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D A Collier

Publications and source records attributed to D A Collier.

At least 73 records · Page 4Linked to original sources
PubMed1998

5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease.

The psychopathology of Alzheimer's disease (AD) is varied and includes both behavioural and psychological symptoms. Behavioural and psychological symptoms are common and contribute to the difficulties experienced by carers. However, the mechanism whereby these symptoms occur in some individuals with AD is not understood. We hypothesized that common genetic polymorphisms in neurotransmitter systems are risk factors for these symptoms in the course of AD. A total of 211 subjects from a population-based prospective study of psychopathology within late-onset AD were genotyped for the 5-HT2A receptor polymorphism 102-T/C and the 5-HT2C receptor polymorphism Cys23Ser. Associations were found between the presence of the C102 allele and the presence of visual (Fisher's exact test, one-tailed, P = 0.003) and auditory hallucinations (Fisher's exact test, one-tailed, P = 0.004) and between the presence of the Ser23 allele and visual hallucinations (chi2 = 7.5, df = 1, P = 0.006) (P = 0.03, 0.04 and 0.06, respectively, after Bonferroni correction). In addition, there was an association between the Cys23Ser polymorphism and hyperphagia (chi2 = 6.7, df = 2, P = 0.03) (P = 0.3 after Bonferroni correction). We conclude that common 5-HT2A and 5-HT2C genetic polymorphisms previously showing only weak associations with psychotic illness are associated with psychotic symptoms in AD but are clinically silent until the onset of the neurodegenerative process.

Age of Onset↗
PubMed1998

Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response.

Dopamine receptors are strong candidates for involvement in schizophrenia and are targeted by a wide variety of antipsychotics. We hypothesized that genetic variation in these neurotransmitter receptors may influence clinical response to clozapine, an antipsychotic which displays high affinity for dopamine D2 receptors in the limbic system. To test this hypothesis, we studied a functional polymorphism in the promoter region of the D2 receptor gene (-141C Ins/Del) in a sample of 151 clozapine treated patients of British origin. In addition, the influence of this polymorphism on antipsychotic response in general was investigated on a sample of 146 Han Chinese schizophrenic patients treated with a variety of antipsychotics. No association was found between this polymorphism and clinical response in either of the two samples suggesting that genetic variation in D2 receptors does not play a major role in determining clinical response to antipsychotic treatment.

Antipsychotic Agents↗
PubMed1998

Linkage analysis between bipolar affective disorder and markers on chromosome X.

Since 1969, several classical linkage studies suggested an X-chromosome locus for bipolar affective disorder. However, methods using highly polymorphic DNA markers have provided conflicting evidence for linkage, and an X-chromosomal locus for bipolar disorder remains controversial. More recently, Pekkarinen et al. (1995) found a maximum LOD score of 3.54 at the marker DXS994 in a large bipolar Finnish kindred. In the present study, we attempted to replicate this finding using 43 families multiply affected by bipolar affective disorder. These families were selected for the absence of male-to-male transmission of the disease, and were genotyped for two microsatellte markers, DXS1227 and DXS1062 (which is about 2 cM telomeric to DXS994). Linkage to this region was excluded either using a two-point lod score method with two plausible genetic models, or by a model-free lod score analysis which does not require specification of a particular mode of transmission. We conclude that there is no evidence of a common major gene for bipolar affective disorder at Xq25-q27 in our set of families.

Bipolar Disorder↗
PubMed1997

Systematic screening of the LDL-PLA2 gene for polymorphic variants and case-control analysis in schizophrenia.

Systematic scans of the genome using microsatellite markers have identified chromosome 6p21.1 as a putative locus for schizophrenia in multiply affected families. There is also evidence from a series of studies for a role of abnormal phospholipid metabolism in schizophrenia. In light of these findings, and the role of platelet activating factor in neurotransmission and neurodevelopment, we have examined the LDL-PLA2 (plasma PAF acetylhydrolase, PAF-AH) gene, a serine dependent phospholipase that has been mapped by hybrid mapping to chromosome 6p21.1, as a positional candidate gene for schizophrenia. The gene was systematically screened using SSCP/HD analysis for polymorphisms associated with the disease. Four polymorphic variants were found within the gene and studied in a group of 200 schizophrenic patients and 100 controls. The variant in exon 7 (Iso195Thr) was found to be weakly associated with schizophrenia (p = 0.04) and the variant in exon 11 (Val379Ala) almost reached significance (p = 0.057). After correcting for multiple testing no significant associations were detected. Haplotype analysis combining pairs of polymorphisms also provided no evidence for association of this gene with schizophrenia in our sample of patients.

Alleles↗
PubMed1997

No evidence for an association of affective disorders with high- or low-activity allele of catechol-o-methyltransferase gene.

Catechol-o-methyltransferase (COMT) is an enzyme that inactivates biologically active or toxic catechols. Previous studies have yielded inconsistent results on the relationship between erythrocyte COMT activity and affective disorders. Recently an amino acid change (Val-108-Met) of the COMT protein was shown to determine high- and low-activity alleles of the enzyme. Using polymerase chain reaction and the restriction enzyme NLaIII, we genotyped 107 patients with bipolar disorder, 62 with unipolar depression, and 121 controls. Neither bipolar nor unipolar patients differ significantly in the genotypic or allelic frequency from the control group. Even when the bipolar and unipolar patients were pooled into a single group, the distributions of both the genotypes and the alleles for the patient group were similar to those for the controls. We conclude that genetic variation that determines high and low activities of COMT does not have a major effect on the vulnerability to affective disorders in our sample.

Adult↗
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

High and low activity alleles of catechol-O-methyltransferase gene: ethnic difference and possible association with Parkinson's disease.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates catecholamines such as adrenaline, noradrenaline, dopamine, and levodopa. Recently an amino acid change (Val-108-Met) of the COMT protein was found to determine high and low activity alleles of the COMT gene. We genotyped 109 Japanese patients with Parkinson's disease (PD) and 153 controls by using polymerase chain reaction (PCR) amplification and digestion by the restriction enzyme NlaIII. The frequency of low activity allele in the controls was 0.29, which was significantly different from that reported in Caucasians (0.50). When comparison was made between patients with PD and controls, homozygosity for the low activity allele was significantly more common among the patients than among the controls (P = 0.017; odds ratio, 2.8, 95% CI 1.2-6.5), suggesting that homozygosity for the low activity allele may increase susceptibility to PD.

Adult↗
PubMed1997

Association analysis of the dopamine D4 gene exon III VNTR and heroin abuse in Chinese subjects.

Although social and cultural influences are clearly important, family, twin and adoption studies indicate that genes contribute significantly to substance abuse. Substance abuse is associated with novelty seeking, a heritable human personality trait which may be influenced by alleles of the dopamine D4 (DRD4) gene exon III VNTR. Consequently Kotler et al analysed the DRD4 VNTR in opiate-dependent subjects from Israel, and found a significant excess of the 7-repeat allele. We have attempted to replicate this finding using a Han Chinese case-control sample of 121 heroin-dependent subjects and 154 normal controls. We found two 7-repeat alleles which occurred exclusively in the patient group, and overall there was an excess of longer alleles, which did not reach significance (chi 2 = 7.04; P = 0.07). When the D4 VNTR was divided into 'long' (5-7 repeats) and 'short' (2-4 repeats), a significant excess of long alleles was observed in the patient group (P = 0.023, one-tailed), with an odds ratio of 2.30 (95% CI 1.07-4.93). We conclude that our findings support the hypothesis that alleles of the DRD4 exon III VNTR are susceptibility factors for heroin abuse.

Adolescent↗
PubMed1997

Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder.

Catechol-O-methyltransferase catalyses the O-methylation of biologically active or toxic catechols and is a major component of the metabolism of drugs and neurotransmitters such as L-dopa, noradrenaline, adrenaline, and dopamine. Human catechol-O-methyltransferase activity is an autosomal partially dominant trait and is strongly associated with a valine to methionine substitution at codon 158 of the protein. About 25% of Caucasians have low activity, 50% intermediate activity and 25% high activity as determined by either phenotypic or genotypic measurement. In black populations, the low activity allele (Met158; COMTL) is less frequent with about 7% being homozygous. Using a PCR based genotyping assay, we report that the Met158 allele is also less frequent in normal Han Chinese subjects with about 3% of the population being homozygous. Because of its role in catecholamine metabolism and several lines of evidence pointing to a locus for psychosis near the COMT gene on chromosome 22q11, we have analysed the COMT Val158Met polymorphism as a candidate susceptibility factor for bipolar affective disorder. We report an association between bipolar affective disorder and the Met158 allele (p = 0.004) and genotype (p = 0.01) in 93 affected Chinese subjects and 98 controls. We hypothesize that either the low activity allele of catechol-O-methyltransferase is a risk factor for bipolar affective disorder in Chinese populations or is in linkage disequilibrium with a nearby susceptibility gene or polymorphism.

Bipolar Disorder↗
PubMed1997

Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families.

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamines, noradrenaline and adrenaline. It exists as common high and low activity alleles in the population (determined by a valine 158 methionine polymorphisms), and high red blood cell activity of COMT has previously been associated with schizophrenia. To examine the relationship between COMT and schizophrenia genetically, the transmission disequilibrium test was performed on 22 multiply affected Caucasian and Japanese families genotyped for val158met and a second, silent, polymorphism (C256G), using PCR based assays. The high activity val158 allele was transmitted from parents to the affected individuals more frequently than the low activity met158 allele, although this was not statistically significant. Combining this data with a previous study using Chinese family trios with schizophrenia (Li et al., 1996) gave a highly significant result (p = 0.0015). The G256 allele was also transmitted preferentially to the affected offspring, and this was statistically significant when schizophrenia, schizoaffective disorder and unspecified functional psychosis were included in the definition of the affected phenotype (p = 0.03). Overall, these findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity. Other reported associations of COMT with obsessive compulsive and rapid cycling bipolar disorder indicate that the COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Amino Acid Substitution↗
PubMed1996

Linkage studies in bipolar affective disorder with markers on chromosome 21.

Straub et al. (1994: Nature Genet. 8. 291-296) have suggested that a susceptibility gene for bipolar affective disorder is located at chromosome 21q22.3, on the basis of linkage analysis in one large family. This result has been supported by Gurling et al. (1995: Nature Genet. 10, 8-9) who also found some evidence for linkage to this region under locus heterogeneity. In order to investigate the validity of these results and to estimate how broadly applicable they are, we performed a linkage study between bipolar affective disorder and two DNA markers (D21S171 and PFKL) from 21q22.3 using 60 bipolar pedigrees from three European centres and Brazil. The most positive result obtained was a maximised admixture lod score of 1.2 for the marker PFKI, under the assumption of locus heterogeneity, dominant transmission and a diagnostic classification which included recurrent unipolar depression. However, since lod scores obtained for both markers were substantially negative overall, we conclude that there is no common major gene for bipolar affective disorder at 21q22.3. It remains possible that a gene of major effect in this region operates in a minority of families.

Bipolar Disorder↗
PubMed1996

No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase.

Idiopathic Parkinson's disease (IPD) is characterised by the loss of pigmented neurones in the substantia nigra, leading to reduced tyrosine hydroxylase activity and depletion of dopamine. Treatments attempt to correct this deficit by the use of levodopa and inhibitors of dopamine metabolising enzymes such as catechol-O-methytransferase (COMT). A common amino-acid polymorphism in COMT, valine-108-methionine, results in a low activity form of the enzyme which we hypothesised may influence susceptibility to IPD. We examined this polymorphism in 139 Caucasian subjects with IPD and 173 control subjects, using a PCR-RFLP and a novel Amplification Refractory Mutation System (ARMS) assay. Allele and genotype frequencies were similar in the affected and control subjects, indicating that variation of COMT activity is not an aetiological factor in IPD. We have also characterised a new polymorphism, 256C/G, which is not associated with IPD. However it remains possible that allelic variation in COMT influences severity, type of pathology or treatment response to levodopa or COMT inhibitors.

Alleles↗
PubMed1996

A linkage study of schizophrenia with DNA markers from chromosome 8p21-p22 in 25 multiplex families.

Two recent genome-wide searches for linkage (Lasseter et al., 1994; Moises et al., 1995) suggested that a susceptibility gene for schizophrenia might be located at chromosome 8p21-p22. We attempted to replicate these findings by performing a linkage study of schizophrenia with four DNA markers from this region using 25 multiply affected families. Neither the lod score method nor non-prametric extended sib-pair analysis yielded any evidence for linkage, even under the assumption of locus heterogeneity. We conclude that there is unlikely to be a major gene in the 8p21-p22 region which confers susceptibility to schizophrenia in our set of families. However we cannot exclude the possibility of a major gene present in other families, or of a susceptibility gene with a moderate but widespread effect which we cannot detect.

Autoradiography↗
PubMed1996

Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine.

Clozapine is an atypical antipsychotic with affinity for a broad range of receptors, including serotonin (5-HT) and dopamine receptors. It is successful in treating about 60% of patients refractory to other antipsychotic drugs. Since genetic variation in clozapine's neurotransmitter receptor targets may affect clinical response through altering drug binding or receptor expression, we have studied a His452Tyr polymorphism in the 5-HT2A receptor (HTR2A) in a sample of 153 schizophrenic patients undergoing clozapine treatment and 178 normal controls. An association was found between the allele Tyr452 and poor clinical response.

Alleles↗