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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

Molecular Psychiatry volume 19, pages 334–341 (2014)Cite this article

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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 Arg452 allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg452 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 Arg452 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.

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Acknowledgements

We thank Dzana Hukic, Inger Römer Ek, Martina Wennberg, Agneta Carlswärd-Kjellin, Stina Stadler and Emarndeena Haji Cheteh for assistance. For microarray data, we acknowledge Stanley Medical Research Institute and Drs Bahn, Kato, Vawter, Young, Dobrin and Altar (Supplementary Text S2). This project was funded by Karolinska Institutet, Stockholm County Council (ALF), Swedish Research Council, Söderström-Königska Foundation, Royal Physiographic Society in Lund, Fredrik and Ingrid Thuring Foundation, Åhléns-stiftelsen and Psychiatry Southwest, Stockholm. The research was further supported by the William Lion Penzner Foundation (Department of Psychiatry and Human Behavior, University of California, Irvine), and NIMH Grant R01MH085801 (MPV).

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Authors and Affiliations

  1. Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden

    C Lavebratt, L Frisén, U Ösby & M Schalling

  2. Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

    C Lavebratt, L Frisén, P Nikamo, U Ösby & M Schalling

  3. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    S Olsson, P Nikamo, G Engberg & S Erhardt

  4. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    L Backlund & L Frisén

  5. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    C Sellgren & M Landén

  6. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    L Priebe & S Cichon

  7. Institute of Human Genetics, University of Bonn, Bonn, Germany

    L Priebe & S Cichon

  8. Department of Clinical Sciences, University Hospital, Lund, Sweden

    L Träskman-Bendz

  9. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Center Juelich, Juelich, Germany

    S Cichon

  10. Department of Psychiatry and Human Behavior, Functional Genomics Laboratory, University of California Irvine School of Medicine, Irvine, CA, USA

    M P Vawter

  11. Department of Psychiatry, Tiohundra AB, Norrtälje, Sweden,

    U Ösby

  12. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

    M Landén

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Lavebratt, C., Olsson, S., Backlund, L. et al. 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. Mol Psychiatry 19, 334–341 (2014). https://doi.org/10.1038/mp.2013.11

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