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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.

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