ACSL6 is associated with the number of cigarettes smoked and its expression is altered by chronic nicotine exposure.
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.
Department of Psychiatry and Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Jingchun
J
Chen
Darlene H
DH
Brunzell
Kia
K
Jackson
Andrew
A
van der Vaart
Jennie Z
JZ
Ma
Thomas J
TJ
Payne
Richard
R
Sherva
Lindsay A
LA
Farrer
Pablo
P
Gejman
Douglas F
DF
Levinson
Peter
P
Holmans
Steven H
SH
Aggen
Imad
I
Damaj
Po-Hsiu
PH
Kuo
Bradley T
BT
Webb
Raymond
R
Anton
Henry R
HR
Kranzler
Joel
J
Gelernter
Ming D
MD
Li
Kenneth S
KS
Kendler
Xiangning
X
Chen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics; D012907:Smoking / Q000235:genetics*; D013997:Time Factors; D055815:Young Adult
D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine; D003066:Coenzyme A Ligases; C403665:ACSL6 protein, human