title: The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression.
abstract: The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P≤0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
authors: 1] Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors: C
authors: C
authors: Lavebratt
authors: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: S
authors: S
authors: Olsson
authors: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: L
authors: L
authors: Backlund
authors: 1] Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden [3] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: L
authors: L
authors: Frisén
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: C
authors: C
authors: Sellgren
authors: 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: L
authors: L
authors: Priebe
authors: 1] Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden [2] Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: P
authors: P
authors: Nikamo
authors: Department of Clinical Sciences, University Hospital, Lund, Sweden.
authors: L
authors: L
authors: Träskman-Bendz
authors: 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany [3] Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Center Juelich, Juelich, Germany.
authors: S
authors: S
authors: Cichon
authors: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine School of Medicine, Irvine, CA, USA.
authors: M P
authors: MP
authors: Vawter
authors: 1] Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden [3] Department of Psychiatry, Tiohundra AB, Norrtälje, Sweden.
authors: U
authors: U
authors: Osby
authors: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: G
authors: G
authors: Engberg
authors: 1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden [2] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors: M
authors: M
authors: Landén
authors: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: S
authors: S
authors: Erhardt
authors: 1] Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors: M
authors: M
authors: Schalling
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001714:Bipolar Disorder / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid*; D050601:Kynurenine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism; D011618:Psychotic Disorders / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000134:cerebrospinal fluid / Q000378:metabolism; D055815:Young Adult
chemical_list: D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid