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W J Muir

Publications and source records attributed to W J Muir.

At least 55 records · Page 3Linked to original sources
PubMed1996

A genome-wide search for linkage in a large bipolar family: comparison of genotyping accuracy using di- and tetranucleotide repeat microsatellite markers.

Linkage of bipolar disease to several markers mapping to chromosome 4p has been reported in an extended family multiply affected with bipolar affective disorder and no linkage was found at other locations with 106 microsatellite markers, of which 58 were dinucleotide and 48 tetranucleotide repeats [Blackwood et al. (1996), Nature Genetics, 12, 427-430]. Collecting these data provided the opportunity to assess the usefulness and accuracy of the automated linkage preprocessor (ALP) programme in a linkage study and to make a detailed comparison of di- and tetranucleotides with this semi-automated system. Genotypes were acquired using the automated linkage preprocessor (ALP) without any manual intervention at any stage of the procedure and results of analyses of these data were compared with results based on genotypes checked by visual inspection of the data. The ALP program was found to be timesaving and reliable and yielded similar results to non-automated reading using both di- and tetranucleotide repeat microsatellite markers. Tetranucleotides had fewer errors due to multiple genotypes and a lower incidence of stutter peaks making them more informative than dinucleotides in this linkage study.

Bipolar Disorder↗
PubMed1996

Structure of a variable number tandem repeat of the serotonin transporter gene and association with affective disorder.

We have recently reported an association between a polymorphism of a variable number tandem repeat (VNTR) region of the serotonin transporter gene and susceptibility to major depressive disorder. We identified three alleles containing respectively 9 (STin2.9), 10 (STin2.10) and 12 (STin2.12) copies of a repetitive element. We report here the sequences of the three alleles. The repetitive element conformed to the consensus sequence, GGCTGYGACCY(R)GRRTG, where Y = T/C, R = G/A, with loss of the 12th base pair in one of the repeating elements. We have also extended the numbers of cases and controls in the study. The frequencies of the three alleles in 119 individuals with single or recurrent major depressive episodes, 128 individuals with bipolar disorder and a group of 346 controls were compared. There was a significant difference between patients with affective disorder and controls in the proportion of individuals carrying the STin2.9 allele. For the risk of unipolar disorder given a single STin2.9 allele, the odds ratio was 4.44 (95% Cl, 1.65-11.95) and for bipolar disorder 3.22 (95% Cl, 1.15-9.09). The findings support the hypothesis that allelic variation in the serotonin transporter gene may contribute to susceptibility for both major depression and bipolar disorder.

Alleles↗
PubMed1996

Recombination patterns around the breakpoints of a balanced 1;11 autosomal translocation associated with major mental illness.

The frequency and extent of pairing failure around human translocations are unknown. We have examined the pattern of recombination around the breakpoints of a balanced autosomal translocation t(1;11) (q43;q21) associated with major mental illness. DNA was available from 17 carriers and 10 non-translocation carriers with meioses involving four generations. The derivative 1 and 11 chromosomes were also isolated in somatic cell hybrids and used to confirm phase. We have genotyped pedigree members using 20 polymorphic markers within 10 cM on either side of both chromosome 1 and 11 breakpoints. We find no significant reduction of recombination in the vicinity of either breakpoint. However we estimate that there are insufficient meioses even in this large family to make a meaningful interpretation and suggest that sperm typing alone can answer these interesting questions.

Chromosome Mapping↗
PubMed1996

Implications of comorbidity for genetic studies of bipolar disorder: P300 and eye tracking as biological markers for illness.

In large families with affective illness, identification of a biological variable is needed that reflects brain dysfunction at an earlier point than symptom development. Eye movement disorder, a possible vulnerability marker in schizophrenia, is less clearly associated with affective illness, although a subgroup of affective disorders shows smooth-pursuit eye movement disorder. The auditory P300 event-related potential may be a useful marker for risk to schizophrenia, but a role in bipolar illness is less certain. The distribution of these two biological variables and their association with symptoms in two multiply affected bipolar families is described. In a single, five-generation family identified for linkage studies through two bipolar I (BPI) probands, 128 members (including 20 spouses) were interviewed. The 108 related individuals had diagnoses of BPI (7), bipolar II (2), cyclothymia (3), or major depressive disorder (19). Eight others had generalised anxiety (1), minor depression (5), intermittent depression (1), or alcoholism (1). Sixty-nine subjects had no psychiatric diagnosis. P300 latency (81) and eye tracking (71) were recorded from a subgroup of relatives within the pedigree. Eye tracking was abnormal in 11 of 71 relatives (15.5%) and was bimodally distributed. In these 11 relatives, clinical diagnoses included minor depression (1), alcoholism (1) and generalised anxiety disorder (1). P300 latency was normally distributed and did not differ from controls. In a second family in which five of seven siblings have BPI illness, P300 latency and eye movement disorder were found in affected relatives and in some unaffected offspring. In these large families, clinical diagnoses of general anxiety, alcoholism and minor depression, when associated with eye tracking abnormality, may be considered alternative clinical manifestations of the same trait that in other relatives is expressed as bipolar illness.

Anxiety Disorders↗
PubMed1995

Automated linkage analysis in psychiatric disorders.

A genome-wide search for linkage of microsatellite markers to chromosomal loci containing genes responsible for the major psychoses is a laborious task which can be carried out with greater speed and economy by introducing automation to several steps in the procedure. We describe the use of the Automated Linkage Preprocessor (ALP) program for the computer analysis of the waveform generated by fluorescein-labelled markers after electrophoretic separation. (To obtain a copy send a request to A.F. Brown at the below MRC address or use Anonymous FTP to ftp.hgu.mrc.ac.uk. Software is in directory pub/ALP). The program runs on a PC in the Microsoft Windows environment, and is used in conjunction with an automated laser fluorescence (ALF) sequencer (Pharmacia) and its Fragment Manager software to detect and size the PCR products, filter out peaks of fluorescence due to nonallele fragments, and generate genotypes in a format suitable for direct input to standard linkage analysis programs. The method should offer the advantages of speed, accuracy, and reduced cost. Its use in linkage studies in a large family with manic-depressive illness is discussed.

Automation↗
PubMed1995

Auditory P300 event-related potentials and neuropsychological performance in schizophrenia and bipolar affective disorder.

The auditory P300 event-related potential (ERP) and performance on neuropsychological tests were evaluated in 26 subjects with schizophrenia, 19 with bipolar affective disorder, and 27 controls. The schizophrenic and the bipolar groups were similar in having prolonged P300 latency recorded from central and temporal leads. The P300 was significantly reduced in amplitude in the schizophrenic group at midline leads and the left temporal lead but was not significantly reduced in amplitude at any electrode site when the bipolar group was compared to controls. Schizophrenics performed significantly less well than bipolars and controls on tests of verbal fluency and, within this group, a significant correlation was found between the latency of P300 and verbal fluency test scores. While the bipolar group of patients was similar to the schizophrenic group in having prolonged P300 latency, these groups differed in P300 amplitude, performance on verbal fluency tests, and the relationship between the physiological and neuropsychological variables.

Adolescent↗
PubMed1995

Identifying genes within microdissected genomic DNA: isolation of brain expressed genes from a translocation region associated with inherited mental illness.

An improved protocol has been developed for physical enrichment of cDNA sequences by hybridization to genomic DNA. When applied to microdissection recombinants derived from a translocation breakpoint region associated with inherited mental illness, a single cycle of the procedure permitted enriched cDNAs to be visualized directly by agarose gel electrophoresis. Hybridization screening of a library of clones derived from the enriched cDNAs, employing the genomic resource as a probe, led to the identification of six novel gene fragments. This general approach to the isolation of regionally encoded genes could be applied to any subchromosomal interval as a first step towards global transcription map construction.

Animals↗
PubMed1995

Direct microdissection and microcloning of a translocation breakpoint region, t(1;11)(q42.2;q21), associated with schizophrenia.

We describe the generation of large-fragment microclone libraries from the chromosomal breakpoint of a reciprocal balanced translocation linked to schizophrenia. The abnormality was visible under the phase-contrast microscope, allowing direct dissection from unstained, unbanded metaphases. Two separate microdissection experiments yielded 443 and 672 recombinants, respectively. Following complete EcoRI digestion, inserts with an average size of 0.3 kb (range, 0.2-3 kb) were obtained in the first experiment and 1.5 kb (range, 0.15-6.5 kb) in the second. FISH analysis of pooled clones "painted" back onto the derivative chromosome and assignment of microclones to somatic cell hybrids confirmed the fidelity of the method. Microdissection of chromosome regions identified by karyotype rearrangements in unstained, unbanded metaphases is a potentially powerful tool for positional cloning.

Base Sequence↗
PubMed1994

Schizophrenia and mental retardation associated in a pedigree with retinitis pigmentosa and sensorineural deafness.

A family is presented with multiple cases of mild mental retardation, schizophrenia and other functional psychoses, progressive hearing loss, and retinitis pigmentosa (RP). It closely resembles a previously reported Finnish family. We suggest that the phenotypes are not associated in this family by chance, but define a novel syndrome which may be caused by a mutant allele at a single genetic locus.

Adolescent↗
PubMed1994

"Schizoid" personality in childhood: auditory P300 and eye tracking responses at follow-up in adult life.

The auditory P300 response and smooth pursuit eye tracking were recorded from a group of 23 male adult subjects who had been diagnosed in childhood as having schizoid personality. No differences were found in these physiological measures between the study group, their matched controls of other child psychiatric patients, and a group of population controls. The essentially negative findings are discussed in the light of abnormalities of these psychophysiological responses previously found in schizophrenic patients, in some of their biological relatives, and in other groups of psychiatric patients, including autistic children and adults with a diagnosis of borderline and schizotypal personality disorder. Results suggest that "schizoid" children, despite their high scores on a measure of schizotypy, do not have schizophrenia spectrum disorder or that schizotypy is a heterogeneous condition.

Acoustic Stimulation↗
PubMed1994

Correlation of regional cerebral blood flow equivalents measured by single photon emission computerized tomography with P300 latency and eye movement abnormality in schizophrenia.

Single photon emission tomography with the intravenous blood flow marker 99mTc-exametazime was carried out in 14 acutely ill drug-free schizophrenic patients from whom P300 event-related potential, smooth eye pursuit eye tracking and verbal fluency were measured within a few days of scanning. Smooth pursuit eye movement abnormality correlated significantly with abnormal tracer uptake in superior pre-frontal cortex on the right and left and inferior pre-frontal cortex on the left. Abnormal eye movement was also associated with higher tracer uptake in left anterior cingulate and left posterior cingulate. P300 latency was significantly correlated with higher tracer uptake in left superior pre-frontal and left parietal regions. Verbal fluency performance was negatively correlated with tracer uptake in left frontal region. Eye tracking abnormality in schizophrenia is associated with bilateral frontal lobe disturbance and P300 latency increase with left-sided frontal and temporoparietal dysfunction. There was, however, a significant inverse relation between eye tracking abnormalities and abnormal perfusion in the left anterior cingulate region.

Adult↗
PubMed1994

Segregation analysis of complex phenotypes: an application to schizophrenia and auditory P300 latency.

Traditional models of the genetic transmission of human diseases have often assumed that the phenotype is a simple dichotomous trait, which is unrealistic for many psychiatric conditions, and may result in loss of valuable information. We describe a new model for complex phenotypes, implemented in the program COMDS, which subclassifies normal and affected individuals into polychotomies correlated with the underlying genetic liability to the disorder. The model is applied to 18 Scottish pedigrees ascertained for schizophrenia, in which auditory P300 latency had been measured as a possible correlate of the genetic predisposition to schizophrenia. The results suggest that there may be a major locus for schizophrenia, but that there are also other familial determinants, possibly a second modifier locus. In addition, the results indicate that auditory P300 latency may be a useful measure of the genetic predisposition to schizophrenia among asymptomatic relatives, although the relationship between P300 latency and the degree of genetic predisposition in clinical cases was not significant, presumably because other factors are operating on P300 latency. Because of the possible selection biases in this sample, there is a need to replicate these findings in systematically ascertained pedigrees.

Discriminant Analysis↗
PubMed1993

Neuropsychological and P300 abnormalities in schizophrenics and their relatives.

Schizophrenic subjects (N = 30) performed less well than controls (N = 30) on neuropsychological tests sensitive to frontal and temporal lobe impairment and showed prolonged latency of the P300 event-related potential. Relatives of schizophrenic probands were also tested. Relatives with an abnormal P300 had a similar range of neuropsychological deficits as were found in the schizophrenic group and relatives with a normal P300 response performed as well as the normal control group. The results suggest that neurophysiological and neuropsychological testing of relatives may help to clarify the mode of inheritance of schizophrenia in some families.

Adult↗
PubMed1992

The effects of cortisol infusion upon hormone secretion from the anterior pituitary and subjective mood in depressive illness and in controls.

The aims of this study were to determine whether the administration of cortisol has a significant effect on mood in patients with depression and whether the effects of cortisol on changes in plasma hormone concentrations are like those of synthetic corticosteroids. Twelve patients had major depression and one each had dysthymic disorder and a depressive adjustment disorder. Five were male and nine were female. All were in-patients. Eight normal subjects, two females and six males, were used as controls. Basal beta-endorphin concentrations were 2- to 3-fold higher in depressed patients than in control subjects, but there were no significant differences between the patient and control groups in the basal (pre-infusion) plasma concentrations of ACTH, cortisol, growth hormone or prolactin. Cortisol, but not saline infusion resulted in a significant improvement in self rated mood. Surprisingly, cortisol infusion at first increased plasma beta-endorphin concentrations. At later times after cortisol infusion, plasma beta-endorphin concentrations decreased as did the plasma concentrations of ACTH and growth hormone; prolactin levels were increased. These results show (i) that cortisol infusion raises mood significantly in major depression, (ii) that plasma beta-endorphin concentration is a potential marker of major depression (iii) that rather than blunting of corticosteroid effects, responses to cortisol may even be enhanced in depressive illness. The unexpected, initial increase in beta-endorphin stimulated by cortisol, suggests that the action of cortisol is not simply one of negative feedback inhibition, but may involve mineralocorticoid, as well as glucocorticoid receptors.

Adrenocorticotropic Hormone↗
PubMed1992

Eye-tracking dysfunction in the affective psychoses and schizophrenia.

Smooth pursuit eye movements to a sinusoidally moving target were recorded using the electro-oculogram in 49 subjects with bipolar disorder, 19 with major depressive disorder and 61 with definite schizophrenia, and compared with 145 normal controls. The signals were analysed in the frequency domain to yield a signal to noise ratio that is known to relate to accuracy of smooth pursuit. Smooth pursuit was found to be significantly poorer in schizophrenics than in bipolars, major depressed or controls. Eye-tracking performance was independent of the effects of neuroleptics, tricyclic antidepressants or lithium, and was not altered by the severity of depression in the affective psychoses. There was a small, but significant worsening of smooth pursuit with age in controls and schizophrenics, but this did not account for the group differences. The results support the view that among the major psychoses eye-tracking dysfunction is specific to schizophrenia.

Adolescent↗