1. A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder
- Author
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Camilla I. Svensson, Mikael Landén, Pamela Sklar, Paul Lichtenstein, C J Ekman, Martin Schalling, Carl M. Sellgren, Marquis P. Vawter, Patrik K. E. Magnusson, Sara K. Olsson, Patrick F. Sullivan, Jordan W. Smoller, Sarah E. Bergen, Max Larsson, Lena Backlund, Göran Engberg, Sophie Erhardt, Lilian Walther-Jallow, Magdalena E. Kegel, and Christina M. Hultman
- Subjects
0301 basic medicine ,Adult ,Male ,Psychosis ,medicine.medical_specialty ,Kynurenine pathway ,Bipolar Disorder ,Genome-wide association study ,Bioinformatics ,Kynurenic Acid ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,Kynurenic acid ,medicine ,Humans ,Cognitive Dysfunction ,Bipolar disorder ,Psychiatry ,Molecular Biology ,Sorting Nexins ,Aged ,Brain ,Middle Aged ,medicine.disease ,3. Good health ,Psychiatry and Mental health ,030104 developmental biology ,chemistry ,Psychotic Disorders ,Schizophrenia ,Chromosomes, Human, Pair 1 ,Original Article ,Female ,Psychopharmacology ,Psychology ,Cognition Disorders ,030217 neurology & neurosurgery ,Genome-Wide Association Study - 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.
- Published
- 2015