title: Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis.
abstract: Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden. Electronic address: dimitrios.andreou@sll.se.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Andreou
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Söderman
authors.affiliation: Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
authors.forename: Göran C
authors.initials: GC
authors.lastname: Sedvall
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Terenius
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.affiliation: Department of Clinical Neuroscience, Psychiatry Section, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden; NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Jönsson
mesh_terms: D000328:Adult; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004298:Dopamine / Q000134:cerebrospinal fluid; D005260:Female; D018698:Glutamic Acid / Q000134:cerebrospinal fluid* / Q000235:genetics*; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D050601:Kynurenine 3-Monooxygenase / Q000134:cerebrospinal fluid / Q000235:genetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid; D009638:Norepinephrine / Q000134:cerebrospinal fluid; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011618:Psychotic Disorders / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000235:genetics*; D012701:Serotonin / Q000134:cerebrospinal fluid
chemical_list: D015306:Biogenic Monoamines; D015415:Biomarkers; D012701:Serotonin; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D050601:Kynurenine 3-Monooxygenase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid
keywords: 3-methoxy-4-hydroxyphenylglycol (MHPG); 5-hydroxyindoleacetic acid (5-HIAA); Homovanillic acid (HVA); Psychiatric genetics; Schizophrenia