Padraig Wright

Schizophrenia and HLA: a review.

A number of reports of genetic association of human leucocyte antigens (HLA) and alleles with schizophrenia have recently been published. A schizophrenia locus on chromosome 6p near the HLA region has also been reported, on the basis of linkage studies. We have therefore reviewed the investigations of association of HLA with schizophrenia published from 1974 to date, and have also briefly reviewed the chromosome 6p linkage studies. Two or more groups of investigators have reported association of each of the following HLA antigens or alleles with schizophrenia - A9 or its A24 subspecificity, A28, A10, DRB1*01 and DRw6. However, these results may represent Type I errors caused by small sample size, inappropriate diagnostic, laboratory and/or statistical methodology, and/or incorrectly chosen comparison subjects. Hypothesis-driven negative associations of DRB1*04 and DQB1*0602 with schizophrenia have also been reported. Taken together, however, HLA association investigations provide only weak evidence for the existence of either resistance or susceptibility loci for schizophrenia close to the HLA region at the 6p21.3 band and, indeed, recently reported investigations that controlled for most of these confounders found no evidence of association. Linkage studies suggest that a susceptibility locus may exist and that it may be within the HLA region, but again the evidence is far from conclusive. Further HLA association investigations should employ operational diagnostic criteria, comparison subjects screened for illness and HLA genotyping, and should include both association studies of candidate alleles and transmission disequilibrium and haplotype relative risk studies.

Autoimmune diseases in the pedigrees of schizophrenic and control subjects

Autoimmune diseases aggregate in individuals and within pedigrees, and it has been postulated that autoimmune mechanisms may account for a proportion of schizophrenia. Structured questionnaires were used to interview the mothers of 121 DSM-III-R schizophrenic patients and the mothers of 116 controls in order to determine the prevalence of schizophrenia and of autoimmune diseases in their pedigrees. Patients with a schizophrenic first degree relative were significantly more likely to also have a parent or sibling with an autoimmune disease (60% vs. 20%, OR = 6.1, 95% CI = 2.3-6.5, p = 0.0003). A significant excess of insulin dependent diabetes mellitus (IDDM) was present in the parents and siblings of schizophrenic patients (OR = 9.65, 95% CI = 1.3-429.2, p = 0.009). These findings suggest that autoimmune mechanisms may play a role in the aetiology of schizophrenia, particularly familial schizophrenia. Associations have been established between autoimmune diseases and the HLA encoding genes of the major histocompatibility complex on chromosome six, and it may be that some of the genetic liability to schizophrenia involves these genes.

Family history of autoimmune diseases in psychosis

The mothers of 101 psychotic patients and 116 normal controls were interviewed using a semi-structured questionnaire designed to determine the presence or absence of autoimmune disorders in first degree relatives of the probands. Thyrotoxicosis and insulin-dependent diabetes mellitus were significantly more common in the relatives of the psychotic patients than in the control relatives; in particular thyrotoxicosis was more frequent in the mothers of patients (11%) than the mothers of controls (2.6%). None of the examined characteristics of the patients, including RDC-diagnosis, family history of psychosis, age at onset of psychosis and winter birth, was predictive of thyrotoxicosis and insulin-dependent diabetes mellitus in relatives.

Transmission disequilibrium analysis of HLA class II DRB1, DQA1, DQB1 and DPB1 polymorphisms in schizophrenia using family trios from a Han Chinese population

Our goal was to evaluate the role of HLA in the risk of developing schizophrenia, in a Han Chinese population. In several Japanese studies, there is evidence of association with DR1 and schizophrenia. A variety of other associations have been reported in other populations, including negative associations with DQbeta(*)0602 and positive associations with DR1(*)0101. Using sequence specific oligonucleotides, we genotyped four HLA markers (DRB1, DQA1, DQB1 and DPB1) in 165 family trios, consisting of Han Chinese schizophrenic subjects and their parents. Individual markers were analysed for transmission distortion in the trios using the transmission disequilibrium test. Multiple haplotype transmission was performed using the program TRANSMIT v2.5. The four markers were in strong linkage disequilibrium with each other (P value from 0.002 to 0). There was no evidence of overall transmission disequilibrium for each of the four loci. For DRB1, we did not find transmission distortion for the DRB1(*)04 and DRB1(*)08 alleles, as reported previously, but the DRB1(*)03 allele was preferentially not transmitted (P=0.009), and the DRB1(*)13 allele was preferentially transmitted from parents to schizophrenic offspring (P=0.041). Using haplotypes of pairs of markers, a significant global P value of 0.019 was achieved when using DRB1 and DQA1, mainly as a result of the excess transmission of DRB1(*)13-DQA1(*)01 (P=0.012) and a deficit in transmission of DRB1(*)03-DQA1(*)05 (P=0.002). In summary, we did not confirm any of the specific HLA allelic associations reported previously in Japanese or other populations. However, our results are compatible with the view that this region of HLA might contain a susceptibility gene which is in linkage disequilibrium with DRB1 and DQA1 genes.

Schizophrenia: Prenatal Influenza and Autoimmunity

The schizophrenic syndrome may represent a stereotyped response by the developing brain to various insults, including micro-organisms. We review studies that have examined the association between schizophrenia and infectious agents, and examine the current evidence for the hypothesis that exposure to influenza during fetal life increases the risk of later schizophrenia. A prenatal autoimmune basis for some cases of schizophrenia is proposed.

An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia.

Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin‐3 (NT‐3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT‐3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy‐Weinberg equilibrium and, in a test of all alleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P= 0.029).

A transmission/disequilibrium study of the DRB1*04 gene locus on chromosome 6p21.3 with schizophrenia.

Patients with schizophrenia rarely develop rheumatoid arthritis, an autoimmune disease that exhibits genetic association with the HLA DRB1*04 gene. We previously investigated the hypothesis that schizophrenia is negatively associated with DRB1*04, and found that only half the expected number of schizophrenic patients had this gene when compared with controls. We now report the results of DRB1*04 genotyping in pedigrees multiply affected with schizophrenia. Polymerase chain reaction amplification and sequence-specific oligonucleotide probes were used to determine the DRB1 genotypes of the 187 members of 23 pedigrees multiply affected with RDC schizophrenia. DQA1, DQB1 and DPB1 genotypes were similarly determined. We analysed data using the extended transmission/disequilibrium test and found a trend for the preferential non-transmission of DRB1*04 alleles from heterozygous parents to their schizophrenic offspring (16 of 23 alleles not transmitted, chi 2 = 3.5, p = 0.06). We found no evidence for a gene of major effect using GENEHUNTER for parametric and non-parametric linkage analysis. The results from this small sample need to be interpreted with caution, but they are in keeping with previous reports and suggest that HLA DRB1*04 alleles may be associated with a reduced risk of schizophrenia.

Follow-up studies of schizophrenia I: Natural history and non-psychopathological predictors of outcome

Treatment-resistant schizophrenia does not exist as a discrete entity, so separating patients who will fail to respond to traditional antipsychotics from those who will respond is impossible with 100% accuracy. However, several predictors of poor clinical outcome have emerged from recent research and knowledge of the processes that lead to poor outcome has become increasingly important with the advent of atypical antipsychotics that may be used in patients with treatment-resistant illness. Much of the variation in outcome can be understood in terms of differences in sample selection, outcome definition and stringency of the diagnostic criteria used. Failure to appreciate these mechanisms may lead to over- or underestimation of the proportion of patients with poor treatment response in clinical and research settings. The importance of factors that predict poor outcome should be judged in terms of their effect size and the degree to which alternative explanations for the association with outcome have been excluded. Although much current research is being focused on specific biological predictors, baseline demographic and illness-related factors, such as ethnic group, sex, social class, type of onset, age of onset and concurrent misuse of alcohol or drugs, have large effects on outcome. Although duration of untreated psychosis before first contact with services may independently predict poor outcome. confounding by variables that are associated with both pathways to care and clinical outcome has not been excluded.

Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?:

Background: The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes. Methods: A Caucasian sample of 70 patients was recruited in 1996–1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months prior to assessment. All patients were genotyped for CYP2D6 alleles*3–5, *41, and for amplifications of the gene. Results: There were 13 patients with TD. The mean (standard deviation (SD)) years of duration of antipsychotic treatment in TD-positive was 15.8 (7.9) vs TD-negative 11.1 (7.4) (p=0.04). Increased odds of experiencing TD were associated with increased ability to metabolize CYP2D6, as measured by genotypic category (odds ratio (OR)=4.2), increasing duration in treatment (OR=1.0), and having drug-induced Parkinsonism (OR=9.7). Discussion: We found a significant association between CYP2D6 genotypic category and TD with the direction of effect being an increase in the number of functional CYP2D6 genes being associated with an increased risk of TD. This is the first study to examine the association between TD and CYP2D6 in Caucasians with this number of genotypic categories. In the future, metabolomics may be utilized in the discovery of biomarkers and novel drug targets.

Risperidone is associated with blunting of D-fenfluramine evoked serotonergic responses in schizophrenia

The high 5-HT affinity of some atypical antipsychotic agents is thought to contribute to their clinical efficacy. We examined central 5-HT responses in two groups of ten schizophrenic patients by measuring serum prolactin and cortisol responses to the neuroendocrine challenge D-fenfluramine. One group of patients with schizophrenia was tested after a 2-week neuroleptic free period. A similar group were tested after a mean of 12 weeks treatment with the atypical antipsychotic risperidone, A significant elevation of baseline serum prolactin levels, consistent with dopaminergic antagonism was seen after risperidone treatment. Significantly reduced 5-HT mediated serum prolactin responses were seen in risperidone treated patients, D-fenfluramine evoked serum prolactin responses were positively correlated with positive but not negative schizophrenic symptoms for all 20 patients. Risperidone treatment was associated with a significant functional in-vivo 5-HT antagonism similar to clozapine. 5-HT antagonism may contribute to the efficacy of risperidone against positive schizophrenic symptoms.