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A G Cardno

Publications and source records attributed to A G Cardno.

At least 37 records · Page 2Linked to original sources
PubMed1999

CAG repeat length in the hKCa3 gene and symptom dimensions in schizophrenia.

BACKGROUND: Long CAG repeats in the hKCa3 potassium channel gene have been associated with schizophrenia. We sought evidence for associations between this polymorphism and aspects of the schizophrenia phenotype. METHODS: Associations were investigated between CAG repeat length and gender, age of illness onset, and psychotic symptom dimensions in 203 unrelated individuals with DSM-IIIR schizophrenia. RESULTS: No association was found between CAG repeat length and gender or age of onset. Long CAG repeats were associated with higher negative symptom dimension scores. CONCLUSIONS: This study provides preliminary evidence that genetic liability to negative symptoms in schizophrenia may be partly mediated through the hKCa3 gene.

Adult↗
PubMed1999

Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.

BACKGROUND: Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. METHODS: A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. RESULTS: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. CONCLUSIONS: Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.

Adult↗
PubMed1999

A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs.

We undertook a systematic search for linkage in 196 affected sibling pairs (ASPs) with DSMIV schizophrenia. In stage 1 we typed 97 ASPs with 229 microsatellite markers at an average inter-marker distance of 17.26 cM. Multipoint affected sib pair analysis identified seven regions with a maximum lod score (MLS) at or above the level associated with a nominal pointwise significance of 5%, on chromosomes 2q, 4p, 10q, 15q, 18p, 20q and Xcen. In stage 2 we genotyped a further 54 markers in 196 ASPs together with parents and unaffected siblings. This allowed the regions identified in stage 1 to be typed at an average spacing of 5.15 cM, while the region of interest on chromosome 2 was typed to 9.55 cM. Analysis was performed on the whole data set. Simulation studies suggested that we would expect one multipoint MLS of 1.5 per genome scan in the absence of linkage. An MLS of 3 would be expected only once in every 20 genome scans and thus corresponds to a genome-wide significance of 0.05. We obtained three multipoint MLSs >1.5 and, on this basis, the results on chromosomes 4p, 18q and Xcen can be considered suggestive. However, none approached a genome-wide significance of 0. 05. The power of this study was >0.95 to detect a susceptibility locus of lambda(s)= 3 with a genome-wide significance of 0.05, but only 0.70 to detect a locus of lambda(s)= 2. Our results suggest that common genes of major effect (lambda(s)> 3) are unlikely to exist for schizophrenia.

Chromosome Mapping↗
PubMed1999

Dimensions of psychosis in affected sibling pairs.

Factor analytical studies of schizophrenia symptoms have consistently suggested three or more symptom dimensions, but it is not known whether any of these dimensions have a genetic basis. The purpose of this study was to investigate to what extent the dimensions show familial aggregation. Symptom ratings were made using the SAPS and SANS and the OPCRIT checklist on the members of 109 sibling pairs with DSM-IV schizophrenia or schizoaffective disorder. Factor analyses were performed on the ratings of both instruments, and correlations were made of within-pair factor scores. Analyses were also performed on the 89 pairs in which both members had a diagnosis of schizophrenia. Factor analysis of SAPS and SANS ratings resulted in positive, negative, and disorganization factors; analysis of OPCRIT ratings resulted in positive, negative, disorganization, and first-rank delusion factors. Only the disorganization dimension showed significant within-pair correlations, but these were of modest size and not significantly greater than the correlations for the other dimensions. None of the dimensions showed sufficient familial aggregation to suggest that they are close markers of genetic or common environmental factors that contribute liability to schizophrenia. They may be weakly associated with such factors and with factors that do not contribute liability to schizophrenia but do influence the form taken by the illness.

Adult↗
PubMed1998

Sibling pairs with schizophrenia or schizoaffective disorder: associations of subtypes, symptoms and demographic variables.

BACKGROUND: Affected sibling pairs provide a valuable means of investigating the familial basis of clinical heterogeneity in schizophrenia. METHODS: Associations of schizophrenia subtypes, psychotic symptoms (defined by SAPS/SANS and OPCRIT), affective episodes and demographic variables were studied in 109 sibling pairs with DSM-IV schizophrenia or schizoaffective disorder. RESULTS: None of the subtypes or affective episodes were significantly associated within pairs. A broad definition of positive formal thought disorder, grandiose delusions and delusions of influence (all from OPCRIT) were modestly associated. There was no excess of same-sex pairs. There were modest associations for age of illness onset, pre-morbid adjustment and illness severity. Caution is required in interpreting the results because many statistical tests were carried out. CONCLUSIONS: None of the variables appears to be closely associated with specific genetic or shared environmental factors that contribute liability to schizophrenia. They are at best only weakly associated with such factors, and/or are associated with factors unrelated to the aetiology of schizophrenia.

Adult↗
PubMed1998

Linked polymorphisms upstream of exons 1 and 2 of the human cholecystokinin gene are not associated with schizophrenia or bipolar disorder.

The evidence for a significant genetic contribution to the functional psychoses (schizophrenia and bipolar disorder) is now well established. However, in both cases, the non-mendelian mode of inheritance has made the identification of susceptibility loci particularly challenging. The neuropeptide cholecystokinin (CCK) is present both in the gut and the CNS. Studies of CCK-like immunoreactivity and CCK mRNA levels in human brains have revealed high concentrations in numerous loci and shown colocalisation of CCK with, for example, dopamine and tyrosine hydroxylase. Furthermore, antagonists of CCK-B receptors, which are found most frequently in the brain, inhibit the activity of brain dopamine neurons. Such findings suggest that, with respect to neuropsychiatric disorders, CCK is a suitable candidate for analysis using methods to detect gene variations which have the potential to affect protein structure or expression. In the present study, mutation analyses were carried out on the human CCK gene. Linked polymorphisms were found in the promoter region and in intron 1 close to the 3' mRNA splice acceptor site. However, the allele frequencies of these polymorphisms in samples of individuals affected with either schizophrenia (n=117) or bipolar disorder (n=124) did not differ from those of control subjects (n=234), suggesting that these variations do not confer a predisposition to either of the functional psychoses.

Alleles↗
PubMed1998

Further support for an association between a polymorphic CAG repeat in the hKCa3 gene and schizophrenia.

A recent study has suggested that a polymorphism in the hKCa3 potassium channel may be associated with raised susceptibility to schizophrenia. Despite its modest statistical significance, the study is intriguing for two reasons. First, hKCa3 contains a polymorphic CAG repeat in its coding sequence, with large repeats more common in schizophrenics compared with controls. This is interesting in view of several repeat expansion detection (RED) studies that have reported an excess of large CAG repeats in psychotic probands. Second, the hKCa3 gene is a functional candidate gene because studies of antipsychotic and psychotogenic compounds suggest that glutamatergic systems modulated by SKCa channels may be important in schizophrenia pathogenesis. In the light of the above, we have tested the hypothesis of an association between schizophrenia and the hKCa3 CAG repeat polymorphism using a case control study design. Under the same model of analysis as the earlier study, schizophrenic probands had a higher frequency of alleles with greater than 19 repeats than controls (chi 2 = 2.820, P = 0.047, 1-tail). Our data therefore provide modest support for the hypothesis that polymorphism in the hKCa3 gene may contribute to susceptibility to schizophrenia.

Alleles↗
PubMed1998

Association between functional psychosis and expanded CAG/CTG repeats is not explained by health stratification.

A number of studies have reported an association between large CAG/CTG repeats and both schizophrenia and bipolar disorder. Recently, we reported an inverse correlation between CAG/CTG repeat size and age in a health-selected population, raising the possibility that selection of control groups for physical health was a confounding factor in our previous association studies. We investigated this by health-selection of patients with schizophrenia and bipolar disorder. The maximum CAG/CTG repeat size remained significantly larger in probands with functional psychosis compared with control individuals, and in probands with a diagnosis of schizophrenia compared with control individuals. The number of probands in the healthy bipolar group was small, and although on average this group also had longer CAG/CTG repeats than control individuals, this failed to reach statistical significance. Our findings do not support the notion that the original results with psychosis as a whole, and schizophrenia specifically, are attributable to a stratification effect consequent on health selection. Nevertheless, we are unable formally to reject the hypothesis that the previously observed difference between bipolar probands and control individuals is the result of this phenomenon.

Bipolar Disorder↗
PubMed1998

Polydactyly and psychosis. Five cases of co-occurrence.

BACKGROUND: Abnormalities presumed to occur during foetal life have been associated with schizophrenia. Polydactyly is a developmental abnormality but no previous association has been reported between polydactyly and functional psychotic illness. METHOD: Individuals with both polydactyly and a functional psychosis were ascertained during a study of familial schizophrenia. RESULTS: Five such individuals were ascertained in the course of assessing 234 individuals with familial psychosis, giving a rate of polydactyly in the sample of around 10 times the general population rate. CONCLUSIONS: This study provides preliminary evidence that polydactyly is over-represented in individuals with familial schizophrenia and related psychotic illnesses.

Adult↗
PubMed1997

Linkage study of chromosome 6p in sib-pairs with schizophrenia.

Following reports of linkage between schizophrenia and markers in the chromosomal region 6p24-22 we have studied nine microsatellite markers spanning 40 cM of this region in our sample of 102 affected sibling pairs from 86 families. Allele sharing identity by descent was examined using likelihood based sib-pair analysis as implemented by the program SPLINK. No evidence for linkage was obtained and the highest lod score was only 0.192 for D6S309. We conclude that if there is a susceptibility locus for schizophrenia in this region then its effect size is so small as to render our study insufficiently powerful to detect it.

Adult↗
PubMed1997

Factor-derived subsyndromes of schizophrenia and familial morbid risks.

Factor analysis was performed on OPCRIT checklist ratings from 66 patients with RDC schizophrenia. Eight substantive factors were found, characterised respectively by: positive formal thought disorder; first rank delusions; first rank hallucinations; inappropriate affect/bizarre behaviour; negative symptoms; grandiose/bizarre delusions; delusions of influence/persecution; and other hallucinations. A history of schizophrenia and other non-affective psychoses was ascertained in the probands' first-degree relatives using a family history approach. Illness in relatives was best predicted by probands' scores on subsyndromes derived from the inappropriate affect/bizarre behaviour and positive formal thought disorder factors.

Adult↗
PubMed1997

No evidence for an allelic association between schizophrenia and markers D22S278 and D22S283.

We report a case control association study using markers D22S278 and D22S283 in 90 unrelated patients with DSMIII-R schizophrenia and 90 controls matched for ethnicity, age and sex. No differences between allele frequencies for either marker were observed when the two groups were compared (D22S278: chi 2 = 6.53, df = 7, P = 0.51; D22S283: chi 2 = 14.73, df = 15, P = 0.48). These findings fail to support previous work by others suggesting the presence of allelic association between the markers D22S278 and D22S283 and schizophrenia.

Alleles↗
PubMed1997

Association between schizophrenia and a microsatellite polymorphism at the dopamine D5 receptor gene.

An association study of 97 patients with DSM-III-R schizophrenia and 97 matched controls was performed using a polymorphic microsatellite repeat at the dopamine D5 receptor gene. We observed a significant difference between the allele frequencies of patients and controls (chi 2 = 23.4, df = 12, p = 0.019). This reflects an excess of allele 4 (140 bp) in the patients when compared with the control sample (chi 2 = 7.087, p < 0.01; odds ratio = 2.98, 95% CI 1.29-6.86). However, this association remains tentative until confirmation in other samples.

Alleles↗
PubMed1996

Factor analysis of schizophrenic symptoms using the OPCRIT checklist.

Factor analysis was performed on OPCRIT checklist psychotic symptoms rated on 102 patients with DSM-III-R schizophrenia. An initial three-factor solution produced positive, negative, and disorganisation factors. However, application of the scree test suggested five substantive factors, with the positive factor dividing into three factors characterised, respectively, by paranoid symptoms, first rank delusions and first rank hallucinations.

Adult↗
PubMed1996

The molecular genetics of schizophrenia.

There is overwhelming evidence for a significant genetic contribution to the etiology of schizophrenia. Molecular genetic techniques are now sufficiently advanced to be applied to complex genetic disorders with uncertain phenotypes, such as schizophrenia. In this article we first briefly discuss certain pertinent background issues: the evidence that schizophrenia has a heritable basis, the possible modes of inheritance involved, and how best to define schizophrenia in the light of this evidence; we then review the current status of research in the field. Large collaborative studies are currently underway that pave the way for the detection of genes of both major and minor effects. We may now be seeing the first consistently replicated results from chromosome 6 and 22 and from candidate genes, such as the dopamine D3 receptor gene.

Chromosome Mapping↗
PubMed1996

No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity.

OBJECTIVE: Catechol O-methyltransferase (COMT) inactivates catecholamines by methylating their m-hydroxy group. Some previous studies using biochemical methods have found higher levels of COMT activity in schizophrenic patients. Recently, the genetic polymorphism that underlies variation in COMT activity, which results in the creation of a NlaIII restriction site in the low-activity allele, has been elucidated. METHOD: This study investigated this polymorphism in 78 unrelated schizophrenic patients and 78 comparison subjects matched for age and ethnicity. High-molecular-weight DNA was isolated from lymphocytes with routine procedures, and each individual was typed for high and low COMT activity. RESULTS: The frequency of the NlaIII polymorphism was 0.51 in the schizophrenic patients and 0.53 in the comparison subjects, and no significant allelic or genotypic associations were observed. CONCLUSIONS: There was no evidence for variation in COMT activity between a group of schizophrenic patients and matched comparison subjects.

Alleles↗
PubMed1996

Expanded CAG/CTG repeats in schizophrenia. A study of clinical correlates.

BACKGROUND: Schizophrenia is associated with expanded CAG/CTG trinucleotide repeats. We wished to determine whether the presence of such expansions correlated with specific subsyndromes or other clinical features of schizophrenia. METHOD: Seventy patients from England and Wales and 44 patients from Portugal with a DSM-III-R diagnosis of schizophrenia were rated on the OPCRIT checklist. Patient's maximum CAG/CTG repeat length was measured using repeat expansion detection (RED). Significant differences were sought for repeat lengths in subjects categorised according to dimensional and categorical schizophrenia subsyndromes, affective episodes, individual symptoms, and a range of demographic variables. RESULTS: Maximum CAG/CTG repeat length did not differ significantly for any of the clinical or demographic variables studied. CONCLUSION: There are no subsyndromes or other clinical features of schizophrenia associated with CAG/CTG repeat expansion. Therefore, the identification of the gene(s) that contain expanded CAG/CTG repeats and which are associated with schizophrenia is unlikely to be facilitated at present by using any subsyndromes of schizophrenia as phenotypes.

Adult↗