Schizophrenia susceptibility and chromosome 6p24-22.
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Chromosomes, Human, Pair 6↗
Biomedical subjects
H Petursson
Publications and source records attributed to H Petursson.
Investigation by linkage analysis of the XY pseudoautosomal region in the genetic susceptibility to schizophrenia.
BACKGROUND: A susceptibility locus for schizophrenia in the pseudoautosomal region has been proposed on the basis of a possible excess of sex chromosome aneuploidies among patients with schizophrenia and an increased sex concordance in affected sib pairs. Several studies investigating this hypothesis have produced conflicting evidence. METHOD: In a series of Icelandic and British families, we used lod score and sib pair linkage analyses with markers for the MIC2 and DXYS14 loci on the pseudoautosomal XY region. RESULTS: Lod and sib pair linkage analysis with these markers produced strongly negative scores. Heterogeneity testing also produced negative results. CONCLUSION: We conclude that the present study provides no support for the involvement of either the pseudoautosomal region or the nearby region of the sex chromosomes in the aetiology of schizophrenia.
Aneuploidy↗
A linkage study of affective disorder with DNA markers for the ABO-AK1-ORM linkage group near the dopamine beta hydroxylase gene.
Combining data from a number of studies has provided evidence for a susceptibility allele for affective disorder near to the ABO-AK1-ORM region on chromosome 9q34. The dopamine beta hydroxylase gene locus is also at 9q34. Five multigenerational families with bipolar and unipolar affective disorder were analyzed for linkage with highly polymorphic microsatellite markers from the candidate region. The segregation of the illness in these families was compatible with an autosomal dominant susceptibility allele. Linkage analyses using conservative parameters seemed to provide strong evidence against a major susceptibility allele in this region including the candidate gene dopamine beta hydroxylase in these families.
ABO Blood-Group System↗
The Marfan syndrome gene locus as a favoured locus for susceptibility to schizophrenia.
Marfan syndrome (MS) is a rare autosomal dominant disorder of connective tissue with manifestations in the cardiovascular, ocular and skeletal systems. Genetic linkage analysis with random probes has mapped the MS locus to 15q21.1. There have been several reports of Marfan syndrome co-segregating with schizophrenia within families, which suggest that a common genetic factor may be shared between schizophrenia susceptibility and MS. This could be due to a cytogenetic abnormality affecting both genetic loci or due to co-segregation of two disease loci near each other on the same chromosome. We tested this hypothesis by using genetic linkage analysis with multiplex families. Using three genetic markers spanning the MS locus, we were unable to find evidence of linkage with schizophrenia across the Marfan syndrome locus on chromosome 15.
Chromosomes, Human, Pair 15↗
Linkage between tyrosine hydroxylase gene and affective disorder cannot be excluded in two of six pedigrees.
Genetic linkage between manic depression and DNA markers on the short arm of chromosome 11 was first reported in 1987 but not supported by further analyses. However, genetic markers at the tyrosine hydroxylase (TH) gene located within this region have been reported to show allelic association with the affective disorder phenotype. We present the results of a linkage analysis using polymorphic DNA segments within the TH gene and the nearby dopamine D4 receptor (DRD4) gene in 6 families multiply affected with affective disorder. Small positive Lod scores were obtained in 2 of 6 pedigrees with the TH polymorphism which may be indicative of genetic heterogeneity.
Female↗
Segregation and linkage analysis in five manic depression pedigrees excludes the 5HT1a receptor gene (HTR1A).
Five kindreds selected through probands attending an Icelandic hospital were recruited for linkage studies of manic depression. The rates of affection were equal for males and females and the age of onset appeared to be predominantly in early adult life, since prevalence did not rise appreciably with age. A complex segregation analysis was performed using the computer program POINTER to obtain maximum likelihood estimates of the contributions to liability from multifactorial transmission and a single major locus. Likelihood ratios between models supported a role for a single major locus which was dominant and had moderately high penetrance with, in the case of unipolar illness, additional multifactorial transmission. The best-fitting parameters were used to devise a transmission model for linkage analysis. Three markers on chromosome 5 were studied, at D5S76, D5S6 and D5S39. Strongly negative lod scores were obtained which were less than -2 over a distance of 40 cM, which included the region to which the gene for the 5HT1a receptor has been mapped.
Bipolar Disorder↗
Genetic linkage analysis of manic depression in Iceland.
Genetic linkage analysis has been used to study five Icelandic pedigrees multiply affected with manic depression. Genetic markers were chosen from regions which had been implicated by other studies or to which candidate genes had been localized. The transmission model used was of a dominant gene with incomplete penetrance and allowing for a large number of phenocopies, especially for unipolar rather than bipolar cases. Multipoint analysis with linked markers enabled information to be gained from regions spanning large distances. Using this approach we have excluded regions of chromosome 11p, 11q, 8q, 5q, 9q and Xq. Candidate genes excluded include those for tyrosine hydroxylase, the dopamine type 2 receptor, proenkephalin, the 5HT1A receptor and dopamine beta hydroxylase. Nevertheless, we remain optimistic that this approach will eventually identify at least some of the genes predisposing to manic depression.
Algorithms↗
No evidence for a susceptibility locus predisposing to manic depression in the region of the dopamine (D2) receptor gene.
Recent reports of cytogenetic abnormalities linked to psychiatric illness and the localisations of the genes for the dopamine (D2) receptor and tyrosinase on the long arm of chromosome 11 have suggested that susceptibility loci for schizophrenia and manic depression might be situated in this region. We could find no evidence for linkage in five Icelandic pedigrees between manic depression and markers in this region, and we have excluded candidate genes coding for the D2 receptor and tyrosinase. We conclude that mutations at loci in this region are not a common cause of manic depression in the population studied.
Adult↗
Recent and future molecular genetic research into schizophrenia.
The difficulties anticipated in the application of molecular genetics to schizophrenia research have not prevented the first successful localization of a susceptibility gene for a subtype of schizophrenia. It is argued that this approach is the most useful of the possible molecular genetic strategies because it leads both to enhanced clinical genetic investigation and to further recombinant DNA research to clone and sequence schizophrenia susceptibility mutations. Future recombinant DNA research can now use long-range mapping and cloning techniques such as the chromosome walking/jumping approach and the strategy of cloning brain-specific cDNAs from brain mRNA. The identification of carriers for high-risk studies and the genetic validation of diagnosis appear to be the most promising clinical developments. Prenatal counseling will only become widely feasible when much more is known about the extent of heterogeneity of linkage in schizophrenia.
Chromosomes, Human, Pair 5↗
Localization of a susceptibility locus for schizophrenia on chromosome 5.
Schizophrenia is a common disorder with a life time prevalence of approximately 1 per cent. The illness often develops in young adults, who were previously normal, and is characterized by a constellation of symptoms including hallucinations and delusions (psychotic symptoms) and symptoms such as severely inappropriate emotional responses, a disorder of thinking and concentration, erratic behaviour as well as social and occupational deterioration. A considerable proportion of the variance in the liability to develop schizophrenia may be genetic, but segregation analysis, to establish a mode of transmission, has not produced a consistent result. One of these studies was carried out in Iceland and made use of the large family size and extensive geneaological information present in that country. Here we demonstrate genetic linkage of two DNA polymorphisms on the long arm of human chromosome 5 to schizophrenia in seven British and Icelandic families with multiple affected members. The results indicate the existence of a gene locus with a dominant schizophrenia-susceptibility allele. Inheritance of the allele in the families studied suggests that it may also predispose to psychiatric conditions such as schizophrenia spectrum disorders and a variety of other disorders. This report provides the first strong evidence for the involvement of a single gene in the causation of schizophrenia.
Chromosomes, Human, Pair 5↗
Molecular genetics and heterogeneity in manic depression.
Recent research has shown that there are X-linked and possibly chromosome 11-linked forms of manic depression as well as at least one other autosomal form. Segregation analyses of large affected families and the finding of genetic linkage between chromosome specific markers and manic depression mutations provide strong evidence that bipolar as well as unipolar forms of manic depression (MD) within the same family are inherited as a dominant gene disorder. This clarification of the etiology of certain types of depression should bring changed attitudes within psychiatry and may serve to stimulate discussion of the role of evolutionary mechanisms. From a clinical point of view, it has now become possible to determine whether clinical (phenotypic) variation reflects the underlying genotypic heterogeneity of linkage. A preliminary analysis of data from four recent studies shows that there is no clear correlation between such clinical features as the ratio of unipolar to bipolar cases and the genotypic form of manic depression. Further recombinant DNA research, proven to be successful in other genetic diseases, can soon be applied to manic depression. The specific problems posed by manic depression for these techniques are discussed.
Bipolar Disorder↗
Minisatellite mapping in manic depression.
Hypervariable regions of DNA exist at many discrete loci in the human genome. Variations in the length of specific classes of hypervariable DNA termed "minisatellite" sequences may be detected by hybridisation of radioactive probes composed of a common 10-15 base pair repeat or "core" sequence which is shared by each of the minisatellite loci. Such a procedure was used to perform linkage analysis on a kindred in which a disease allele causing manic depression appeared to be segregating as an autosomal dominant. Results indicate no apparent linkage between a manic depression allele and at least 20 hypervariable genetic loci which acted as markers. However, because of the hypervariability of the minisatellite loci these results do not preclude similar analyses of other manic depressive pedigrees being productive because each such family will have distinct observable minisatellite alleles at loci specific to that family. The method could be usefully applied to the genetic analysis of other psychiatric disorders where heterogeneity is suspected and where a single autosomal major gene locus appears to be responsible for causing multiple cases within a single kindred.
Base Sequence↗
Changing characteristics of homicide in Iceland.
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Adult↗
Withdrawal of trihexyphenidyl.
Trihexyphenidyl, a synthetic anticholinergic, used to control extrapyramidal symptoms arising from neuroleptic drug therapy has been a subject of controversy regarding the need for continuous antiparkinsonian therapy. In a group of 22 psychiatric patients receiving long-term antipsychotic medication concurrently with trihexyphenidyl the effects of trihexyphenidyl withdrawal were studied double-blind and placebo controlled. Anxiety, psychotic symptoms, extrapyramidal symptoms and salivary flow were monitored. Blood pressure, pulse, sleep duration, weight and body temperature were recorded daily. The result was a recognizable withdrawal syndrome indicated by an increase in anxiety with various physical complaints, as well as evidence of orthostatic hypotension and tachycardia. A temporary deterioration was noted in psychotic symptomatology and extrapyramidal symptoms. The majority of the parameters regained baseline values, indicating the symptoms were related to the discontinuation of trihexyphenidyl and supporting the existence of a withdrawal syndrome.
Adult↗
Computed axial brain tomography in long-term benzodiazepine users.
Twenty patients who had taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean ventricular/brain area measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings is unclear.
Adult↗
Psychiatric court reports in Iceland 1970-1982.
This paper looks closely at psychiatric court reports in criminal cases in Iceland. Psychiatric court reports are in the great majority of cases requested by the State Criminal Investigation Police (SCIP) on behalf of the court in major criminal cases (e.g. homicide, sexual offences, arson, physical assault). Reports are very rarely requested by the defence. During the 13-year period 1970-1982 there were 97 requests for psychiatric reports by the police/court (i.e. an annual rate of about 7.5 reports). About two-thirds of the defendants were found to have some psychiatric abnormality, although only a minority (8%) were considered criminally insane at the time of the offence. Psychiatric reports were most often requested to assess criminal responsibility, and, to a much lesser extent, sentencing issues. Psychiatric experts almost never have to present their evidence in person in court, nor are they cross-examined on their evidence. This paper discusses some of the strengths and limitations of psychiatric evidence in Iceland, and the need for an organized forensic service.
Criminal Psychology↗
Trihexyphenidyl dependence.
Trihexyphenidyl, a synthetic anticholinergic, is frequently used concurrently with neuroleptics to control extrapyramidal side effects. We present two case reports of trihexyphenidyl abuse which concur with the increasing concern expressed regarding the abuse potential of trihexyphenidyl. In one of the cases a double-blind, placebo-controlled withdrawal was conducted and monitored on a number of physiological parameters and the Hamilton Anxiety Rating Scale. A recognizable withdrawal syndrome followed discontinuation of the drug. In addition to the abuse potential it is suggested that dependence liability be considered in maintenance therapy with trihexyphenidyl and other antiparkinsonians.
Adult↗
Long-term benzodiazepine administration blunts growth hormone response to diazepam.
Growth hormone and prolactin responses to diazepam were measured in eight male patients who had been receiving long-term treatment with benzodiazepines and eight age-matched drug-free controls. The growth hormone response was significantly attenuated during benzodiazepine administration, but increased significantly after benzodiazepine treatment was discontinued. Growth hormone responses four days after the drug therapy withdrawal in patients, however, were still significantly less than in drug-free controls. Prolactin levels were unaltered after diazepam challenge, both in patients and in controls. The results clearly demonstrate tolerance to the growth hormone-releasing effect of diazepam, but do not suggest receptor supersensitivity after withdrawal of benzodiazepine therapy. It is possible that pituitary mammotropes lack benzodiazepine receptors.
Adult↗