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MAPK14 and CNR1 gene variant interactions: effects on brain volume deficits in schizophrenia patients with marijuana misuse

Published online by Cambridge University Press:  31 July 2012

O. E. Onwuameze ,
K. W. Nam ,
E. A. Epping ,
T. H. Wassink ,
S. Ziebell ,
N. C. Andreasen  and
B.-C. Ho
O. E. Onwuameze
Affiliation:
Department of Psychiatry, Southern Illinois University Medical School, Springfield, IL, USA
K. W. Nam
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
E. A. Epping
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
T. H. Wassink
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
S. Ziebell
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
N. C. Andreasen
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
B.-C. Ho*
Affiliation:
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA
*
*Address for correspondence: Dr B.-C. Ho, Department of Psychiatry, W278 GH, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. (Email: [email protected])
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Abstract

Background

Adolescent marijuana use is associated with increased risk for schizophrenia. We previously reported that marijuana misuse in conjunction with specific cannabinoid receptor 1 (CNR1) genetic variants (rs12720071-G-allele carriers) contributed to white-matter (WM) brain volume deficits in schizophrenia patients. In this study, we assessed the influence of another cannabinoid-related gene, mitogen-activated protein kinase 14 (MAPK14), and potential MAPK14–CNR1 gene–gene interactions in conferring brain volume abnormalities among schizophrenia patients with marijuana abuse/dependence. MAPK14 encodes a member of the MAPK family involved in diverse cellular processes, including CNR1-induced apoptosis.

Method

We genotyped 235 schizophrenia patients on nine MAPK14 tag single nucleotide polymorphisms (tSNPs). Approximately one quarter of the sample had marijuana abuse or dependence. Differential effects of MAPK14 tSNPs on brain volumes across patients with versus without marijuana abuse/dependence were examined using ANCOVA.

Results

Of the MAPK14 tSNPs, only rs12199654 had significant genotype effects and genotype × marijuana misuse interaction effects on WM volumes. rs12199654-A homozygotes with marijuana abuse/dependence had significantly smaller total cerebral and lobar WM volumes. The effects of MAPK14 rs12199654 on WM volume deficits remained significant even after controlling for the CNR1 rs12720071 genotype. There were significant main effects of the MAPK14 CNR1 diplotype and diplotype × marijuana interaction on WM brain volumes, with both genetic variants having additive contributions to WM volume deficits only in patients with marijuana misuse.

Conclusions

Given that CNR1-induced apoptosis is preceded by increased MAPK phosphorylation, our study suggests that potential MAPK14–CNR1 gene–gene interactions may mediate brain morphometric features in schizophrenia patients with heavy marijuana use.

Keywords

Cannabisepistasisgene–environment interactionMRIwhite matter
Type
Original Articles
Information
Psychological Medicine , Volume 43 , Issue 3 , March 2013 , pp. 619 - 631
Copyright
Copyright © Cambridge University Press 2012

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