from different centres.

Carrier Proteins↗
PubMed1999

Accuracy and sensitivity of DNA pooling with microsatellite repeats using capillary electrophoresis.

DNA pooling is a genetic screening method that combines DNA from many individuals in a single polymerase chain reaction (PCR) reaction to generate a representation of allele frequencies. The substantial saving in effort with DNA pooling over individual genotyping facilitates linkage disequilibrium scanning of the human genome using many thousands of genetic markers, and is applicable to mapping of complex diseases such as schizophrenia. However, the literature to date has not addressed several crucial technical aspects of DNA pooling. These include: DNA quantification; the choice of electrophoresis methods; sensitivity (the minimum reliably detectable difference between pools); and methods of dealing with 'plus-A' stutter. We have examined these points and make recommendations as to the best procedures to adopt as well as quantifying reproducibility and sensitivity. We conclude that, although allele frequencies derived from microsatellite pooling are distorted, differences of 5% or greater between pools can be reliably detected.

Alleles↗
PubMed1999

Factor analysis of symptoms in schizophrenia: differences between White and Caribbean patients in Camberwell.

BACKGROUND: The incidence of schizophrenia among African-Caribbeans living in Britain has been frequently reported to be increased. We sought to determine whether the symptom profile in schizophrenic patients from this group differed from that of their White counterparts. METHODS: Factor analysis was applied to symptom data obtained by the Present State Examination (PSE) from a group of White (N = 96) and Afro-Caribbean (N = 64) patients who satisfied Research Diagnostic Criteria criteria for broad schizophrenia. We identified six symptom dimensions: mania, depression, first-rank delusions, other delusions, hallucinations and one which comprised both manic and catatonic symptoms. RESULTS: The only difference between the two ethnic groups was seen on the mixed mania-catatonia dimension with the Afro-Caribbean group being over-represented. There were no other significant differences between the groups. Discriminant analysis, however, revealed no significant differences between the groups in any dimension. CONCLUSIONS: These results indicate that there are no differences between White and African-Caribbean patients with schizophrenia in terms of the core symptoms of the disorder, however, the African-Caribbean patients may present with more symptoms of a mixed affective nature.

Adolescent↗
PubMed1999

Fatigue and psychiatric disorder: different or the same?

BACKGROUND: Fatigue and psychiatric symptoms are common in the community, but their association and outcome are sparsely studied. METHOD: A total of 1177 patients were recruited from UK primary care on attending their general practitioner. Fatigue and psychiatric disorder was measured at three time points with the 12-item General Health Questionnaire and the 11-item Fatigue Questionnaire. RESULTS: Total scores for fatigue and psychiatric disorder did not differ between the three time points and were closely correlated (r around 0.6). The association between non-co-morbid ('pure') fatigue and developing psychiatric disorder 6 months later was the same as that for being well and subsequent psychiatric disorder. Similarly, having non-co-morbid psychiatric disorder did not predict having fatigue any more than being well 6 months previously. Between 13 and 15% suffered from non-co-morbid fatigue at each time point and 2.5% suffered from fatigue at two time points 6 months apart. Less than 1% of patients suffered from non-co-morbid fatigue at all three time points. CONCLUSIONS: The data are consistent with the existence of 'pure' independent fatigue state. However, this state is unstable and the majority (about three-quarters) of patients become well or a case of psychiatric disorder over 6 months. A persistent, independent fatigue state lasting for 6 months can be identified in the primary-care setting, but it is uncommon of the order of 2.5%. Non-co-morbid (pure) fatigue did not predict subsequent psychiatric disorder.

Adolescent↗
PubMed1999

Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping.

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

Adolescent↗
PubMed1998

Differences in distribution of ages of onset in males and females with schizophrenia.

An earlier age at onset of schizophrenia in men as opposed to women, has been widely reported, but hitherto, insufficient account has been taken of parameters that might confound this finding. Furthermore, few explanatory models have accounted for the differences in shape of the age-at-onset distributions in males and females with schizophrenia. A catchment area sample of 477 first contact cases with schizophrenia or related disorders was ascertained through a case register. Differences in age at onset distributions between males and females were determined, and adjustment made for potential confounding factors. The most powerful predictors of early illness-onset were poor premorbid occupational functioning, single marital status, and male sex. The earlier onset in males was robust to controlling for other parameters. The shape of the onset distribution also differed between the sexes: SKUMIX analysis revealed a two-peak distribution for males, and a three-peak distribution for females. The mean age at onset for schizophrenia is earlier in males, and the onset distribution differs between the sexes. Psychosocial variables cannot explain these findings. Possible explanations for these gender differences include males and females being differentially susceptible to subtypes of illness with different mean ages at onset; precipitating and/or ameliorating factors operating at different stages of life in males and females; and/or an X-linked susceptibility locus that determines the age at onset.

Age Factors↗
PubMed1998

Case-control, haplotype relative risk and transmission disequilibrium analysis of a dopamine D2 receptor functional promoter polymorphism in schizophrenia.

The dopamine system has long been suspected of aetiological involvement in schizophrenia because of a number of lines of evidence pointing to excess dopaminergic activity in the illness. Recently, negative allelic association was reported between a single base deletion in the promoter region of the DRD2 gene, -141 delta C, and schizophrenia, with an odds ratio of 0.60. This was of particular interest since the deletion, which occurs in about 22% of the Japanese population, is functional in that it results in reduced (20-40% of wild-type) basal levels of receptor expression. We have examined this polymorphism in 229 family trios from SW China, consisting of both parents and a single offspring affected by schizophrenia, and 151 Caucasian cases with schizophrenia and 145 Caucasian normal controls from the UK. Using the haplotype-based haplotype relative risk method (HHRR), the frequency of the -141 delta C allele was 6.9% in the affected Chinese subjects compared to an estimated frequency of 9.0% in this population (chi 2 = 1.21, 1 df, ns), with an odds ratio of 0.76 (95% CI 0.46-1.25). Using the transmission disequilibrium test, we likewise found no evidence for linkage or linkage disequilibrium with this polymorphism (chi 2 = 0.94, 1 df, ns). In the Caucasian cases, the frequency of the -141 delta C was 13% compared to 10% in controls (chi 2 = 1.57, p = 0.21) with an odds ratio of 1.39 (95% CI 0.81-2.40). We thus conclude that the DRD2 -141 delta C polymorphism is less frequent in Chinese and Caucasian populations (9%) than in Japan (22%) and is not a significant risk factor for schizophrenia in our populations. The -141 delta C allele remains a strong candidate for a variety of other traits and diseases, including reward-related behaviours such as drug abuse, which have been associated with the dopamine system.

Adolescent↗
PubMed1998

Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response.

Serotonin (5-HT) neurotransmitter receptors are targeted by atypical antipsychotic drugs. We hypothesized that genetic variation in these receptors may affect clinical response to the drugs targeting them. This hypothesis has been tested by several studies in which the correlation between polymorphic variants in the 5-HT2A receptor gene and clinical response to the atypical antipsychotic clozapine was investigated. The results of these studies either found association between 5-HT2A genetic variants and clozapine response or found differences in the same direction which did not reach statistical significance. Meta-analysis of these studies including 373 patients who responded to the treatment and 360 non-responders showed association between two 5-HT2A polymorphisms, 102-T/C and His452Tyr, and clozapine response. Statistical analysis of extreme responders showed a clearer association of the 102-T/C with clozapine response. These results reinforce the hypothesis and strengthen the candidacy of these receptors as important therapeutic targets.

Alleles↗
PubMed1998

Obstetric complications and familial morbid risk of psychiatric disorders.

Obstetric complications (OCs) have been found to occur in higher frequency in patients with schizophrenia. One explanation for this finding is that the genes that contribute to the schizophrenia phenotype also influence the likelihood to experience OCs. If this were true, morbid risk of psychiatric illness should be higher in the first-degree relatives of both schizophrenic and control probands exposed to OCs, compared to probands not exposed to OCs. We set out to test this hypothesis. Information on OCs, blind to family history of psychiatric disorder, was collected retrospectively through maternal interview in 151 psychotic patients and 100 controls. Family history (FH) in relatives of cases (n = 600) and controls (n = 461) was assessed with the FH-RDC and through personal interviews. Tests for associations between family history and OCs were conducted using Cox proportional hazard regression. In the cases, familial morbid risk of affective disorder was greater in those with a history of OCs (hazard ratio (HR) = 1.9, P = 0.007). Analyses examining individual complications revealed associations between FH of affective disorder and pre-eclampsia (HR = 2.9, P = 0.003) and FH of affective disorder and breech presentation (HR = 2.8, P = 0.02), especially when family history in the relatives was confined to affective illness in the mother (HR pre-eclampsia = 4.4, P = 0.009; HR breech-presentation = 4.2, P = 0.008). In controls, affective illness in the mother was not only associated with breech presentation (HR = 7.0, P = 0.01) and pre-eclampsia (HR = 4.4, P = 0.03) but also with other complications. Familial morbid risk of schizophrenia and related psychoses was not associated with OCs. The positive associations between OCs and familial morbid risk of affective disorder suggest that the factors that contribute to familial aggregation of affective symptoms in psychotic patients also influence the likelihood to experience OCs. Although the proportion of OCs that could be attributed to these factors was very small, part of the relationship between family history of affective disorder and psychosis may be mediated by OCs.

Age of Onset↗
PubMed1998

Risk factors for onset and persistence of psychosis.

Clinical practice, training and evaluation of treatment in the functional psychoses continues to be carried out mostly along the traditional line of separation by diagnostic entity. However, the combined evidence from research on risk factors for onset and for persistence of psychotic illness indicates quantitative, but not qualitative, differences between categories of schizophrenia and affective psychosis. "Developmental" factors, such as childhood dysfunction, increased cerebral ventricle size and familial morbid risk of schizophrenia operate preferentially, though not specifically, at that end of the psychopathological spectrum characterised by a preponderance of negative features. On the other hand, "social" factors, such as ethnic group, adverse life events and familial morbid risk of affective disorder have a larger impact at the end associated with predominance of affective features. Heterogeneity in the functional psychoses may thus be best conceived as two discrete effects operating at different ends of a continuous psychopathological spectrum. The use of highly reliable but arbitrary diagnostic categories may introduce serious bias in aetiological and treatment research. Evidence supporting the validity of a model of shared risk factors for continuous characteristics needs to be further elaborated and incorporated into our concepts of psychotic illness.

Affective Disorders, Psychotic↗
PubMed1998

Does the method of data collection affect the reporting of depression in the relatives of depressed probands?

BACKGROUND: Data is usually collected from different sources in family studies in depression. We sought to determine what effect different methods of data collection had on the reporting of the lifetime prevalence of depression in the relatives of depressed probands. METHOD: We examined the psychiatric histories of 519 first-degree relatives of a consecutive series of 89 hospitalised depressed probands to ascertain their lifetime prevalence of RDC Major Depression. These data on relatives were obtained either directly with the SADS-L (n = 116), indirectly with the Family History RDC (FH-RDC) (n = 283) or by examining the casenotes of the probands (n = 120). RESULTS: The method of data collection had a marked effect on the reported prevalence of depression, with direct interview being much more sensitive in detecting the less severe forms of the illness. The lifetime prevalence of hospitalised depression in relatives, however, was unaffected by the method of the data collection. Variation in lifetime prevalence of depression between the SADS-L and FH-RDC appeared to be due mainly to differences in the sensitivity of the instrumentation rather than to biases in sampling. CONCLUSION: We confirm that indirect sources of family information have reduced sensitivity for the detection of depression in relatives compared with direct interview. LIMITATIONS: The numbers of relatives directly interviewed were small and the probands represented a severely affected sample which limits the generalisability of the findings. CLINICAL RELEVANCE: Combining data from different methods of collection in family studies is therefore problematic unless a narrow definition of caseness is used (e.g. depression requiring hospitalisation).

Bias↗
PubMed1998

Quality of parenting and vulnerability to depression: results from a family study.

BACKGROUND: We examined a group of subjects at familial risk of depression and explored the relationship between the perceptions of parents and a history of depression. We also investigated: (a) whether any difference in perceived parenting found between those with and without a past history of depression was an artefact of the depression; and (b) whether the relationship between parenting and depression was explained by neuroticism. METHOD: We took a sample of first-degree relatives selected from a family study in depression and subdivided them by their history of mental illness on the SADS-L, into those: (a) without a history of mental illness (N = 43); and (b) those who had fully recovered from an episode of RDC major depression (N = 34). We compared the perceptions of parenting, as measured by the Parental Bonding Instrument (PBI), in these two groups having adjusted for the effect of neuroticism and subsyndromal depressive symptoms. We also had informants report on parenting of their siblings, the latter being subdivided into those with and without a past history of depression. RESULTS: Relatives with a past history of depression showed lower care scores for both mother and father combined compared with the never ill relatives. The presence of a history of depression was associated with a non-significant reduction in the self-report care scores compared to the siblings report. Vulnerable personality (as measured by high neuroticism) and low perceived care were both found to exert independent effects in discriminating between the scores of relatives with and without a history of depression and there was no interaction between them. CONCLUSION: This study confirmed that low perceived parental care was associated with a past history of depression, that it was not entirely an artefact of having been depressed, and suggested that this association was partially independent of neuroticism.

Adult↗
PubMed1998

Family history as a predictor of poor long-term outcome in depression.

BACKGROUND: We investigated whether family history had prognostic significance in depression in a study which addressed some of the methodological shortcomings of previous studies. METHOD: We collected family history data on a consecutive series of 89 patients admitted with RDC major depression, blind to the outcome of the proband. This comprised 116, 283 and 120 first-degree relatives examined with the SADS-L, FH-RDC and case note data, respectively. The outcome of 74 of these probands (83%), previously categorised into four operationally defined groups, was then examined. RESULTS: A positive family history of severe psychiatric illness (i.e. a relative with a history of either a psychosis, hospitalised depression or suicide) was associated with poor outcome in the proband. This association persisted after controlling for variable family size, age structure and gender. As family history was correlated with neither Kendell's neurotic/psychotic index nor the proband's neuroticism score, an individual with high scores an all three would have a greatly increased chance of having a poor outcome. CONCLUSIONS: A family history of severe psychiatric illness in a first-degree relative may be useful as one of the vulnerability factors for predicting poor long-term outcome in depression.

Adolescent↗
PubMed1997

5-HT2A receptor and bipolar affective disorder: association studies in affected patients.

The aim of this study was to investigate the possible involvement of genetic variation in serotonin receptors in the aetiology of bipolar affective disorder. The 5-HT2A receptor gene was systematically screened for genetic variants by single strand conformation polymorphism (SSCP) methods in subjects with bipolar affective disorder. Four polymorphisms (two structural changes, Thr25Asn and His4 M52Tyr, and two silent polymorphisms, 102-T/C and 516-C/T) which had previously been found in patients with schizophrenia and control subjects were detected. No novel polymorphisms were found in patients with bipolar affective disorder. These polymorphisms were genotyped in a sample of 129 patients and 252 controls of German origin and 176 patients and 182 controls of British origin. No strong associations were found between any of these polymorphisms and bipolar affective disorder. Genetic variation at the 5-HT2A receptor gene does not play a major role in the pathogenesis of the disorder.

Alleles↗
PubMed1997

Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations.

Previously we reported suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32. We have now studied an additional independent sample of 44 pedigrees consisting of 34 Taiwanese, 9 English and 1 Welsh family in an attempt to replicate this finding. Narrow and broad models based on Research Diagnostic Criteria or the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised, were used to define the schizophrenia phenotype. Under a dominant genetic model, two-point lod scores obtained for most of the markers were negative except that marker D13S122 gave a total lod score of 1.06 (theta = 0.2, broad model). As combining pedigrees from different ethnic origins may be inappropriate, we combined this replication sample and our original sample, and then divided the total sample into Caucasian (English and Welsh pedigrees) and Oriental (Taiwanese and Japanese pedigrees) groups. The Caucasian pedigrees produced maximized admixture two-point lod scores (A-lod) of 1.41 for the marker D13S119 (theta = 0.2, alpha = 1.0) and 1.54 for D13S128 (theta = 0, alpha = 0.3) with nearby markers also producing positive A-lod scores. When five-point model-free linkage analysis was applied to the Caucasian sample, a maximum lod score of 2.58 was obtained around the markers D13S122 and D13S128, which are located on chromosome 13q32. The linkage results for the Oriental group were less positive than the Caucasian group. Our results again suggest that there is a potential susceptibility locus for schizophrenia on chromosome 13q14.1-q32, especially in the Caucasian population.

Asian People↗
PubMed1997

Psychopathological syndromes and familial morbid risk of psychosis.

BACKGROUND: Familial liability in the functional psychoses had traditionally been examined by comparing mutually exclusive diagnostic categories. This study examines overlapping psychopathological dimensions in relation to familial morbid risk of psychosis. METHOD: We tested for associations between seven factor-analysis derived psychopathological dimensions and familial morbid risk of psychosis, in a sample of 150 patients with recent-onset functional psychosis and 548 of their first-degree relatives. RESULTS: A syndrome characterised by affective blunting and insidious and early onset of illness, non-specifically predicted psychosis in the first-degree relatives, whereas a manic syndrome specifically predicted affective psychosis in the relatives. No other main effects were observed, but there were interactions with proband diagnosis: a syndrome characterised by bizarre behaviour, inappropriate affect, catatonia and poor rapport predicted psychosis in relatives of schizophrenic probands, and a syndrome of depressive: symptoms predicted psychosis in relatives of schizoaffective probands. Positive symptoms were not associated with illness in the relatives. CONCLUSIONS: Genetic effects in the functional psychoses may comprise non-specific components that canalise a general, early-onset, affective blunting phenotype and several other, more specific, influences on phenotypic variation.

Adult↗