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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
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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
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Journal Article
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
2014
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Acids
/ Adult
/ Adult and adolescent clinical studies
/ Aged
/ Alleles
/ Biological and medical sciences
/ Biopsy
/ Bipolar Disorder - complications
/ Bipolar Disorder - diagnosis
/ Bipolar Disorder - metabolism
/ Dopamine
/ Female
/ Genetic Predisposition to Disease - genetics
/ Genomics
/ Humans
/ Kynurenic Acid - cerebrospinal fluid
/ Kynurenine 3-Monooxygenase - biosynthesis
/ Kynurenine 3-Monooxygenase - genetics
/ Male
/ Medicine
/ mRNA
/ Prefrontal Cortex - metabolism
/ Psychology. Psychoanalysis. Psychiatry
/ Psychotic Disorders - complications
/ Psychotic Disorders - genetics
/ Psychotic Disorders - metabolism
