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D A Collier

Publications and source records attributed to D A Collier.

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

[Linkage disequilibrium analysis of chromosome 22 and schizophrenia in a Chinese population].

OBJECTIVE: To explore the molecular genetic relations of chromosome 22 and schizophrenia and locate the susceptibility gene of schizophrenia. METHODS: Six dinucleotide tandem repeat loci on chromosome 22 were chosen to analyze 126 affected sib-pair nuclear families of schizophrenia in Chinese population by fluorescent labeled auto-mated genotyping and transmission/ disequilibrium test(TDT). RESULTS: The TDT-chi square value of IL2Rbeta was 25.30(P=0.01), which suggests there is linkage disequilibrium between IL2R beta and schizophrenia. The P vaules of the other five loci (D22S944, D22S264, D22S303, D22S278 and CYP2D6) were greater than 0.05. CONCLUSION: A susceptive gene of schizophrenia may be located in IL2Rbeta locus or adjacent region.

Chromosomes, Human, Pair 22↗
PubMed2000

Systematic screening of the 14-3-3 eta (eta) chain gene for polymorphic variants and case-control analysis in schizophrenia.

The neuronal protein 14-3-3 eta is a candidate gene for schizophrenia because it maps chromosome 22q12, a region implicated in the disease by linkage analysis, and is involved in brain development. We systematically screened this gene for polymorphic variants by comparison of public EST sequence data (five cDNAs and 72 ESTs, 21,155 bp of sequence) in parallel with single-stranded conformational polymorphism analysis, and we compared these methods by using a simple power calculation. Twelve potential polymorphisms were identified from EST sequence comparison, and two of these (a 5'-VNTR and 753G/A) were confirmed by SSCP analysis and sequencing. Three additional infrequent polymorphisms (-408T/G; 177 C/G; and 989 A/G) were found by SSCP only. We next examined these variants for association with schizophrenia. One variant in untranslated region of exon 1 (-408 T/G) was found to occur more frequently in the schizophrenic subjects (8%) than the controls (3%; P = 0.01). After fivefold correction of the P value for multiple testing, marginal association was found. Haplotype analysis of pairs of polymorphisms provided no evidence for association of this gene with schizophrenia in the population studied. Am. J. Med. Genet. (Neuropsychiatr. Genet. ) 96:736-743, 2000.

14-3-3 Proteins↗
PubMed2000

Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects.

Heroin abuse is a major social and public health problem in many parts of the world, yet relatively little is known about its etiology. Although genes play a role in determining susceptibility, they are expected to be of small effect with considerable heterogeneity. Because the dopamine system is involved in reward, its neurotransmitter receptors are candidates for etiological involvement in addiction. In the present study, we examine two polymorphisms in the dopamine D4 receptor, a VNTR in exon III and a point mutation in the promoter (-512C/T) that affects transcriptional efficiency. We examined a sample of 405 heroin-abusing subjects and 304 controls from Sichuan Province, Southwest China. One hundred twenty-one of these cases and 154 controls were previously used in a study of the DRD4 VNTR [Li et al., 1997], and the remainder are newly ascertained. The two polymorphisms were in weak but detectable linkage disequilibrium (1, 418 chromosomes, P < 0.00001, D' = 0.17). When we compared the heroin-abuse group with controls, we found no significant difference between the patients and controls for either polymorphism in the DRD4 gene or their haplotypes. We were also unable to replicate our earlier association between "long" DRD4 alleles and heroin abuse. However, division of the sample by route of administration (nasal inhalers or injectors) produced a significant difference between inhalers and controls for the DRD4 VNTR (six-fold corrected P = 0. 018 by allele) but not for injectors of heroin. The association we observed between inhalers and the DRD4 polymorphism is difficult to interpret, although it is possible that the association is explained by different levels of novelty seeking between the two subgroups.

Administration, Inhalation↗
PubMed2000

Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response.

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.

Alleles↗
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

Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11.

Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84.

Adolescent↗
PubMed2000

Identification of novel polymorphisms in the 5' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance.

CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYPIA2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T-3591G substitution, a G-3595T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P < 0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T-3591G and the G-3595T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T-3591G mutation was shown to be nonfunctional, while although the G-3595T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G-3649C, deltaT-3650, deltaA-4072, and C-4093 ins).

Black or African American↗
PubMed2000

Clozapine pharmacokinetics and pharmacodynamics studied with Cyp1A2-null mice.

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

Animals↗
PubMed1999

Linkage studies of bipolar disorder with chromosome 18 markers.

Evidence consistent with the existence of genetic linkage between bipolar disorder and three regions on chromosome 18, the pericentromeric region, 18q21, and 18q22-q23 have been reported. Some analyses indicated greater evidence for linkage in pedigrees in which paternal transmission of disease occurs. We have undertaken linkage analyses using 12 highly polymorphic markers spanning these three regions of interest in a sample of 48 U.K. bipolar pedigrees. The sample comprises predominantly nuclear families and includes 118 subjects with Diagnostic and Statistical Manual of Mental Disorders (DSM IV) bipolar I disorder and 147 subjects with broadly defined phenotype. Our data do not provide support for linkage using either parametric or nonparametric analyses. Evidence for linkage was not significantly increased by analyses that allowed for heterogeneity nor by analysing the subset of pedigrees consistent with paternal transmission.

Bipolar Disorder↗
PubMed1999

Association analysis between dopamine receptor genes and bipolar affective disorder.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.

Adult↗
PubMed1999

Stereological estimation of the total number of neurons in the murine hippocampus using the optical disector.

Using a stereological method, the optical disector, we examined three inbred strains of mice (NZB/BINJ, DBA/2, and C57BL/6J) for morphological differences in volume, neuronal number, and density of the pyramidal cell and dentate gyrus granule cell layers of the hippocampus. We found significant differences in volume and neuronal number for both regions between the three strains at 9 weeks of age, but only modest differences in neuronal density. The left dentate volume was 90% larger in the NZB strain and 70% greater in the DBA strain (P<0.0001), and the left pyramidal cell layer was 144% larger in the NZB strain and 150% larger in the DBA strain, than in the B6 strain (P<0.0001). Neuron number in the left dentate was 81% greater in NZB and 37% greater in DBA (P<0.001), and in the left pyramidal cell layer 118% greater in the NZB and 92% greater in the DBA (P<0.01). Differences in neuronal density of the left dentate were not significant (P = 0.060, ns). For the left pyramidal cell layer, neuronal density was 14% greater in B6 and 34% greater in NZB than the DBA strain (P = 0.016). No significant differences were found in left-right laterality, or according to sex. We found that strain accounted for 60% of the variance in hippocampal volume and 44% of neuron number. These differences thus mainly reflect genetic variation in hippocampal volume and may have important implications for brain evolution, behaviour, and human diseases where hippocampal degeneration is involved.

Algorithms↗