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M J Owen

Publications and source records attributed to M J Owen.

At least 19 recordsLinked to original sources
PubMed2001

Sustained and selective attention as measures of genetic liability to schizophrenia.

We tested for a relationship between attention and genetic liability to schizophrenia. Samples of probands with DSM-IV schizophrenia (n=20), their well first-degree relatives (n=40) and healthy controls (n=82) were tested using measures of sustained attention (degraded-stimulus continuous performance test: DS-CPT) and selective attention (spatial negative priming task). Assuming a liability-threshold model, we predicted that probands would display greater attentional decrements than controls and that the relatives would show intermediate levels of decrement. We did not observe the predicted pattern of effect using either measure, although the probands showed a trend towards less negative priming. However, our results may have been affected by self-selection bias in probands and relatives and clinical heterogeneity among probands, which could have reduced our power to detect effects.

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

No association between apolipoprotein E polymorphisms and general cognitive ability in children.

In this work we explored the hypothesis that variation in the gene encoding apolipoprotein E (ApoE) is a factor modifying general cognitive ability (g). A case control sample of 101 high g and 101 average g children was scored for ApoE genotypes and two variants in the transcriptional regulatory region of the gene (Th1/E47cs and -491 AT). No evidence of association between these polymorphisms and g was found. We conclude that variation at these loci is not a factor with a measurable impact on general cognitive ability in the healthy population.

Adolescent↗
PubMed2001

Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice.

Chondrocyte hypertrophy is a mandatory step during endochondral ossification. Cbfa1-deficient mice lack hypertrophic chondrocytes in some skeletal elements, indicating that Cbfa1 may control hypertrophic chondrocyte differentiation. To address this question we generated transgenic mice expressing Cbfa1 in nonhypertrophic chondrocytes (alpha1(II) Cbfa1). This continuous expression of Cbfa1 in nonhypertrophic chondrocytes induced chondrocyte hypertrophy and endochondral ossification in locations where it normally never occurs. To determine if this was caused by transdifferentiation of chondrocytes into osteoblasts or by a specific hypertrophic chondrocyte differentiation ability of Cbfa1, we used the alpha1(II) Cbfa1 transgene to restore Cbfa1 expression in mesenchymal condensations of the Cbfa1-deficient mice. The transgene restored chondrocyte hypertrophy and vascular invasion in the bones of the mutant mice but did not induce osteoblast differentiation. This rescue occurred cell-autonomously, as skeletal elements not expressing the transgene were not affected. Despite the absence of osteoblasts in the rescued animals there were multinucleated, TRAP-positive cells resorbing the hypertrophic cartilage matrix. These results identify Cbfa1 as a hypertrophic chondrocyte differentiation factor and provide a genetic argument for a common regulation of osteoblast and chondrocyte differentiation mediated by Cbfa1.

Animals↗
PubMed2001

Searching for schizophrenia genes.

Schizophrenia is characterized by profound disturbances of cognition, emotion and social functioning. It carries a lifetime risk within the general population of approximately 1%. Genetic epidemiological studies have shown that the syndrome has a high heritability, indicating a significant genetic component to its aetiology. However, the undoubted complexity and probable heterogeneity of the disorder continue to confound research, and the precise underlying neurobiological mechanisms remain largely unknown. Although molecular-genetic approaches face formidable difficulties, the identification of susceptibility genes is likely to provide valuable insights into the aetiology and pathogenesis that could lead to the development of more effective treatments.

Chromosome Mapping↗
PubMed2001

Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder.

Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.

Adult↗
PubMed2001

DR3 regulates negative selection during thymocyte development.

DR3 (Ws1, Apo3, LARD, TRAMP, TNFSFR12) is a member of the death domain-containing tumor necrosis factor receptor (TNFR) superfamily, members of which mediate a variety of developmental events including the regulation of cell proliferation, differentiation, and apoptosis. We have investigated the in vivo role(s) of DR3 by generating mice congenitally deficient in the expression of the DR3 gene. We show that negative selection and anti-CD3-induced apoptosis are significantly impaired in DR3-null mice. In contrast, both superantigen-induced negative selection and positive selection are normal. The pre-T-cell receptor-mediated checkpoint, which is dependent on TNFR signaling, is also unaffected in DR3-deficient mice. These data reveal a nonredundant in vivo role for this TNF receptor family member in the removal of self-reactive T cells in the thymus.

Animals↗
PubMed2001

Genetic risk of Alzheimer's disease: advising relatives.

BACKGROUND: Clinicians are increasingly asked by relatives of patients with Alzheimer's disease to advise on their genetic risk of developing Alzheimer's disease in later life. Many clinicians find this a difficult question to answer. AIMS: To provide information for old age psychiatrists wishing to advise relatives of their risk of developing Alzheimer's disease. METHOD: A selective review of the key literature on the genetic epidemiology of Alzheimer's disease. RESULTS: Currently a DNA diagnosis is attainable in some 70% of families with autosomal dominant Alzheimer's disease. In first-degree relatives of most cases, risk is increased some three- or four-fold relative to controls, but only one-third of this is realised in the average life span. Apolipoprotein E genotyping cannot be used as a predictive test and confers only minimal diagnostic benefit. CONCLUSIONS: Pedigrees with familial Alzheimer's disease should be referred to a Regional Centre for Medical Genetics. Accurate risk prediction is not possible in the vast majority of pedigrees with Alzheimer's disease, although it is possible for the psychiatrist to give a rough estimate of the risk, which can reasonably the couched in reassuring terms.

Aged↗
PubMed2000

Susceptibility locus for Alzheimer's disease on chromosome 10.

The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.

Age of Onset↗
PubMed2000

Long repeat tracts at SCA8 in major psychosis.

Expansion at a recently identified unstable trinucleotide repeat on chromosome 13q21 has been reported as the molecular cause for spinocerebellar ataxia type 8 (SCA8). The trinucleotide repeat, which consists of a [CTA]n repeat and adjacent [CTG]n repeat, was reported to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a large ataxia kindred. This repeat region was also cloned by our group from a bipolar affective disorder (BPAD) patient, who has approximately 600 combined repeats, and large alleles (>100 repeats) were reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1,120, respectively). We have followed up these findings by screening three new samples of BPAD and schizophrenia (SCZ) patients and controls, including 272 individuals from 14 BPAD families from Sweden, 130 individuals from 32 SCZ and BPAD families/trios from the Azores Islands, and 206 SCZ individuals from the United Kingdom and Ireland, and 219 matched controls. We found large repeat alleles above the SCA8 pathogenic range in individuals from 3 of 32 Azorean pedigrees and in 1 of 206 SCZ individuals from the United Kingdom, and repeat alleles within the SCA8 pathogenic range in 1 of 14 Swedish families. Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:873-876, 2000.

Alleles↗
PubMed2000

Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3).

WSL-1/TRAMP (DR3) is a member of the tumour necrosis factor (TNF) receptor superfamily which exhibits effects on NF-kappaB activation and apoptosis. TWEAK, a novel TNF-related molecule, has been proposed as the ligand for this receptor. Utilising both human and murine TWEAK ligand, it is shown that TWEAK and WSL-1/TRAMP do not interact in an in vitro binding assay and that TWEAK binds strongly to cells that do not express WSL-1/TRAMP on the cell surface. Biological activity of TWEAK is also observed in these cells. Finally, cells isolated from WSL-1/TRAMP knockout mice are shown to retain their ability to interact with TWEAK. These results suggest that WSL-1/TRAMP is not the major receptor for TWEAK

Animals↗
PubMed2000

The kings schizotypy questionnaire as a quantitative measure of schizophrenia liability.

We used a new self-report measure, the Kings Schizotypy Questionnaire (KSQ; Williams, M. The psychometric assessment of schizotypal personality. PhD thesis. Institute of Psychiatry, University of London, 1993), to investigate schizotypy as a quantitative measure of familial liability to schizophrenia. The KSQ was administered to 135 DSM-IV schizophrenia probands, 153 of their healthy first-degree relatives, and 267 control subjects. We found that the questionnaire clearly differentiated schizophrenic from non-schizophrenic individuals, but failed to differentiate the relatives from controls. Possible reasons for this include defensive responding among relatives, self-selection bias among relatives, differences in data collection methods, and the possibility that positive aspects of schizotypy may not be closely related to familial liability to schizophrenia.

Adult↗
PubMed2000

Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III.

Schizophrenia candidate regions 33-51 cM in length on chromosomes 5q, 6q, 10p, and 13q were investigated for genetic linkage with mapped markers with an average spacing of 5.64 cM. We studied 734 informative multiplex pedigrees (824 independent affected sibling pairs [ASPs], or 1,003 ASPs when all possible pairs are counted), which were collected in eight centers. Cases with diagnoses of schizophrenia or schizoaffective disorder (DSM-IIIR criteria) were considered affected (n=1,937). Data were analyzed with multipoint methods, including nonparametric linkage (NPL), ASP analysis using the possible-triangle method, and logistic-regression analysis of identity-by-descent (IBD) sharing in ASPs with sample as a covariate, in a test for intersample heterogeneity and for linkage with allowance for intersample heterogeneity. The data most supportive for linkage to schizophrenia were from chromosome 6q; logistic-regression analysis of linkage allowing for intersample heterogeneity produced an empirical P value <.0002 with, or P=.0004 without, inclusion of the sample that produced the first positive report in this region; the maximum NPL score in this region was 2.47 (P=.0046), the maximum LOD score (MLS) from ASP analysis was 3.10 (empirical P=.0036), and there was significant evidence for intersample heterogeneity (empirical P=.0038). More-modest support for linkage was observed for chromosome 10p, with logistic-regression analysis of linkage producing an empirical P=. 045 and with significant evidence for intersample heterogeneity (empirical P=.0096).

Chromosome Mapping↗
PubMed2000

Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene.

A number of linkage studies provide evidence consistent with the existence of a bipolar susceptibility gene on chromosome 4p16. The gene for Wolfram syndrome, a rare recessive neurodegenerative disorder, lies in this region and has recently been cloned. Psychiatric disturbances including psychosis, mood disorder, and suicide have been reported at increased frequency in Wolfram patients and in heterozygous carriers of a Wolfram mutation. In the current investigation we have undertaken a case-control association study using a single nucleotide polymorphism (causing an amino acid change) in exon 8 of the Wolfram gene in a UK Caucasian sample of 312 Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM IV) bipolar I probands and 301 comparison individuals. We found no evidence that variation at this polymorphism influences susceptibility to bipolar disorder. It remains possible that variation at other sites within or near the Wolfram gene plays important roles in determining susceptibility to affective illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:154-157, 2000.

Bipolar Disorder↗
PubMed2000

Family-based association mapping provides evidence for a gene for reading disability on chromosome 15q.

Family-based association mapping was used to follow up reports of linkage between reading disability (RD) and a genomic region on chromosome 15q. Using a two-stage approach, we ascertained 101 (stage 1) and 77 (stage 2) parent-proband trios, in which RD was characterized rigorously. In stage 1, a set of eight microsatellite markers spanning the region of putative linkage was used and a highly significant association was detected between RD and a three-marker haplotype (D15S994/D15S214/D15S146: P and empirical P < 0.001). A significant association with the same three-marker haplotype was also observed in the second-stage sample (P = 0.009, empirical P = 0.006). Our data therefore provide strong evidence for one or more genes contributing to RD being located in the vicinity of the region including D15S146 and D15S994. In addition, our results provide support for association analysis being a useful method to map susceptibility loci for complex disorders.

Chromosome Mapping↗
PubMed2000

The p24 family member p23 is required for early embryonic development.

The p24 family of type I integral-membrane proteins, which are localised in the endoplasmic reticulum (ER), the intermediate compartment and the Golgi apparatus, are thought to function as receptors for cargo exit from the ER and in transport vesicle formation. Members of the p24 family have been found in a molecular complex and are enriched in COPI-coated vesicles, which are involved in membrane traffic between the ER and Golgi complex. Although expressed abundantly, simultaneous deletion of several family members does not appear to affect cell viability and protein secretion in yeast. In order to gain more insights into the physiological roles of different p24 proteins, we generated mice deficient in the expression of one family member, p23 (also called 24delta1, see for alternative nomenclature). In contrast to yeast genetics, in mice disruption of both p23 alleles resulted in early embryonic lethality. Inactivation of one allele led not only to reduced levels of p23 itself but also to reduced levels of other family members. The reduction in steady-state protein levels also induced structural changes in the Golgi apparatus, such as the formation of dilated saccules. The generation of mice deficient in p23 expression has revealed an essential and non-redundant role for p23 in the earliest stages of mammalian development. It has also provided genetic evidence for the participation of p24 family members in oligomeric complexes and indicates a structural role for these proteins in maintaining the integrity of the early secretory pathway.

Alleles↗
PubMed2000

Co-ordination of the expression of the protein tyrosine kinase p56(lck) with the pre-T cell receptor during thymocyte development.

The protein tyrosine kinase p56(lck) is essential for the regulation of early thymocyte development by transducing pre-T cell receptor (pre-TCR) mediated-signals. Here we have investigated the developmental timing of expression of p56(lck) in the thymus. We show that p56(lck) transcripts are detectable in each CD4(-)CD8(-) double-negative (DN) thymocyte subset defined by CD25 and CD44. The steady-state level of p56(lck) mRNA with these four DN subsets is similar, varying by less than 2-fold. However, p56(lck) protein levels are undetectable in DN subsets 1 and 2, but are at least 20-fold up-regulated between DN subsets 2 and 3. Analysis of independent transgenic mouse lines in which the proximal p56(lck) promoter was used to drive expression of a green fluorescent protein (GFP) reporter gene revealed a lack of correlation between GFP mRNA expression and transgene copy number and variable expression of GFP protein in different lines. Taken together these results show that the expression of the p56(lck) gene is developmentally regulated at the post-transcriptional level at the precise developmental stage at which its upstream receptor complex, the pre-TCR, is expressed. These results also have implications for the interpretation of the phenotype of transgenic mice which utilize the p56(lck) proximal promoter.

Animals↗