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Mol Psychiatry. 2016 Oct;21(10):1342-50. doi: 10.1038/mp.2015.186. Epub 2015 Dec 15.

A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.

Author information

1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
2
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
3
Section of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
4
Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine School of Medicine, Irvine, CA, USA.
5
Neurogenetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
6
Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
7
Department of Genetic and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
8
Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
9
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics, Research, Massachusetts General Hospital, Boston, MA, USA.
10
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
11
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
13
The Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.

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.

PMID:
26666201
PMCID:
PMC4965332
DOI:
10.1038/mp.2015.186
[Indexed for MEDLINE]
Free PMC Article

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