Genetic basis of schizophrenia.
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Adoption↗
Biomedical subjects
P McGuffin
Publications and source records attributed to P McGuffin.
No evidence for allelic association between bipolar disorder and monoamine oxidase A gene polymorphisms.
We have tested the hypothesis that DNA markers in the MAOA gene show allelic association with bipolar affective disorder. Eighty-four unrelated Caucasian patients with DSM III-R bipolar disorder and 84 Caucasian controls were typed for three markers in MAOA: a dinucleotide repeat in intron 2, a VNTR in intron 1, and an Fnu4HI RFLP in exon 8. No evidence for allelic association was observed between any of the markers and bipolar disorder.
Adult↗
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↗
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↗
Morbid risk of schizophrenia for relatives of patients with cannabis-associated psychosis.
Twenty-three patients admitted with acute psychosis who were cannabis positive on urinary screening were each matched, with respect to sex, with two psychotic controls who screened negatively for all substances. The lifetime morbid risk of psychiatric disorder was estimated among the first degree relatives of cases and controls, using RDC-FH criteria to define diagnoses, and Weinberg's shorter method of age correction. The cases had a significantly greater familial morbid risk of schizophrenia (7.1%) than the controls (0.7%), while the risks of other psychoses, and of non-psychotic conditions were similar. The same pattern of familial risk was evident when the analysis was restricted to patients with DSM-III schizophrenia. The data suggest that the development or recurrence of acute psychosis in the context of cannabis use may be associated with a genetic predisposition to schizophrenia.
Adult↗
Expanded CAG repeats in schizophrenia and bipolar disorder.
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Adult↗
Association study of bipolar disorder using a functional polymorphism (Ser311-->Cys) in the dopamine D2 receptor gene.
Several pieces of evidence are consistent with the involvement of dopamine neurotransmission in the aetiology of bipolar disorder. We have tested the hypothesis that the functional mutation Ser311-->Cys of the dopamine D2 receptor gene confers susceptibility to bipolar disorder. There was no increased frequency of the mutation in 82 bipolar probands compared with 72 controls, showing that this mutation is not involved in the pathogenesis of (at least) the vast majority of cases of bipolar disorder. Our findings are consistent with other evidence from linkage and association studies against the involvement of the dopamine D2 receptor in bipolar disorder.
Alleles↗
Are anxiety symptoms in childhood heritable?
Although childhood anxiety appears to aggregate in families, transmission could be explained by both genetic and shared environmental factors. Twin studies can be used to disentangle genetic and environmental effects. In this study, a systematically ascertained sample of twins was used to investigate whether anxiety symptoms are heritable. Parent-rated anxiety symptoms could best be explained by an additive genetic model with heritability estimated at 59%. However, when self ratings were analysed (in the adolescent subsample), familial transmission could be accounted for by shared environmental factors only.
Adolescent↗
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↗
Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brains.
By employing multiprobe oligonucleotide solution hybridisation (MOSH) we have measured the levels of mRNA encoding the NMDA receptor subtypes (R1, R2A, R2B and R2C) and the non-NMDA glutamate receptor subtypes (GluR1, 2, 3, and 4) within rat brain following, 1-32 days of antipsychotic or antidepressant drug administration. The results suggest that the drugs studied do not significantly alter rat glutamatergic system mRNA levels when compared to controls.
Animals↗
The genetic basis of complex human behaviors.
Quantitative genetic research has built a strong case for the importance of genetic factors in many complex behavioral disorders and dimensions in the domains of psychopathology, personality, and cognitive abilities. Quantitative genetics can also provide an empirical guide and a conceptual framework for the application of molecular genetics. The success of molecular genetics in elucidating the genetic basis of behavioral disorders has largely relied on a reductionistic one gene, one disorder (OGOD) approach in which a single gene is necessary and sufficient to develop a disorder. In contrast, a quantitative trait loci (QTL) approach involves the search for multiple genes, each of which is neither necessary nor sufficient for the development of a trait. The OGOD and QTL approaches have both advantages and disadvantages for identifying genes that affect complex human behaviors.
Genetics, Behavioral↗
Variation at the fragile X locus does not influence susceptibility to bipolar disorder.
Over the last 20 years several pedigrees have been reported which are suggestive of linkage between susceptibility to bipolar disorder and markers on chromosome Xq28. Other workers have failed to replicate these reports and the methodology of the positive reports has been criticised. Recently there have been several reports of an association between fragile X (FRA(X)) and affective disorder within families and in unrelated individuals compared with controls. Such reports could be consistent with the Xq28 marker reports because FRA(X) maps to Xq27.3. We report a study at the FRA(X) CGG repeat locus in 79 unrelated Caucasian bipolar probands without fragile X syndrome and 77 unrelated controls. We found no evidence that variation at this locus confers susceptibility to bipolar disorder.
Adult↗
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↗
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↗
The lymphoblast beta-adrenergic receptor in bipolar depressed patients: effect of chronic incubation with lithium chloride.
We have recently reported a study of beta-adrenergic receptor binding characteristics in lymphoblast cell lines derived from patients with bipolar disorder (BD) and healthy, matched control subjects. In the present study we have investigated the effects of incubating cells from the same subjects with lithium chloride (1 mM) for 7 days prior to assay. There was no difference in beta-adrenergic receptor number between control and BD cell lines and incubation with lithium had no effect on receptor number in either group. Exposure of the cells to isoprenaline (1 nM) for 24 h immediately prior to assay caused significantly less down-regulation in BD cells (15 +/- 5%) than control cells (39 +/- 4%), as described previously. Incubation with lithium significantly increased the down-regulation response to isoprenaline in BD cells (39 +/- 6%) but not in control cells (30 +/- 7%). After lithium, the agonist-induced decrease in beta-AR number in BD cells was no longer significantly different from that in control cells. We conclude that lithium selectively enhanced the agonist down-regulation of beta-adrenergic receptors in cells derived from patients with bipolar disorder. The functional significance of this result and the potential biochemical mechanisms responsible for this effect are discussed.
Adult↗
The gene for Darier's disease maps between D12S78 and D12S79.
Darier's disease is a dominantly inherited skin disorder in which there is abnormal adhesion between keratinocytes. We and others have recently mapped the disease gene to chromosome 12q23-q 24.1. In the present study we have established that the disease gene lies between the loci D12S78 and D12S79 which are 12cM apart. We have also obtained direct evidence that the disease is unlikely to result from a mutation in one of the members of the keratin gene cluster on chromosome 12q.
Chromosome Mapping↗
The molecular genetics of schizophrenia.
There is strong evidence for a genetic component in schizophrenia but its precise nature remains unclear. Positional cloning and studies of potential candidate genes offer prospects for progress. The diagnosis of schizophrenia can now be made reliably but questions remain over the most valid phenotypic definition. To deal with this and uncertainties regarding mode of transmission a 'polydiagnostic' approach is advisable. A wealth of new DNA markers has enhanced the potential for linkage studies which have so far focused on large multiply-affected families. Multi-centre collaborative studies that are currently under way are likely to identify genes of major effect but other strategies are required if it turns out that most cases result from the combined effect of multiple genes.
Genetic Markers↗