title: Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis.
abstract: Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.
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.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Jönsson
mesh_terms: D000328:Adult; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000134:cerebrospinal fluid* / Q000235:genetics*; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D050641:Receptors, Dopamine D5 / Q000235:genetics; D055815:Young Adult
chemical_list: C583260:DRD1 protein, human; C581293:DRD2 protein, human; C493593:DRD3 protein, human; C493599:DRD4 protein, human; C493605:DRD5 protein, human; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Dopamine receptor D1 gene (DRD1); Homovanillic acid (HVA); Psychiatric genetics; Schizophrenia