ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure.

Jingchun Chen,Darlene H Brunzell,Po-Hsiu Kuo,Joel Gelernter,Henry R Kranzler,Imad Damaj,Xiangning Chen,Kenneth S Kendler,Bradley T Webb,Ming D Li,Thomas J Payne,Steven H Aggen,Lindsay A Farrer,Andrew Van Der Vaart,Richard Sherva,Douglas F Levinson,Pablo V Gejman ,Z Jennie ,Raymond F Anton ,Peter Alan Holmans ,Kia J Jackson

doi:10.1371/journal.pone.0028790

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 of ACSL6 requires nicotinic receptor activation. These findings suggest that variations in the ACSL6 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.

Highlights

Smoking is an important public health problem, and smokingrelated diseases take a heavy toll on society
In our analyses of smoking phenotypes for the control subjects of the Molecular Genetics of Schizophrenia (MGS) sample, we found substantial association in the acyl CoA synthetase long chain 6 (ACSL6) gene with a phenotype based on a categorized number of cigarettes smoked per day
Of the 24 markers typed in our previous schizophrenia study [9], rs667437 and rs477086 in the ACSL6 gene are amongst the markers with the lowest p values for number of cigarettes smoked per day (numCIG) (p = 0.0005; see Figure 1 and Table 1)

Summary

Introduction

Smoking is an important public health problem, and smokingrelated diseases take a heavy toll on society. Many studies have shown that smoking is addictive and both genetic and environmental factors influence smoking behaviors. With the application of genome-wide association study (GWAS) approach, genetic studies of smoking have made significant progress. One example is the identification of the CHRNA5/ CHRNA3/CHRNB4 locus as a risk factor for smoking quantity [1,2,3]. This and other established loci explain only a small proportion of the heritability observed for smoking behaviors. Many more genes remain to be identified for their effects on smoking behaviors

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Results

Conclusion