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A G Cardno

Publications and source records attributed to A G Cardno.

At least 19 recordsLinked to original sources
PubMed2001

A genomewide linkage study of age at onset in schizophrenia.

There is strong evidence for a genetic contribution to age at onset of schizophrenia, which probably involves both susceptibility loci for schizophrenia and modifying loci acting independent of disease risk. We sought evidence of linkage to loci that influence age at onset of schizophrenia in a sample of 94 affected sibling pairs with DSM-IV schizophrenia or schizoaffective disorder, and age at first psychiatric contact of 45 years or less. Individuals were genotyped for 229 microsatellite markers spaced at approximately 20 cM intervals throughout the genome. Loci contributing to age at onset were sought by a quantitative maximum-likelihood multipoint linkage analysis using MAPMAKER/SIBS. A nonparametric multipoint analysis was also performed. The genomewide significance of linkage results was assessed by simulation studies. There were six maximum-likelihood LOD score peaks of 1.5 or greater, the highest being on chromosome 17q (LOD = 2.54; genomewide P = 0.27). This fulfils Lander and Kruglyak's [1995: Nat Genet 11:241-247] criteria for suggestive linkage in that it would be expected to occur once or less (0.3 times) per genome scan. However, this finding should be treated with caution because the LOD score appeared to be almost solely accounted for by the pattern of ibd sharing at one marker (D17S787), with virtually no evidence of linkage over flanking markers. None of the linkage results achieved genomewide statistical significance, but the LOD score peak on chromosome 13q (LOD = 1.68) coincided with the region showing maximum evidence for linkage in the study by Blouin et al. [1998: Nat Genet 20:70-73] of categorical schizophrenia.

Age of Onset↗
PubMed2001

Sustained and selective attention as measures of genetic liability to schizophrenia.

We tested for a relationship between attention and genetic liability to schizophrenia. Samples of probands with DSM-IV schizophrenia (n=20), their well first-degree relatives (n=40) and healthy controls (n=82) were tested using measures of sustained attention (degraded-stimulus continuous performance test: DS-CPT) and selective attention (spatial negative priming task). Assuming a liability-threshold model, we predicted that probands would display greater attentional decrements than controls and that the relatives would show intermediate levels of decrement. We did not observe the predicted pattern of effect using either measure, although the probands showed a trend towards less negative priming. However, our results may have been affected by self-selection bias in probands and relatives and clinical heterogeneity among probands, which could have reduced our power to detect effects.

Adolescent↗
PubMed2001

Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

Case-Control Studies↗
PubMed2001

Twin study of symptom dimensions in psychoses.

BACKGROUND: Symptomatology in psychoses can be summarised as quantitative symptom dimensions, but their genetic basis is unknown. AIMS: To investigate whether genes make an important contribution to symptom dimensions. METHOD: A total of 224 probandwise twin pairs (106 monozygotic, 118 same-gender dizygotic) where probands had psychosis were ascertained from the Maudsley Twin Register in London. Factor analysis was performed on lifetime symptoms rated on the Operational Checklist for Psychotic Disorders (OPCRIT). Correlations of dimension scores within monozygotic and dizygotic pairs concordant for Research Diagnostic Criteria psychoses were performed. Relationships between dimension scores and genetic loading for psychoses were assessed using logistic regression. RESULTS: Patterns of familial aggregation consistent with a genetic effect were found for the disorganised dimension and for some measures of the negative, manic and general psychotic dimensions. Disorganised dimension scores were related significantly to genetic loading for psychoses. CONCLUSIONS: The disorganised dimension, and possibly other symptom dimensions, may be useful phenotypes for molecular genetic studies of psychoses.

Diseases in Twins↗
PubMed2001

Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype.

BACKGROUND: Evidence exists for an association between aggression and schizophrenia. Although the aetiology of aggression is multifactorial, three studies have reported associations between polymorphisms of the catechol-O-methyltransferase (COMT) gene and aggression in schizophrenia. AIMS: To replicate these findings in a larger sample using the Overt Aggression Scale (OAS). METHOD: A sample of 180 people with DSM-IV schizophrenia were rated for aggression using the OAS. Kruskal-Wallis and contingency table analyses were applied to the OAS results. RESULTS: The high-activity homozygotes showed significantly higher scores of aggression, whereas the heterozygotes showed significantly lower scores. The odds ratio for aggression for the high-activity homozygotes was 2.07 (95% Cl=1.03-4.15), whereas that for the heterozygotes was 0.54 (95% Cl=0.30-1.00). CONCLUSIONS; The high-activity COMT homozygote confers a higher risk of recorded aggression in schizophrenia. Heterozygotes had a significantly lower risk, which may represent an example of heterosis/heterozygote advantage.

Aggression↗
PubMed2000

The kings schizotypy questionnaire as a quantitative measure of schizophrenia liability.

We used a new self-report measure, the Kings Schizotypy Questionnaire (KSQ; Williams, M. The psychometric assessment of schizotypal personality. PhD thesis. Institute of Psychiatry, University of London, 1993), to investigate schizotypy as a quantitative measure of familial liability to schizophrenia. The KSQ was administered to 135 DSM-IV schizophrenia probands, 153 of their healthy first-degree relatives, and 267 control subjects. We found that the questionnaire clearly differentiated schizophrenic from non-schizophrenic individuals, but failed to differentiate the relatives from controls. Possible reasons for this include defensive responding among relatives, self-selection bias among relatives, differences in data collection methods, and the possibility that positive aspects of schizotypy may not be closely related to familial liability to schizophrenia.

Adult↗
PubMed2000

Psychiatric genetics: back to the future.

For the last decade or more geneticists have been predicting that advances in molecular genetics are going to revolutionize our understanding of psychiatric disorders and human behavior. However, with a few exceptions, these expectations have yet to be fulfilled. As the century draws to a close and we contemplate the prospect of the complete sequence of the human genome it seems timely to consider the state of the field and to consider carefully how it might advance, the problems to be faced and the resources required. Molecular Psychiatry (2000) 5, 22-31.

Animals↗
PubMed2000

Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder.

Aromatic L-amino acid decarboxylase (AADC) is a relatively non specific enzyme involved in the biosynthesis of several classical neurotransmitters including dopamine and 5-hydroxytryptamine (5HT; serotonin). AADC does not catalyse the rate limiting step in either pathway, but is rate limiting in the synthesis of 2-phenylethylamine (2PE) which is a positive modulator of dopaminergic transmission and a candidate natural psychotogenic compound.1 We and others have proposed that polymorphism in AADC resulting in altered 2PE activity might contribute to the pathogenesis of psychosis. In order to test this hypothesis, we have used denaturing high performance liquid chromatography (DHPLC)3 to screen 3943 bases of the AADC gene and its promoter regions for variants that might affect protein structure or expression in 15 unrelated people with schizophrenia, and 15 unrelated people with bipolar disorder. Three polymorphisms were identified by DHPLC: a insertion/deletion polymorphism in the 5' UTR of the neuronal specific mRNA (g.-33-30delAGAG, bases 586-589 of GenBank M77828), a T>A variant in the non-neuronal exon 1 (g. -67T>A, GenBank M88070), and a G>A polymorphism within intron 8 (g. IVS8 +75G>A, GenBank M84598). Case-control analysis did not suggest that genetic polymorphism in the AADC gene is associated with liability for developing schizophrenia or bipolar disorder.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed2000

The high affinity neurotensin receptor gene (NTSR1): comparative sequencing and association studies in schizophrenia.

Neurotensin and its high affinity receptor (NTSR1) localise within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems and it is now clear that neurotensin can selectively modulate dopaminergic neurotransmission. This has led to the hypothesis that altered neurotensin function contributes to the pathogenesis of schizophrenia and other psychoses. This hypothesis has been supported circumstantially by a number of lines of evidence. (1) Central administration of neurotensin produces effects similar to those produced by the peripheral administration of atypical antipsychotics. (2) Observations of low levels of neurotensin in the CSF of schizophrenics. (3) Reduced numbers of neurotensin receptors in the brains of schizophrenics. Given the above link between neurotensin and dopamine, and the evidence implicating altered neurotensin function in psychosis, we have postulated that DNA sequence variation in neurotensin or its receptors might be associated with schizophrenia. In keeping with this hypothesis, an association has recently been reported between schizophrenia and the gene encoding the neurotensin high affinity receptor (NTSR1). However, caution is required because the associated marker, a tetranucleotide repeat, is located 3 kb away from the 3' end of the gene and there is no evidence that it is functional. Therefore, as a follow-up to our earlier work on neurotensin, we have now sought to test the hypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs) are associated with schizophrenia. However, while we found 14 novel sequence variants in 28 probands with psychosis, none resulted in an amino acid change, and neither direct nor indirect association studies suggested these are involved in susceptibility to schizophrenia.

Brain Chemistry↗
PubMed2000

Repeat sizes at CAG/CTG loci CTG18.1, ERDA1 and TGC13-7a in schizophrenia.

A number of studies using the repeat expansion detection (RED) technique have suggested an association between unknown large CAG/CTG repeats and schizophrenia. The polymorphic CAG/CTG repeat loci CTG18.1 and ERDA1 have been reported to account for a high proportion (approximately 90%) of the large repeats detected by RED and may therefore be responsible for the cited association. The recently described locus TGC13-7a contains a highly polymorphic CTA/TAG and CAG/CTG composite repeat, and is thus another authentic candidate. In the present investigation, each locus was analysed for association with schizophrenia in a sample of 206 patients and 219 group-matched controls. No evidence for association of CTG18.1, ERDA1 and/or TGC13-7a with schizophrenia was found. The combined data accounted for only 54% of the CAG/CTG arrays of > 40 repeats found in our previous RED analysis.

Adult↗
PubMed2000

No evidence for association between a non-synonymous polymorphism in the gene encoding human metabotropic glutamate receptor 7 and schizophrenia.

The cDNA sequence of the gene encoding human metabotropic glutamate receptor type 7 (mGluR7) contains the single nucleotide polymorphism 1536A > T [GenBank sequence X94552 (Makoff et al., 1996)]. This sequence variation is predicted to result in an amino acid change (F433Y) in the gene product and thus has the potential to affect receptor function. Since disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia, we have used a novel and robust polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to genotype this polymorphism in a case-control sample comprising 181 schizophrenic patients and 182 group-matched unaffected individuals. No evidence was found for association between this polymorphism and schizophrenia. We have also localised mGluR7 to chromosome 3p25-22 using radiation hybrid (RH) mapping.

Alleles↗
PubMed2000

Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics.

Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.

Data Interpretation, Statistical↗
PubMed1999

No evidence for allelic association between schizophrenia and a functional variant of the human dopamine beta-hydroxylase gene (DBH).

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinepherine, has been proposed as being involved in the aetiology of schizophrenia. Previous work identified a functional polymorphism at nucleotide 910 of the DBH gene that results in a codon change in the mature protein Ala304Ser, with the mutant allele being associated with a lower enzymatic activity. In this study we performed an RFLP analysis in an association study consisting of 178 unrelated schizophrenic patients and 178 unrelated control subjects, matched for age, sex, and ethnicity. The frequency of the Ser304 DBH allele was 0.10 in the patient group and 0.08 in the control group, with no significant allelic or genotypic association observed. Therefore, we were unable to obtain evidence that this polymorphism contributes directly to susceptibility to schizophrenia.

Adult↗
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↗