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Stanley Zammit

Publications and source records attributed to Stanley Zammit.

17 recordsLinked to original sources
PubMed2006

Schizophrenia and neural tube defects: comparisons from an epidemiological perspective.

In this review, we examine and compare epidemiological studies of schizophrenia and neural tube defects (NTDs). Although there is no apparent link between these 2 disparate disorders in terms of clinical manifestation or phenotypes, overlapping patterns in the variation of incidence of schizophrenia with that of NTDs indicate the existence of one or more shared etiological risk factors. Evidence in support of such a phenomenon may enhance our understanding of underlying pathological mechanisms and may guide future studies of etiology and prevention. The similarities that occur in a number of epidemiological observations for these disorders are in keeping with a hypothesis of nutritional deficiencies in utero acting as a risk factor for both schizophrenia and NTDs. Programes of periconceptual folate and multivitamin supplementation aimed to reduce the risk of NTDs are already in place in many countries. Nevertheless, evidence of additional effects of specific maternal micronutrient deficiency on risk of schizophrenia may not only increase enthusiasm for expansion of such programes but also enhance understanding of etiology of this disorder and offer the potential for targeted interventions in high-risk groups.

Birth Intervals↗
PubMed2006

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2006

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Adult↗
PubMed2006

Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder.

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.

Bipolar Disorder↗
PubMed2006

Self-reported psychotic symptoms in the general population: results from the longitudinal study of the British National Psychiatric Morbidity Survey.

BACKGROUND: Scarce longitudinal data exist on the occurrence of psychotic symptoms in the general population. AIMS: To estimate the incidence of, and risk factors for, self-reported psychotic symptoms in Great Britain. METHOD: Data from the 18-month follow-up of a national survey were used. Incident cases were those who endorsed one or more items on the Psychosis Screening Questionnaire at follow-up, but not at baseline. The association between factors recorded at baseline and incident self-reported symptoms was examined. RESULTS: At follow-up, 4.4% of the general population reported incident psychotic symptoms. Six factors were independently associated with incident symptoms: living in a rural area; having a small primary support group; more adverse life events; smoking tobacco; neurotic symptoms; and engaging in a harmful pattern of drinking. CONCLUSIONS: A small but not insignificant percentage of the population of Great Britain reported incident psychotic symptoms over 18 months. The risk factors for psychotic symptoms showed some similarities with risk factors for schizophrenia, but there were also some striking differences. The relationship between such risk factors and the factors that perpetuate psychotic symptoms remains to be ascertained.

Adolescent↗
PubMed2006

Stressful life events, 5-HTT genotype and risk of depression.

Studies of how genetic and environmental exposures interact may be essential for understanding the aetiology of complex psychiatric disorders. In this issue of the Journal an Australian study reports evidence of such an interaction on risk of depression. We discuss findings in this field in the context of the limitations inherent in studies of gene-environment interactions.

Depressive Disorder↗
PubMed2005

Phenotypic variation between parent-offspring trios and non-trios in genetic studies of schizophrenia.

BACKGROUND: Phenotypic differences between parent-offspring trios and non-trios have been reported for various psychiatric disorders, and it has been suggested that this may make comparisons of case-control and family-based results for gene-disease association studies inappropriate. AIMS: To compare phenotypes between trios and non-trios with schizophrenia, and explore possible reasons for differences observed. METHOD: Phenotypes were compared between trios (n=75) and non-trios (n=424) collected as part of a case-control study. RESULTS: Differences were observed for most phenotypes investigated, although all were eliminated after adjusting for confounding. CONCLUSIONS: Confounding, genetic heterogeneity or selection bias could result in differences in case-control and family-based results. However as we discuss, where adequately designed case-control studies are used, gene-disease association results would be incomparable between family-based and case-control studies only if genetic heterogeneity was present. These results do not support the presence of such genetic heterogeneity in schizophrenia.

Adolescent↗
PubMed2005

No evidence for association between polymorphisms in GRM3 and schizophrenia.

BACKGROUND: Three studies have previously reported data that were interpreted by the authors as supportive of association between schizophrenia and polymorphisms in the gene encoding the metabotropic glutamate receptor GRM3. METHODS: In a bid to examine this hypothesis, we examined seven SNPs spanning GRM3 in a UK case-control sample (schizophrenic cases n = 674, controls n = 716). These included all SNPs previously reported to be associated, alone or in haplotypes, with schizophrenia in European or European American samples. RESULTS: Our data showed no evidence for association with single markers, or 2, 3, 4 and 5 marker haplotypes, nor did any specific haplotypes show evidence for association according to previously observed patterns. CONCLUSION: Examination of our own data and those of other groups leads us to conclude that at present, GRM3 should not be viewed as a gene for which there is replicated evidence for association with schizophrenia.

Adult↗
PubMed2005

A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk.

Epigenetic mechanisms such as methylation of DNA, could lead to abnormal neurodevelopment and may be important in the etiology of schizophrenia. Maternal dietary folate intake may play a role in determining methylation levels. The MTHFR gene C677T polymorphism influences folate metabolism and intracellular availability of folate metabolites for methylation. We carried out a meta-analysis of MTHFR C677T genotype and schizophrenia risk, and found that TT homozygotes had a significantly increased risk, OR 1.48 (1.18-1.86). This supports the hypothesis that folate status is a determinant of schizophrenia risk. Larger studies of this issue are required, together with studies of maternal genotype which could identify whether maternal folate status during pregnancy is important.

Alleles↗
PubMed2005

No association between schizophrenia and polymorphisms in COMT in two large samples.

OBJECTIVE: A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses. METHOD: They reviewed data from more than 2,800 individuals, including almost 1,200 with schizophrenia, from case-control and family-based European association samples. RESULTS: The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. CONCLUSIONS: The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies.

Case-Control Studies↗
PubMed2004

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia.

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

Aggression↗
PubMed2004

Support for RGS4 as a susceptibility gene for schizophrenia.

BACKGROUND: The gene encoding the regulator of G-protein signaling 4 has recently been associated with susceptibility to schizophrenia. This finding is particularly interesting, because it was replicated within the same study and also because there are functional, positional, and expression data to support the regulator of G-protein signaling 4 as a schizophrenia candidate gene. Although the original report was highly suggestive, a limitation was that the study was conducted on rather small samples. METHODS: We have examined a large case (n = 709) control (n = 710) sample for association between schizophrenia using four markers investigated in the earlier study, denoted single nucleotide polymorphisms 1, 4, 7, and 18. RESULTS: We were able to replicate the associations with single nucleotide polymorphisms 4 and 18 that had previously been reported individually and have also identified significant association with haplotypes constructed from single nucleotide polymorphisms 1 and 4. CONCLUSIONS: Our data give modest support for the hypothesis that the regulator of G-protein signaling 4 is a susceptibility gene for schizophrenia.

Adult↗
PubMed2004

A longitudinal study of premorbid IQ Score and risk of developing schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses.

CONTEXT: Longitudinal studies indicate that a lower IQ score increases risk of schizophrenia. Preliminary evidence suggests there is no such effect for nonpsychotic bipolar disorder. To our knowledge, there are no prior population-based, longitudinal studies of premorbid IQ score and risk of developing severe depression requiring hospital admission. OBJECTIVES: To investigate the association between premorbid IQ score and risk of developing schizophrenia, other nonaffective psychoses, bipolar disorder, and severe depression and to investigate effects of confounding and examine possible causal pathways by which IQ may alter these risks. DESIGN: Historical cohort study, using record linkage for hospital admissions during a 27-year follow-up period. SETTING: Survey of Swedish conscripts (1969-1970). PARTICIPANTS: Population-based sample of 50,087 male subjects. Data were available on IQ score at conscription and on other social and psychological characteristics. MAIN OUTCOME MEASURES: International Classification of Diseases, Eighth Revision or Ninth Revision diagnoses of schizophrenia, bipolar disorder, severe depression, and other nonaffective psychoses. RESULTS: There was no association between premorbid IQ score and risk of bipolar disorder. Lower IQ was associated with increased risk of schizophrenia, severe depression, and other nonaffective psychoses. Risk of schizophrenia was increased in subjects with average IQ compared with those with high scores, indicating that risk is spread across the whole IQ range. CONCLUSIONS: Lower IQ score was associated with increased risk for schizophrenia, severe depression, and other nonaffective psychoses, but not bipolar disorder. This finding indicates that at least some aspects of the neurodevelopmental etiology of bipolar disorder may differ from these other disorders.

Adolescent↗
PubMed2003

Investigating the association between cigarette smoking and schizophrenia in a cohort study.

OBJECTIVE: Many case-control and cross-sectional studies have observed an association with cigarette smoking after the onset of schizophrenia, and there is evidence to suggest that smoking may improve symptoms in people with this disorder. Here, the authors investigated whether cigarette smoking alters the risk of subsequently developing schizophrenia. No longitudinal studies have previously examined this relationship. METHOD: A cohort of 50,087 Swedish conscripts (98% were ages 18-20) was followed up by record linkage to the National Register of Inpatient Care from 1970 to 1996 to determine hospital admission for schizophrenia. Cox regression was used to obtain hazard ratios and 95% confidence intervals (CIs) for schizophrenia, according to smoking status. RESULTS: Smoking cigarettes at ages 18-20 was associated with a lower rate of developing schizophrenia after adjustment for confounders. There was a linear relationship between the number of cigarettes smoked and a lower risk of schizophrenia (adjusted hazard ratio for linear trend across smoking categories, 0.8 [95% CI=0.7-0.9]), with an adjusted hazard ratio for heavy smokers of 0.5 (95% CI=0.3-0.9) compared to that of nonsmokers. This association persisted when analysis was restricted to subjects diagnosed after the first 5 years following conscription to reduce possible prodromal effects of schizophrenia on smoking. CONCLUSIONS: Cigarette smoking may be an independent protective factor for developing schizophrenia. These results are consistent with animal models showing both neuroprotective effects of nicotine and differential release of prefrontal dopamine in response to nicotine. The harmful effects of cigarette smoking vastly outweigh any possible benefits, but nevertheless, further investigation may lead to important insights regarding the etiology of schizophrenia at a molecular level.

Adolescent↗
PubMed2003

Paternal age and risk for schizophrenia.

BACKGROUND: Previously reported associations between advancing paternal age and schizophrenia could be due to an increase in paternal germ cell mutations or be confounded by heritable personality traits associated with schizophrenia that result in delayed parenthood. AIMS: To investigate this association while adjusting for personality traits related to poor social integration in the subjects. METHOD: A cohort of 50,087 adolescent males was followed up by record linkage to determine hospital admissions for schizophrenia between 1970 and 1996. RESULTS: Advancing paternal age was associated with an increased risk of developing schizophrenia in a 'dose-dependent' manner. The adjusted odds ratio for each 10-year increase in paternal age was 1.3 (95% CI 1.0-1.5; P=0.015). CONCLUSIONS: Advancing paternal age is an independent risk factor for schizophrenia. Adjusting for social integration in subjects made little difference to this association, consistent with the hypothesis that advancing paternal age may increase liability to schizophrenia owing to accumulating germ cell mutations.

Adolescent↗
PubMed2002

Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study.

OBJECTIVES: An association between use of cannabis in adolescence and subsequent risk of schizophrenia was previously reported in a follow up of Swedish conscripts. Arguments were raised that this association may be due to use of drugs other than cannabis and that personality traits may have confounded results. We performed a further analysis of this cohort to address these uncertainties while extending the follow up period to identify additional cases. DESIGN: Historical cohort study. SETTING: 1969-70 survey of Swedish conscripts (>97% of the country's male population aged 18-20). PARTICIPANTS: 50 087 subjects: data were available on self reported use of cannabis and other drugs, and on several social and psychological characteristics. MAIN OUTCOME MEASURES: Admissions to hospital for ICD-8/9 schizophrenia and other psychoses, as determined by record linkage. RESULTS: Cannabis was associated with an increased risk of developing schizophrenia in a dose dependent fashion both for subjects who had ever used cannabis (adjusted odds ratio for linear trend of increasing frequency 1.2, 95% confidence interval 1.1 to 1.4, P<0.001), and for subjects who had used only cannabis and no other drugs (adjusted odds ratio for linear trend 1.3, 1.1 to 1.5, P<0.015). The adjusted odds ratio for using cannabis >50 times was 6.7 (2.1 to 21.7) in the cannabis only group. Similar results were obtained when analysis was restricted to subjects developing schizophrenia after five years after conscription, to exclude prodromal cases. CONCLUSIONS: Cannabis use is associated with an increased risk of developing schizophrenia, consistent with a causal relation. This association is not explained by use of other psychoactive drugs or personality traits relating to social integration.

Adult↗