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Biomedical subjects

David Curtis

Publications and source records attributed to David Curtis.

At least 19 recordsLinked to original sources
PubMed2006

Case report: rapidly fatal bowel ischaemia on clozapine treatment.

BACKGROUND: There have been previous reported deaths due to clozapine-induced constipation. In all these cases patients have experienced prior abdominal symptoms over a period of weeks or months. CASE PRESENTATION: We report the sudden death due to constipation of a healthy young male patient on clozapine without any known history of prior abdominal symptoms. CONCLUSION: Psychiatrists need to be alert to the medical emergencies which can occur in the context of clozapine treatment and also need to make other clinicians who may have contact with their patients aware of these.

Adult↗
PubMed2006

Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4).

The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility.

Alleles↗
PubMed2006

Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.

Adult↗
PubMed2006

Identification of the Slynar gene (AY070435) and related brain expressed sequences as a candidate gene for susceptibility to affective disorders through allelic and haplotypic association with bipolar disorder on chromosome 12q24.

OBJECTIVE: Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. METHOD: DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. RESULTS: Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. CONCLUSIONS: These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.

Alleles↗
PubMed2005

Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Application of logistic regression to case-control association studies involving two causative loci.

Models in which two susceptibility loci jointly influence the risk of developing disease can be explored using logistic regression analysis. Comparison of likelihoods of models incorporating different sets of disease model parameters allows inferences to be drawn regarding the nature of the joint effect of the loci. We have simulated case-control samples generated assuming different two-locus models and then analysed them using logistic regression. We show that this method is practicable and that, for the models we have used, it can be expected to allow useful inferences to be drawn from sample sizes consisting of hundreds of subjects. Interactions between loci can be explored, but interactive effects do not exactly correspond with classical definitions of epistasis. We have particularly examined the issue of the extent to which it is helpful to utilise information from a previously identified locus when investigating a second, unknown locus. We show that for some models conditional analysis can have substantially greater power while for others unconditional analysis can be more powerful. Hence we conclude that in general both conditional and unconditional analyses should be performed when searching for additional loci.

Case-Control Studies↗
PubMed2005

The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia.

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.

Adaptor Proteins, Vesicular Transport↗
PubMed2005

Genetic linkage analysis supports the presence of two susceptibility loci for alcoholism and heavy drinking on chromosome 1p22.1-11.2 and 1q21.3-24.2.

BACKGROUND: In order to confirm a previous finding of linkage to alcoholism on chromosome 1 we have carried out a genetic linkage study. METHODS: DNA from eighteen families, densely affected by alcoholism, was used to genotype a set of polymorphic microsatellite markers at loci approximately 10 centimorgans apart spanning the short arm and part of the long arm of chromosome 1. Linkage analyses were performed using the classical lod score and a model-free method. Three different definitions of affection status were defined, these were 1. Heavy Drinking (HD) where affected subjects drank more than the Royal College of Psychiatrists recommended weekly amount. 2. The Research Diagnostic Criteria for alcoholism (RDCA) 3. Alcohol Dependence Syndrome (ADS) as defined by Edwards and Gross (1976) and now incorporated into ICD10 and DSMIV. RESULTS: Linkage analyses with the markers D1S1588, D1S2134, D1S1675 covering the cytogenetic region 1p22.1-11.2 all gave positive two point and multipoint lods with a maximum lod of 1.8 at D1S1588 (1p22.1) for the RDCA definition of alcoholism. Another lod of 1.8 was found with D1S1653 in the region 1q21.3-24.2 using the HD affection model. CONCLUSION: These results both support the presence of linkage in the 1p22.1-11.2 region which was previously implicated by the USA Collaborative Study of the Genetics of Alcoholism (COGA) study and also suggest the presence of another susceptibility locus at 1q21.3-24.2.

Alcohol Drinking↗
PubMed2005

Genetic linkage analysis of the X chromosome in autism, with emphasis on the fragile X region.

The higher prevalence of autism in males than in females suggests the possible involvement of the X chromosome. To test the hypothesis that there are mutations increasing susceptibility to autism on the X chromosome, and in particular the distal portion of the long arm that encompasses the FMRI and MECP2 loci, a genetic linkage study was performed. Twenty-two fragile X-negative families multiplex for autism and related disorders were used for the study. Linkage analysis, for markers in the Xq27-q28 region, using model-free likelihood-based analysis, produced a maximum MLOD of 1.7 for the narrowest diagnostic category of the typical autism/severe autism spectrum, and nonparametric analysis produced a maximum non-parametric lod (NPL) score of 2.1 for a broad phenotype diagnostic model. Thus, this study offers modest support for a susceptibility locus for autism within the Xq27-q28 region. Further genetic investigations of this region are warranted.

Autistic Disorder↗
PubMed2005

A new method of linkage analysis using LOD scores for quantitative traits supports linkage of monoamine oxidase activity to D17S250 in the Collaborative Study on the Genetics of Alcoholism pedigrees.

OBJECTIVE: Although LOD score methods have been applied to diseases with complex modes of inheritance, linkage analysis of quantitative traits has tended to rely on non-parametric methods based on regression or variance components analysis. Here, we describe a new method for LOD score analysis of quantitative traits which does not require specification of a mode of inheritance. METHODS: The technique is derived from the MFLINK method for dichotomous traits. A range of plausible transmission models is constructed, constrained to yield the correct population mean and variance for the trait but differing with respect to the contribution to the variance due to the locus under consideration. Maximized LOD scores under homogeneity and admixture are calculated, as is a model-free LOD score which compares the maximized likelihoods under admixture assuming linkage and no linkage. These LOD scores have known asymptotic distributions and hence can be used to provide a statistical test for linkage. The method has been implemented in a program called QMFLINK. It was applied to data sets simulated using a variety of transmission models and to a measure of monoamine oxidase activity in 105 pedigrees from the Collaborative Study on the Genetics of Alcoholism. RESULTS: With the simulated data, the results showed that the new method could detect linkage well if the true allele frequency for the trait was close to that specified. However, it performed poorly on models in which the true allele frequency was much rarer. For the Collaborative Study on the Genetics of Alcoholism data set only a modest overlap was observed between the results obtained from the new method and those obtained when the same data were analysed previously using regression and variance components analysis. Of interest is that D17S250 produced a maximized LOD score under homogeneity and admixture of 2.6 but did not indicate linkage using the previous methods. However, this region did produce evidence for linkage in a separate data set, suggesting that QMFLINK may have been able to detect a true linkage which was not picked up by the other methods. CONCLUSION: The application of model-free LOD score analysis to quantitative traits is novel and deserves further evaluation of its merits and disadvantages relative to other methods.

Alcoholism↗
PubMed2004

Re-analysis of collaborative study on the genetics of alcoholism pedigrees suggests the presence of loci influencing novelty-seeking near D12S391 and D17S1299.

A previous genome scan using variance components analysis of 758 sib pairs from families of alcoholics found evidence for linkage of harm avoidance (HA) to markers on 8p21-23, and this finding was supported in a subsequent linkage study of 384 sib pairs. Here the original dataset is analysed using a new method of linkage analysis for quantitative traits that deals with extended pedigrees. As well as supporting linkage of HA to D8S549, this method also produces an MALOD of 2.4 (P=0.002) near DBH and several positive lod scores for novelty-seeking, the largest being MALODs of 3.1 (P=0.0004) near D12S391 and 3.4 (P=0.0003) near D17S1299. There is no support for linkage of novelty-seeking or HA to the regions around DRD4 and 5HTT, respectively. Additional samples will need to be studied in order to discover which regions truly harbour genetic polymorphisms influencing personality traits.

Alcoholism↗
PubMed2004

Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial.

OBJECTIVE: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA). METHODS: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained. RESULTS: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose. CONCLUSION: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Antirheumatic Agents↗
PubMed2003

Mapping loci influencing blood pressure in the Framingham pedigrees using model-free LOD score analysis of a quantitative trait.

This paper presents a method of performing model-free LOD-score based linkage analysis on quantitative traits. It is implemented in the QMFLINK program. The method is used to perform a genome screen on the Framingham Heart Study data. A number of markers that show some support for linkage in our study coincide substantially with those implicated in other linkage studies of hypertension. Although the new method needs further testing on additional real and simulated data sets we can already say that it is straightforward to apply and may offer a useful complementary approach to previously available methods for the linkage analysis of quantitative traits.

Adult Children↗
PubMed2003

Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q.

OBJECTIVE: To localize genes conferring susceptibility to bipolar affective disorder. METHODS: Seven families were selected on the basis of containing multiple cases of bipolar affective disorder present in three or more generations, an absence of schizophrenia and unilineal transmission. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10 cM intervals across the whole genome. All markers were subjected to initial two-point and three-point analyses using LOD score and model-free analysis. All regions producing a result significant at P<0.01 were then subjected to four-point LOD score analysis under the assumption of heterogeneity. RESULTSA four-point LOD score of 2.8 was obtained using a dominant model and including unipolar cases as affected in the region of D12S342. Four-point LOD scores of 2 were obtained around D1S243, D1S251 and D3S1265. The positive results around D1S243 were accounted for by a LOD score of 3.1 occurring in a single pedigree. CONCLUSIONS: Since there has been previous strong support for linkage to the region of 12q23-q24 around D12S342, it now seems very probable that it does indeed contain a gene influencing susceptibility to bipolar affective disorder. Some evidence for linkage in the region of 1q near to D1S251 has been reported in one previous study. It therefore seems that this region of 1q and the region of 1p close to D1S243 may also harbour susceptibility genes.

Bipolar Disorder↗