ACSL6 Is Associated with the Number of Cigarettes Smoked and Its Expression Is Altered by Chronic Nicotine Exposure

Authors

Jingchun Chen, Virginia Commonwealth UniversityFollow
Darlene H. Brunzell, Virginia Commonwealth UniversityFollow
Kia J. Jackson, Virginia Commonwealth University
Andrew van der Vaart, University of Virginia
Jennie Z. Ma, University of Virginia
Thomas J. Payne, University of Mississippi Medical Center
Richard Sherva, University School of Medicine
Lindsay A. Farrer, University School of Medicine
Pablo Gejman, NorthShore University HealthSystem Research Institute
Douglas F. Levinson, Stanford University
Peter Holmans, Cardiff University School of Medicine
Steven H. Aggen, Virginia Commonwealth UniversityFollow
Imad Damaj, Virginia Commonwealth University
Po-Hsiu Kuo, National Taiwan University
Bradley T. Webb, Virginia Commonwealth UniversityFollow
Raymond Anton, Medical University of South Carolina
Henry R. Kranzler, University of Pennsylvania
Joel Gelemter, Yale University School of Medicine
Minf D. Li, University of Virginia
Kenneth S. Kendler, Virginia Commonwealth UniversityFollow
Xiangning Chen, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2011

Journal/Book/Conference Title

PLOS ONE

Volume

6

DOI of Original Publication

10.1371/journal.pone.0028790

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0028790

Date of Submission

November 2014

Abstract

Individuals with schizophrenia tend to be heavy smokers and are at high risk for tobacco dependence. However, the nature of the comorbidity is not entirely clear. We previously reported evidence for association of schizophrenia with SNPs and SNP haplotypes in a region of chromosome 5q containing the SPEC2, PDZ-GEF2 and ACSL6 genes. In this current study, analysis of the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample showed similar pattern of association with number of cigarettes smoked per day (numCIG) for the same region. To further test if this locus is associated with tobacco smoking as measured by numCIG and FTND, we conducted replication and meta-analysis in 12 independent samples (n>16,000) for two markers in ACSL6 reported in our previous schizophrenia study. In the meta-analysis of the replication samples, we found that rs667437 and rs477084 were significantly associated with numCIG (p = 0.00038 and 0.00136 respectively) but not with FTND scores. We then used in vitro and in vivo techniques to test if nicotine exposure influences the expression of ACSL6 in brain. Primary cortical culture studies showed that chronic (5-day) exposure to nicotine stimulated ACSL6 mRNA expression. Fourteen days of nicotine administration via osmotic mini pump also increased ACSL6 protein levels in the prefrontal cortex and hippocampus of mice. These increases were suppressed by injection of the nicotinic receptor antagonist mecamylamine, suggesting that elevated expression ofACSL6 requires nicotinic receptor activation. These findings suggest that variations in theACSL6 gene may contribute to the quantity of cigarettes smoked. The independent associations of this locus with schizophrenia and with numCIG in non-schizophrenic subjects suggest that this locus may be a common liability to both conditions.

Rights

Copyright: © 2011 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Psychiatry Publications