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

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.

[1]  M. Holtze,et al.  Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. , 2012, Schizophrenia bulletin.

[2]  E. Albuquerque,et al.  Regulation of GABAergic Inputs to CA1 Pyramidal Neurons by Nicotinic Receptors and Kynurenic Acid , 2012, Journal of Pharmacology and Experimental Therapeutics.

[3]  T. Brugha,et al.  SCAN. Schedules for Clinical Assessment in Neuropsychiatry. , 1990, Archives of general psychiatry.

[4]  M. Beal,et al.  Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection. , 1990, Analytical biochemistry.

[5]  G. Kirov,et al.  Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. , 2005, Archives of general psychiatry.

[6]  A. Ganong,et al.  Kynurenic acid and quinolinic acid act at N-methyl-D-aspartate receptors in the rat hippocampus. , 1986, The Journal of pharmacology and experimental therapeutics.

[7]  T. Suzuki,et al.  Association study between kynurenine 3‐monooxygenase gene and schizophrenia in the Japanese population , 2006, Genes, brain, and behavior.

[8]  C. Lindgren,et al.  Population Structure in Contemporary Sweden—A Y‐Chromosomal and Mitochondrial DNA Analysis , 2009, Annals of human genetics.

[9]  R. Yolken,et al.  The Stanley Foundation brain collection and Neuropathology Consortium , 2000, Schizophrenia Research.

[10]  K. Larsson,et al.  Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia. , 2009, The international journal of neuropsychopharmacology.

[11]  E. Major,et al.  Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. , 1997, The Biochemical journal.

[12]  A. Isacchi,et al.  Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase. , 2000, European journal of biochemistry.

[13]  S. Erhardt,et al.  Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons , 2001, Amino Acids.

[14]  K. Blennow,et al.  Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia , 2001, Neuroscience Letters.

[15]  A. Chiarugi,et al.  Comparison of the Neurochemical and Behavioral Effects Resulting from the Inhibition of Kynurenine Hydroxylase and/or Kynureninase , 1995, Journal of neurochemistry.

[16]  R. Schwarcz,et al.  (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats. , 1996, European journal of pharmacology.

[17]  S. Weis,et al.  Upregulation of the initiating step of the kynurenine pathway in postmortem anterior cingulate cortex from individuals with schizophrenia and bipolar disorder , 2006, Brain Research.

[18]  R. McIntyre,et al.  Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. , 2009, The Journal of clinical psychiatry.

[19]  E. Jönsson,et al.  Cerebrospinal fluid kynurenic acid in male and female controls - correlation with monoamine metabolites and influences of confounding factors. , 2007, Journal of psychiatric research.

[20]  M. Landén,et al.  Elevation of cerebrospinal fluid interleukin-1ß in bipolar disorder. , 2011, Journal of psychiatry & neuroscience : JPN.

[21]  E. Jönsson,et al.  Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder. , 2010, Journal of psychiatry & neuroscience : JPN.

[22]  G. Lynch,et al.  A Glycine Site Associated with N‐Methyl‐d‐Aspartic Acid Receptors: Characterization and Identification of a New Class of Antagonists , 1989, Journal of neurochemistry.

[23]  M. Brodie,et al.  Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity. , 1992, General Pharmacology.

[24]  S. Erhardt,et al.  Effects of COX‐1 and COX‐2 inhibitors on the firing of rat midbrain dopaminergic neurons—Possible involvement of endogenous kynurenic acid , 2006, Synapse.

[25]  Tyrone D. Cannon,et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study , 2009, The Lancet.

[26]  P. Sullivan,et al.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. , 2003, Archives of general psychiatry.

[27]  B. Brew,et al.  Expression of indoleamine 2,3‐dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons , 2005, Glia.

[28]  M. Landén,et al.  Cognitive manic symptoms associated with the P2RX7 gene in bipolar disorder , 2011, Bipolar disorders.

[29]  D. Bucci,et al.  Elevations of endogenous kynurenic acid produce spatial working memory deficits. , 2007, Schizophrenia bulletin.

[30]  T. Hansen,et al.  Kynurenine 3-monooxygenase (KMO) polymorphisms in schizophrenia: An association study , 2011, Schizophrenia Research.

[31]  Daniel L. Koller,et al.  Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction , 2012, Molecular Psychiatry.

[32]  S. Erhardt,et al.  Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons , 2006, Journal of Neural Transmission.

[33]  R. Yolken,et al.  Meta-analysis of 12 genomic studies in bipolar disorder , 2007, Journal of Molecular Neuroscience.

[34]  A. Carlsson,et al.  EFFECT OF CHLORPROMAZINE OR HALOPERIDOL ON FORMATION OF 3METHOXYTYRAMINE AND NORMETANEPHRINE IN MOUSE BRAIN. , 2009, Acta pharmacologica et toxicologica.

[35]  W. Turski,et al.  Enhancement of brain kynurenic acid production by anticonvulsants--novel mechanism of antiepileptic activity? , 2006, European journal of pharmacology.

[36]  W Hennah,et al.  Replication of 1q42 linkage in Finnish schizophrenia pedigrees , 2004, Molecular Psychiatry.

[37]  D. Kupfer,et al.  Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD) , 2003, Biological Psychiatry.

[38]  P. Deloukas,et al.  Patterns of Cis Regulatory Variation in Diverse Human Populations , 2012, PLoS genetics.

[39]  Tsun-Po Yang,et al.  Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies , 2010, Bioinform..

[40]  C. Parsons,et al.  Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization. , 1997, The Journal of pharmacology and experimental therapeutics.

[41]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[42]  S. Erhardt,et al.  Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. , 2002, Acta physiologica Scandinavica.

[43]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[44]  B. Brew,et al.  Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection , 2001, Journal of neurochemistry.

[45]  S. Powell,et al.  Role of the NMDA-receptor in Prepulse Inhibition in the Rat , 2010, International journal of tryptophan research : IJTR.

[46]  F. Moroni,et al.  Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. , 1999, European journal of pharmacology.

[47]  K. Blennow,et al.  Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia , 2005, Schizophrenia Research.

[48]  J. Schröder,et al.  Activation of brain interleukin-1β in schizophrenia , 2009, Molecular Psychiatry.

[49]  R. Schwarcz,et al.  The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications , 2001, The Journal of Neuroscience.

[50]  R. Schwarcz,et al.  The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. , 2001, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  R. Schwarcz,et al.  Impaired kynurenine pathway metabolism in the prefrontal cortex of individuals with schizophrenia. , 2011, Schizophrenia bulletin.

[52]  O. Andreassen,et al.  The Genetic Structure of the Swedish Population , 2011, PloS one.

[53]  R. Schwarcz,et al.  Kynurenines in the mammalian brain: when physiology meets pathology , 2012, Nature Reviews Neuroscience.

[54]  N. Craddock,et al.  The genetics of schizophrenia and bipolar disorder: dissecting psychosis , 2005, Journal of Medical Genetics.

[55]  Eden R Martin,et al.  A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms , 2008, Genetic epidemiology.

[56]  F. Moroni,et al.  Modulation of Quinolinic and Kynurenic Acid Content in the Rat Brain: Effects of Endotoxins and Nicotinylalanine , 1991, Journal of neurochemistry.

[57]  O. Andreassen,et al.  Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls. , 2012, Journal of psychiatry & neuroscience : JPN.

[58]  L. Clerkin,et al.  Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat , 2003, Neuropsychopharmacology.

[59]  K. Blennow,et al.  Lower CSF HVA and 5-HIAA in bipolar disorder type 1 with a history of childhood ADHD , 2009, Journal of Neural Transmission.

[60]  R. Schwarcz,et al.  Increased cortical kynurenate content in schizophrenia , 2001, Biological Psychiatry.

[61]  M. Geyer,et al.  Endogenous kynurenic acid disrupts prepulse inhibition , 2004, Biological Psychiatry.

[62]  E. Jönsson,et al.  Cerebrospinal fluid kynurenic acid in male patients with schizophrenia – correlation with monoamine metabolites , 2007, Acta Neuropsychiatrica.

[63]  Gilles J Guillemin,et al.  Characterization of the Kynurenine Pathway in Human Neurons , 2007, The Journal of Neuroscience.

[64]  R. Schwarcz,et al.  Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain , 2006, Journal of Neural Transmission.

[65]  M. Landén,et al.  Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder , 2012, Bipolar disorders.

[66]  S. Erhardt,et al.  Clozapine interacts with the glycine site of the NMDA receptor: electrophysiological studies of dopamine neurons in the rat ventral tegmental area. , 2008, Life sciences.

[67]  C. Grossman,et al.  Kynurenic acid antagonises responses to NMDA via an action at the strychnine-insensitive glycine receptor. , 1988, European journal of pharmacology.

[68]  K N Roy Chengappa,et al.  Identifying and treating cognitive impairment in bipolar disorder. , 2009, Bipolar disorders.

[69]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[70]  L Elliot Hong,et al.  Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes. , 2011, Archives of general psychiatry.