Molecular genetic studies on cerebrospinal fluid monoamine metabolites in psychotic patients and healthy individuals
Author: Andreou, Dimitrios
Date: 2015-03-20
Location: Sal 90, Centrum för psykiatriforskning, 6 tr, Norra Stationsgatan 69, 113 64 Stockholm
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
Abstract
Dopamine, serotonin and noradrenaline are the major monoamines in the human central nervous system (CNS) and following their basic pathways they are degraded to their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively. The cerebrospinal fluid (CSF) concentrations of the three monoamine metabolites (MM) are considered to reflect the monoamine turnover rates in the CNS, are under genetic influence and have been associated with schizophrenia.
In the first part of the thesis (Studies I, II and III), 132 healthy individuals (78 men and 54 women) were included, whereas in the second part of the thesis (Studies IV and V) 74 psychotic patients (45 men and 29 women) participated. CSF samples were drawn by lumbar puncture and genomic DNA was extracted from whole blood samples for genotyping.
In the first part of the thesis, we have searched for association between single nucleotide polymorphisms (SNPs) in the tryptophan hydroxylase 1 (TPH1), dystrobrevin binding protein 1 (DTNBP1) and D-amino acid oxidase activator (DAOA) genes and the CSF MM concentrations in healthy individuals in order to shed further light to the understanding of the effect of the genes on CSF MM in humans. One TPH1 SNP and one DTNBP1 SNP were found to be significantly associated with both CSF 5-HIAA and HVA, giving evidence for association between the genes and dopamine and serotonin turnover rates in CNS. Two DAOA SNPs were significantly associated with CSF HVA concentrations, proposing that the DAOA gene is implicated in dopaminergic mechanisms.
In the second part of the thesis, we searched for association between genes implicated in dopamine, serotonin and noradrenalin metabolism (Study IV) and glutamate-related genes (Study V) and CSF MM concentrations in psychotic patients. Several nominal associations and one significant association between MAOB and MHPG in men (Study IV) were found, suggesting that CSF MM concentrations can be considered as psychosis intermediate phenotypes in previously reported associations between gene variants and the disorder.
In the first part of the thesis (Studies I, II and III), 132 healthy individuals (78 men and 54 women) were included, whereas in the second part of the thesis (Studies IV and V) 74 psychotic patients (45 men and 29 women) participated. CSF samples were drawn by lumbar puncture and genomic DNA was extracted from whole blood samples for genotyping.
In the first part of the thesis, we have searched for association between single nucleotide polymorphisms (SNPs) in the tryptophan hydroxylase 1 (TPH1), dystrobrevin binding protein 1 (DTNBP1) and D-amino acid oxidase activator (DAOA) genes and the CSF MM concentrations in healthy individuals in order to shed further light to the understanding of the effect of the genes on CSF MM in humans. One TPH1 SNP and one DTNBP1 SNP were found to be significantly associated with both CSF 5-HIAA and HVA, giving evidence for association between the genes and dopamine and serotonin turnover rates in CNS. Two DAOA SNPs were significantly associated with CSF HVA concentrations, proposing that the DAOA gene is implicated in dopaminergic mechanisms.
In the second part of the thesis, we searched for association between genes implicated in dopamine, serotonin and noradrenalin metabolism (Study IV) and glutamate-related genes (Study V) and CSF MM concentrations in psychotic patients. Several nominal associations and one significant association between MAOB and MHPG in men (Study IV) were found, suggesting that CSF MM concentrations can be considered as psychosis intermediate phenotypes in previously reported associations between gene variants and the disorder.
List of papers:
I. Andreou D., Saetre P., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers. Psychiatry Research 2010:180;63-67.
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II. Andreou D., Saetre P., Kähler A.K., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers. European Neuropsychopharmacology 2011:21;700-704.
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III. Andreou D., Saetre P., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians. European Archives of Psychiatry and Clinical Neurosciences 2012:262;549-556.
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IV. Andreou D., Söderman E., Axelsson T., Sedvall G.C., Terenius L., Agartz I., Jönsson E.G. Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. Behavioral and Brain Functions 2014:10;26.
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V. Andreou D., Söderman E., Axelsson T., Sedvall G.C., Terenius L., Agartz I., Jönsson E.G. Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis. [Submitted]
I. Andreou D., Saetre P., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers. Psychiatry Research 2010:180;63-67.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Andreou D., Saetre P., Kähler A.K., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers. European Neuropsychopharmacology 2011:21;700-704.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Andreou D., Saetre P., Werge T., Andreassen O.A., Agartz I., Sedvall G.C., Hall H., Terenius L., Jönsson E.G. D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians. European Archives of Psychiatry and Clinical Neurosciences 2012:262;549-556.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Andreou D., Söderman E., Axelsson T., Sedvall G.C., Terenius L., Agartz I., Jönsson E.G. Polymorphisms in genes implicated in dopamine, serotonin and noradrenalin metabolism suggest association with cerebrospinal fluid monoamine metabolite concentrations in psychosis. Behavioral and Brain Functions 2014:10;26.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Andreou D., Söderman E., Axelsson T., Sedvall G.C., Terenius L., Agartz I., Jönsson E.G. Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis. [Submitted]
Institution: Karolinska Institutet
Supervisor: Jönsson, Erik
Issue date: 2015-02-26
Rights:
Publication year: 2015
ISBN: 978-91-7549-842-3
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