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P Asherson

Publications and source records attributed to P Asherson.

At least 55 records · Page 3Linked to original sources
PubMed1997

No evidence for an allelic association between schizophrenia and markers D22S278 and D22S283.

We report a case control association study using markers D22S278 and D22S283 in 90 unrelated patients with DSMIII-R schizophrenia and 90 controls matched for ethnicity, age and sex. No differences between allele frequencies for either marker were observed when the two groups were compared (D22S278: chi 2 = 6.53, df = 7, P = 0.51; D22S283: chi 2 = 14.73, df = 15, P = 0.48). These findings fail to support previous work by others suggesting the presence of allelic association between the markers D22S278 and D22S283 and schizophrenia.

Alleles↗
PubMed1997

Association between schizophrenia and a microsatellite polymorphism at the dopamine D5 receptor gene.

An association study of 97 patients with DSM-III-R schizophrenia and 97 matched controls was performed using a polymorphic microsatellite repeat at the dopamine D5 receptor gene. We observed a significant difference between the allele frequencies of patients and controls (chi 2 = 23.4, df = 12, p = 0.019). This reflects an excess of allele 4 (140 bp) in the patients when compared with the control sample (chi 2 = 7.087, p < 0.01; odds ratio = 2.98, 95% CI 1.29-6.86). However, this association remains tentative until confirmation in other samples.

Alleles↗
PubMed1996

Factor analysis of schizophrenic symptoms using the OPCRIT checklist.

Factor analysis was performed on OPCRIT checklist psychotic symptoms rated on 102 patients with DSM-III-R schizophrenia. An initial three-factor solution produced positive, negative, and disorganisation factors. However, application of the scree test suggested five substantive factors, with the positive factor dividing into three factors characterised, respectively, by paranoid symptoms, first rank delusions and first rank hallucinations.

Adult↗
PubMed1996

Linkage analysis of the fragile X gene FMR-1 and schizophrenia: no evidence for linkage but report of a family with schizophrenia and an unstable triplet repeat.

We have examined 23 families multiply affected with schizophrenia for linkage to the FMR-1 gene on the X chromosome. Alleles at the FMR-1 CGG triplet repeat were analysed by the polymerase chain reaction, and methylation status at the FMR-1 locus in individuals with evidence of expanded or unstable repeats was analysed by Southern hybridization. Two-point LOD score analyses with a range of X-linked single gene models and a non-parametric affected sib-pair method revealed no evidence for linkage. In one family, however, a fragile X premutation was found, and one individual with schizophrenia and developmental delay was a mosaic for the full and premutation. We conclude that although mutations within the FMR-1 gene do not have a major aetiological role in schizophrenia in our collection of pedigrees, it is possible that FMR-1 mutations can modify the clinical phenotype of schizophrenia.

Adolescent↗
PubMed1996

No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity.

OBJECTIVE: Catechol O-methyltransferase (COMT) inactivates catecholamines by methylating their m-hydroxy group. Some previous studies using biochemical methods have found higher levels of COMT activity in schizophrenic patients. Recently, the genetic polymorphism that underlies variation in COMT activity, which results in the creation of a NlaIII restriction site in the low-activity allele, has been elucidated. METHOD: This study investigated this polymorphism in 78 unrelated schizophrenic patients and 78 comparison subjects matched for age and ethnicity. High-molecular-weight DNA was isolated from lymphocytes with routine procedures, and each individual was typed for high and low COMT activity. RESULTS: The frequency of the NlaIII polymorphism was 0.51 in the schizophrenic patients and 0.53 in the comparison subjects, and no significant allelic or genotypic associations were observed. CONCLUSIONS: There was no evidence for variation in COMT activity between a group of schizophrenic patients and matched comparison subjects.

Alleles↗
PubMed1996

Concurrent validity of the OPCRIT diagnostic system. Comparison of OPCRIT diagnoses with consensus best-estimate lifetime diagnoses.

BACKGROUND: OPCRIT (a suite of computer programs that allow data entry and generate diagnoses according to 12 operational diagnostic systems) is used in a wide range of psychiatric research including both European Science Foundation and NIMH research initiatives in the molecular genetics of mental disorders. We examined its concurrent validity in 100 subjects collected for linkage studies of Bipolar Disorder and Schizophrenia. METHOD: We compared diagnoses generated by OPCRIT from data rated by two trained clinicians with diagnoses made according to consensus, best-estimate, lifetime procedures by the same two raters according to DSM-III-R and RDC classifications. RESULTS: Good to excellent agreement was achieved between OPCRIT diagnoses and those made by consensus best-estimate procedures. CONCLUSIONS: OPCRIT provides a convenient, reliable, rapid and valid approach to polydiagnostic assessment that can be used as an adjunct to conventional (but time consulting) best-estimate consensus diagnostic procedures.

Bipolar Disorder↗
PubMed1996

Expanded CAG/CTG repeats in schizophrenia. A study of clinical correlates.

BACKGROUND: Schizophrenia is associated with expanded CAG/CTG trinucleotide repeats. We wished to determine whether the presence of such expansions correlated with specific subsyndromes or other clinical features of schizophrenia. METHOD: Seventy patients from England and Wales and 44 patients from Portugal with a DSM-III-R diagnosis of schizophrenia were rated on the OPCRIT checklist. Patient's maximum CAG/CTG repeat length was measured using repeat expansion detection (RED). Significant differences were sought for repeat lengths in subjects categorised according to dimensional and categorical schizophrenia subsyndromes, affective episodes, individual symptoms, and a range of demographic variables. RESULTS: Maximum CAG/CTG repeat length did not differ significantly for any of the clinical or demographic variables studied. CONCLUSION: There are no subsyndromes or other clinical features of schizophrenia associated with CAG/CTG repeat expansion. Therefore, the identification of the gene(s) that contain expanded CAG/CTG repeats and which are associated with schizophrenia is unlikely to be facilitated at present by using any subsyndromes of schizophrenia as phenotypes.

Adult↗
PubMed1996

Linkage, association and mutational analysis of the dopamine D3 receptor gene in schizophrenia.

This study follows the observation of an association between homozygosity of an Mscl polymorphism in exon 1 and schizophrenia, which gives rise to a glycine to serine substitution and may alter the functional properties of the receptor. Alternatively the polymorphism may not itself be of functional significance but may be in linkage disequilibrium with another genetic variant in the coding or regulatory regions. To examine the second possibility we have screened all six exons of DRD3 by single-stranded conformational polymorphism analysis (SSCP) in 36 cases and 36 controls. Our findings suggest that the gene is highly conserved since we found no other mutations which alter protein structure. However we did detect a 5-bp deletion in the 3' intronic sequence flanking exon 5 which occurred in 7-8% of subjects within both case and control samples. A single bp substitution (g to a) in exon 3, which does not alter an amino acid was found in one affected individual. In addition we carried out a linkage study of 24 families multiply affected with schizophrenia and a non-parametric linkage study of 90 affected sibling pairs. These studies give no support for either major or moderate gene effects on schizophrenia susceptibility. Finally we have extended our association sample and observe a non-significant excess of homozygotes for the Mscl polymorphism in the sample overall (chi 2 = 2.09, 1 d.f., P = 0.15). The excess of homozygotes is specific to males (chi 2 = 4.617, 1 d.f., P = 0.032) and not females (chi 2 = 0.243, 1 d.f., NS). When these data are added to our previous published data a highly significant excess of homozygotes is observed in males (chi 2 = 13.766, 1 d.f., P = 0.00021) but not females (chi 2 = 0.606, 1 d.f., NS). In conclusion the accumulated data suggest strongly that genetic variation at the DRD3 locus increases susceptibility of schizophrenia, at least in males. At present the Mscl polymorphism in exon 1 of the gene remains a candidate for bringing about functional change in the receptor but this has not been formally tested. Other coding region polymorphisms have not been detected but it remains possible that variation within the promoter may alter receptor function.

Base Sequence↗
PubMed1995

Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12.

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.

Chromosomes, Human, Pair 12↗
PubMed1995

No evidence for linkage between the X-chromosome marker DXS7 and schizophrenia.

DeLisi et al. (1994b) have examined the X and Y chromosomes for linkage to schizophrenia in 126 small families and report a small positive LOD score for the marker DXS7, adjacent to the MAO locus at Xp11.4-11.3. Because of this, we have examined the DXS7 for linkage to schizophrenia using 17 pedigrees in which male-to-male transmission of schizophrenia was absent. Alleles at DXS7 were genotyped using the PCR and LOD scores calculated using five models of inheritance, including classical dominant recessive and intermediate models. LOD scores were substantially negative for all models examined and analysis for linkage heterogeneity using the LOD2 method showed no significance. Analysis by the nonparametric affected sib-pair method likewise indicated no linkage. We conclude that DXS7 is not a major locus for schizophrenia in our collection of pedigrees.

Family↗
PubMed1995

Linkage studies on chromosome 22 in familial schizophrenia.

As part of a systematic search for a major genetic locus for schizophrenia we have examined chromosome 22 using 14 highly polymorphic markers in 23 disease pedigrees. The markers were distributed at an average distance of 6.6 cM, covering 70-80% of the chromosome. We analyzed the data by the lod score method using five plausible genetic models ranging from dominant to recessive, after testing the power of our sample under the same genetic parameters. The most positive lod score found was 1.51 under a recessive model for the marker D22S278, which is insufficient to conclude linkage. However, an excess of shared alleles in affected siblings (P < .01) was found for both D22S278 and D22S283. For D22S278, the A statistic was equal to the lod score (1.51) and therefore did not provide additional evidence for linkage allowing for heterogeneity, but the Liang statistic was more significant (P = .002). Our results suggest the possibility that the region around D22S278 and D22S283 contains a gene which contributes to the aetiology of schizophrenia.

Alleles↗
PubMed1995

No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT).

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT.

Adolescent↗
PubMed1994

Repeat length variation in the dopamine D4 receptor gene shows no evidence of association with schizophrenia.

The D4 receptor has been shown to exist in several allelic forms (Van Tol et al., Nature 358:149-152, 1992) reflecting variation in the number of 48 base-pair sequence repeats in the putative cytoplasmic loop. We report a comparison of repeat length variation between schizophrenic patients and controls. Our sample of 106 unrelated schizophrenic cases and 119 controls showed no significant differences in allele or genotype distribution between patients and controls. In particular, we were unable to support the previous observation of an excess of 4-repeat homozygotes in patients.

Alleles↗
PubMed1994

Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia.

We report the results of a linkage study in 24 families multiply affected with schizophrenia using a polymorphic DNA sequence encoding the third cytoplasmic loop of the dopamine D4 receptor. Two-point LOD score analyses with a range of single gene models ranging from near dominant to near recessive revealed no evidence for linkage. In addition, we examined the data by non-parametric sib-pair analysis and found no excess sharing of alleles between affected sib-pairs. We therefore conclude that mutations within the dopamine D4 receptor gene do not have a major aetiological role in schizophrenia in our collection of pedigrees.

Alleles↗
PubMed1994

Relationship between homozygosity at the dopamine D3 receptor gene and schizophrenia.

We have reported an association between schizophrenia and homozygosity of a Bal I polymorphism in the first exon of the dopamine D3 receptor gene (Crocq et al.: Journal of Medical Genetics 29:858-860, 1992). The present study consists of an attempt to replicate this finding in a further sample of 66 patients and 97 controls. Once again more patients than controls were homozygous, but the effect was not as strong as in our first study (chi 2 = 2.53, P = 0.05, one tailed). When pooled data from our two studies were analysed, excess homozygosity in patients remained highly significant (P = 0.002) with a particular excess of the 1:1 genotype (P = 0.01). This reflected a departure from Hardy-Weinberg equilibrium in the patients (P = 0.0005) but not the controls (P = 0.24). This led us to explore the possibility that there might be important differences between the patients in our two studies and that excess homozygosity might be a characteristic of particular subgroups of schizophrenics. Our findings suggest that the effect is consistently at its strongest in those patients who have a high familial loading and in those who have a good response to neuroleptic treatment, and that differences between our two samples might have contributed to the quantitatively different outcomes.

Adult↗
PubMed1994

The strength of the genetic effect. Is there room for an environmental influence in the aetiology of schizophrenia?

The evidence for a genetic contribution to schizophrenia is compelling. However, the pattern of inheritance is complex and it is usually assumed that environmental factors also have a role that will eventually be identified. We argue that this is not necessarily the case. While a hypothesis combining genetic diathesis with environmental stress cannot be disproved, it is also possible that 'non-genetic' factors consist entirely of stochastic events affecting gene expression or structure.

Diseases in Twins↗