Influence of kynurenine 3-monooxygenase (KMO) gene polymorphism on cognitive function in schizophrenia

SCHIZOPHRENIA RESEARCH

卷:160

Article

Wonodi, Ikwunga¹  McMahon, Robert P.¹  Krishna, Nithin¹  Mitchell, Braxton D.²  Liu, Judy¹  Glassman, Matthew¹  Hong, L. Elliot¹  Gold, James M.¹ 

[1] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

关键词: Kynurenine;    KMO;    Genetic association;    Cognition;    P50;    Schizophrenia;   

DOI  :  10.1016/j.schres.2014.10.026

来源: Elsevier

【 摘 要 】

Background: Cognitive deficits compromise quality of life and productivity for individuals with schizophrenia and have no effective treatments. Preclinical data point to the kynurenine pathway of tryptophan metabolism as a potential target for pro-cognitive drug development. We have previously demonstrated association of a kynurenine 3-monooxygenase (KMO) gene variant with reduced KMO gene expression in postmortem schizophrenia cortex, and neurocognitive endophenotypic deficits in a clinical sample. KMO encodes kynurenine 3-monooxygenase (KMO), the rate-limiting microglial enzyme of cortical kynurenine metabolism. Aberration of the KMO gene might be the proximal cause of impaired cortical kynurenine metabolism observed in schizophrenia. However, the relationship between KMO variation and cognitive function in schizophrenia is unknown. This study examined the effects of the KMO rs2275163C>T C (risk) allele on cognitive function in schizophrenia. Methods: We examined the association of KMO polymorphisms with general neuropsychological performance and P50 gating in a sample of 150 schizophrenia and 95 healthy controls. Results: Consistent with our original report, the KMO rs2275163C>T C (risk) allele was associated with deficits in general neuropsychological performance, and this effect was more marked in schizophrenia compared with controls. Additionally, the C (Arg(452)) allele of the missense rs1053230CNT variant (KMO Arg(452)Cys) showed a trend effect on cognitive function. Neither variant affected P50 gating. Conclusions: These data suggest that KMO variation influences a range of cognitive domains known to predict functional outcome. Extensive molecular characterization of this gene would elucidate its role in cognitive function with implications for vertical integration with basic discovery. (C) 2014 Elsevier B.V. All rights reserved.

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