Genetic aspects on schizophrenia and cerebrospinal fluid monoamine metabolites : Focus on association studies with candidate genes
Abstract: Schizophrenia is a syndrome with psychotic symptoms. The pathogenesis of schizophrenia most likely reflects brain abnormalities and heritable components are present. The principal objective of the present thesis was to investigate some possible genetic influences in the genesis or pathophysiology of schizophrenia. Groups of schizophrenic patients (n=134) was examined for DNA markers in candidate genes related to monoaminergic mechanisms and growth factors. A group of healthy subjects (n=99) was used for reference. Some of them were also assessed for polymorphisms in some of the genes of potential pathophysiological relevance for schizophrenia and their relationships to concentrations of monoaminmetabolites in cerebrospinal fluid (CSF). After correction for multiple testing no significant differences in allele or genotype frequencies were found between schizophrenic patients and control subjects when compared for markers in the dopamine receptor D2 (DRD2), D3 (DRD3) and D4, tyrosine hydroxylase (TH), neurotrophin-3, and ciliary neurotrophic factor genes. In healthy control subjects tentative associations were recorded between markers in the DRD2 and TH genes and CSF concentrations of homovanillic acid and 3-methoxy4-hydroxyphenylglycol and between a DRD3 polymorphism and levels of 5-hydroxyindoleacetic acid (5-HIAA). In male subjects a tentative association was also found between a marker in the tryptophanhydroxylase gene and 5- HIAA-levels in CSF. The study indicates that the candidate genes examined have no major effect for the development of schizophrenia. However, it can not be excluded that subtypes of schizophrenia related to family history, gender, or response to neuroleptic drugs may be associated with some of the genes investigated or that the importance of the genes is so limited that a much larger sample size is required to detect association. The tentative associations found between genetic markers and monoamine metabolites in CSF indicate that genotypes for DRD2 and TH differentially influence dopamine synthesis and turnover. However, also these associations need independent replication. Key words: association study, schizophrenia, DNA polymorphisms, dopamine receptors (DRD2, DRD3, DRD4), tyrosine hydroxylase, tryptophan hydroxylase, catechol-O-methyltransferase, neurotrophin-3, ciliary neurotrophic factor, healthy subjects, cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, 3-hydroxy-4-methoxyphenylglycol Stockholm 1997 ISBN 91-628-2339-6
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