title: A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.
abstract: Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C M
authors.initials: CM
authors.lastname: Sellgren
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M E
authors.initials: ME
authors.lastname: Kegel
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Section of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ekman
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Olsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine School of Medicine, Irvine, CA, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Vawter
authors.affiliation: Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Backlund
authors.affiliation: Department of Genetic and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Sklar
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics, Research, Massachusetts General Hospital, Boston, MA, USA.|Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Walther-Jallow
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C I
authors.initials: CI
authors.lastname: Svensson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.identifier: 0000-0003-3037-5287
authors.initials: P
authors.lastname: Lichtenstein
authors.affiliation: Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Engberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|The Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landén
mesh_terms: D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003072:Cognition Disorders / Q000150:complications; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D058305:Sorting Nexins / Q000235:genetics
chemical_list: D058305:Sorting Nexins; D007736:Kynurenic Acid