PubMed Health⌕ Search

Biomedical subjects

S Zammit

Publications and source records attributed to S Zammit.

15 recordsLinked to original sources
PubMed2007

IGF1, growth pathway polymorphisms and schizophrenia: a pooling study.

It has been hypothesized that insulin-like growth factors (IGFs) and components of the growth-hormone (GH)-IGF axis may underlie reported associations of poor fetal and childhood growth with schizophrenia. We have investigated the association of schizophrenia with 16 SNPs spanning the IGF1 gene with an inter-marker distance of approximately 2-3 kb. We also examined associations with four common functional polymorphisms of genes involved in aspects of the GH-IGF system--the IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), growth hormone (GH1), and IGF binding protein-3 (IGFBP3). The study was based on an analysis of pooled DNA samples from 648 UK and Irish cases of schizophrenia and 712 blood donor controls and of 297 Bulgarian parent offspring trios. In replicated pool analyses, none of the 16 SNPs in IGF1 nor the 4 key SNPs in the other growth pathway genes were associated with schizophrenia. SNP coverage of IGF1 was extensive, so our findings do not support a major role for IGF-I in the aetiology of schizophrenia.

Bulgaria↗
PubMed2005

Genome wide significant linkage in schizophrenia conditioning on occurrence of depressive episodes.

BACKGROUND: Schizophrenia shows substantial clinical heterogeneity. One common important clinical variable in presentation is the occurrence of episodes of major depression. METHODS: We undertook analyses in an attempt to detect loci that influence susceptibility to, or modify the clinical expression of, schizophrenia according to the occurrence of episodes of major depression. We used a logistic regression framework in which lifetime presence/absence of major depression was entered as a covariate in the linkage analysis of our UK schizophrenia affected sibling pair series (168 affected sibling pairs typed for a 10 cM map of microsatellite markers). RESULTS: Inclusion of presence/absence of depression as a covariate detected a genome wide significant linkage signal on chromosome 4q28.3 at 130.7 cM (LOD = 4.59; p = 0.038; increase in maximum LOD over univariate analysis (ILOD) = 3.62). Inclusion of the depression covariate also showed suggestive evidence of linkage on 20q11.21 (LOD = 4.10; expected to occur by chance 0.093 times per genome scan, ILOD = 2.83). CONCLUSIONS: Our findings identify loci that may harbour genes that play a role in susceptibility to, or modify the risk of, episodes of major depression in people with schizophrenia.

Analysis of Variance↗
PubMed2004

Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1).

CONTEXT: Recent research suggests that variation in the gene encoding dystrobrevin binding protein (DTNBP1) confers susceptibility to schizophrenia. Thus far, no specific risk haplotype has been identified in more than 1 study. OBJECTIVES: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype. DESIGN: Genetic association study based on mutation detection and case-control analysis. SETTING: All subjects were unrelated and ascertained from general (secondary care) psychiatric inpatient and outpatient services. PARTICIPANTS: The Cardiff, Wales, sample included 708 white subjects from the United Kingdom and Ireland (221 females) who met DSM-IV criteria for schizophrenia and were individually matched for age, sex, and ethnicity to 711 blood donor controls (233 females). Mean +/- SD age at first psychiatric contact for cases was 23.6 +/- 7.7 years; mean age at ascertainment was 41.8 +/- 13.5 years. The Dublin, Ireland, sample included 219 white subjects from the Republic of Ireland who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and 231 controls. The mean age of the Irish cases was 46.0 +/- 8.5 years; mean age at first psychiatric contact was 25.2 +/- 12.4 years. MAIN OUTCOME MEASURE: Evidence for association between the DTNBP1 locus and schizophrenia. RESULTS: In the Cardiff sample, there was no evidence for association with previously implicated haplotypes but strong evidence for association with multiple novel haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P<.001), composed of 1 risk haplotype (P =.01) and 2 protective haplotypes, 1 common (P =.006) and 1 rare (P<.001). Specific risk and protective haplotypes were replicated in the Dublin sample (P =.02,.047, and.006, respectively). The only phenotypic variable associated with any haplotype was between the common protective haplotype and higher educational achievement (P =.02, corrected for multiple tests). CONCLUSIONS: DTNBP1 is a susceptibility gene for schizophrenia. Specific risk and protective haplotypes were identified and replicated. Association with educational achievement may suggest protection mediated by IQ, although this needs to be confirmed in an independent data set.

Adult↗
PubMed2003

A systematic genomewide linkage study in 353 sib pairs with schizophrenia.

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

Genetic Linkage↗
PubMed2003

Mutation screening of the Homer gene family and association analysis in schizophrenia.

Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

Adult↗
PubMed2003

Detailed analysis of PRODH and PsPRODH reveals no association with schizophrenia.

People with deletion of the chromosome 22q11 region associated with velo cardio-facial syndrome (VCFS) have a remarkably high risk of developing schizophrenia. Recently, the gene proline dehydrogenase (PRODH) which maps to 22q11 and is also an excellent functional candidate gene for psychosis, has been reported to show genetic association with schizophrenia. We have screened all the exons and adjacent intronic sequences of PRODH for the presence of sequence variation in 14 DSM IV schizophrenic subjects. Similarly, we also screened all putative exons of a sequence that is similar to proline dehydrogenase (PsPRODH) and which also maps within the deleted region. A total of nine single nucleotide polymorphisms (SNPs) were identified in PRODH, eight of which were exonic, while in PsPRODH, five SNPs were identified, one of which was in a putative exon. All samples were tested for association in a pooled sample of 368 DSM IV diagnosed schizophrenic subjects and 368 matched controls. None of the variants identified in PRODH gave even modest evidence for allelic association (P < 0.1). In PsPRODH, two variants (-3864G > A and 226G > A) gave P values < 0.1. These were individually genotyped in the same subjects that had been used to construct the pools. Although a trend for association was confirmed, neither showed evidence for association at the P </= 0.05 level. These results do not suggest that PRODH or PsPRODH contribute to the aetiology of schizophrenia, and that the putative schizophrenia susceptibility gene in 22q11 remains unknown.

Adult↗
PubMed2003

Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia.

Recently, it has been reported that genetic variants around the gene neuregulin 1 are associated with schizophrenia in an Icelandic sample. Of particular interest was the presence of a single-risk haplotype that was significantly over-represented in schizophrenic individuals compared to controls (15.4 : 7.5%, P=6.7 x 10(-6)). We have attempted to replicate this result in our large collection of 573 schizophrenia cases and 618 controls. We found that the risk haplotype was more common in cases than controls (9.5 : 7.5%; P=0.04), and especially in our subset of 141 cases with a family history of schizophrenia (11.6%; P=0.019). Our results therefore replicate the Icelandic findings in an out-bred Northern European population, although they suggest that the risk conferred by the haplotype is small.

Adult↗
PubMed2002

Screening the human protocadherin 8 (PCDH8) gene in schizophrenia.

Abnormalities in synaptic connectivity and plasticity have been implicated in the pathophysiology of schizophrenia. Molecules involved in the development and maintenance of neural circuitry include the recently cloned protocadherins. Human protocadherin 8 (PCDH8) is homologous to 'arcadlin', a molecule shown to play a role in hippocampal synaptic function in the rat. The gene encoding PCDH8 maps to a region on chromosome 13 where linkage to schizophrenia has been reported. In this study, the entire expressed sequence of the PCDH8 gene and over 800 bp of the 5' flanking region were screened for polymorphisms in 30 DSM-IV schizophrenia individuals using Denaturing High Performance Liquid Chromatography (DHPLC). A total of nine single nucleotide polymorphisms were identified, including three in the first exon that are predicted to change the amino acid sequence. One polymorphism, causing the Trp7Arg change in the putative signal peptide, showed a trend towards excess of the arginine encoding allele in a case-control sample consisting of 520 DSM-IV schizophrenia patients and 535 matched controls from the UK (chi2=3.72, P [1 df]= 0.054). However, this polymorphism did not show preferential transmission to schizophrenic individuals in a separate sample of 203 proband-parent trios from Bulgaria. A second, rare single nucleotide variation, predicting the non-conservative amino acid change Glu39Ala, was found in one schizophrenic individual and their affected sibling but not in a further 352 affected individuals, nor 357 controls. These results suggest that any contribution of PCDH8 polymorphisms to schizophrenia susceptibility is likely to be weak, although the existence of rare variations of stronger effect cannot be excluded.

Adult↗
PubMed2002

Characterisation, mutation detection, and association analysis of alternative promoters and 5' UTRs of the human dopamine D3 receptor gene in schizophrenia.

The dopamine D(3) receptor gene (DRD3) is a candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder and alcohol and drug abuse. Previous studies have reported associations between polymorphisms in DRD3 and these disorders, but these findings may have reflected linkage disequilibrium with pathogenic variants that are further upstream. We have isolated and sequenced approximately 9 kb of genomic sequence upstream of the human DRD3 translational start site. Using 5' RACE, we have identified within this region three additional exons and two putative promoter regions which show promoter activity in three different cell lines. A 5' UTR identified only in lymphoblasts is spread over three exons and is 353 bp long. A second 5' UTR, found in adult and fetal brain, lymphocytes, kidney and placenta is spread over two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to a previously reported EST, but corresponding mRNA could not be found in the tissues above. The EST, 5' UTRs and putative promoter regions have been analysed for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which were tested for association in a large sample of unrelated patients with schizophrenia and matched controls. No associations were observed with schizophrenia. In addition we failed to replicate previous findings of association with homozygosity of the Ser9Gly variant. The results from this study imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia.

5' Untranslated Regions↗
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

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 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↗
PubMed1996

Ultrasensitive detection of prostate-specific antigen by a time-resolved immunofluorometric assay and the Immulite immunochemiluminescent third-generation assay: potential applications in prostate and breast cancers.

We report an ultrasensitive time-resolved immunofluorometric assay (TRIFA) for prostate-specific antigen (PSA). The assay is an improvement of our previous report (Clin Chem 1993;39:2108-14) and includes the utilization of two monoclonal antibodies and a one-step incubation period, which greatly reduces analysis time. The new method demonstrates a superior lower analytical limit of detection (< or = 1 ng/L), a wide dynamic range, absence of a hook effect at 10(6) ng/L PSA, and equimolarity for free PSA and PSA-antichymotrypsin complex. Also, we have compared several aspects of our TRIFA with a commercially available third-generation assay (Immulite). An evaluation of breast tumor cytosol extracts from 315 patients shows PSA immunoreactivity > 15 ng/g of total protein in 28% and 23% by TRIFA and Immulite analysis, respectively. Both methods demonstrate a significant association between breast tumor PSA immunoreactivity and progesterone and estrogen receptor positivity (P <0.001). Analysis of serum samples obtained for monitoring of postradical prostatectomy patients reveals significant PSA changes at concentrations undetectable by conventional methods. The significance of these results as well as the potential applications of ultrasensitive PSA assays in breast and prostate cancers are discussed.

Breast Neoplasms↗