Examination of the Involvement of Cholinergic-Associated Genes in Nicotine Behaviors in European and African Americans.
BACKGROUND
Cigarette smoking is a physiologically harmful habit. Nicotinic acetylcholine receptors (nAChRs) are bound by nicotine and upregulated in response to chronic exposure to nicotine. It is known that upregulation of these receptors is not due to a change in mRNA of these genes, however, more precise details on the process are still uncertain, with several plausible hypotheses describing how nAChRs are upregulated. We have manually curated a set of genes believed to play a role in nicotine-induced nAChR upregulation. Here, we test the hypothesis that these genes are associated with and contribute risk for nicotine dependence (ND) and the number of cigarettes smoked per day (CPD).


METHODS
Studies with genotypic data on European and African Americans (EAs and AAs, respectively) were collected and a gene-based test was run to test for an association between each gene and ND and CPD.


RESULTS
Although several novel genes were associated with CPD and ND at P < 0.05 in EAs and AAs, these associations did not survive correction for multiple testing. Previous associations between CHRNA3, CHRNA5, CHRNB4 and CPD in EAs were replicated.


CONCLUSIONS
Our hypothesis-driven approach avoided many of the limitations inherent in pathway analyses and provided nominal evidence for association between cholinergic-related genes and nicotine behaviors.


CONCLUSIONS
We evaluated the evidence for association between a manually curated set of genes and nicotine behaviors in European and African Americans. Although no genes were associated after multiple testing correction, this study has several strengths: by manually curating a set of genes we circumvented the limitations inherent in many pathway analyses and tested several genes that had not yet been examined in a human genetic study; gene-based tests are a useful way to test for association with a set of genes; and these genes were collected based on literature review and conversations with experts, highlighting the importance of scientific collaboration.
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA.
Whitney E
WE
Melroy-Greif
Massachusetts Institute of Technology, Cambridge, MA.
Matthew A
MA
Simonson
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO.
Robin P
RP
Corley
Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.
Sharon M
SM
Lutz
Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO.
John E
JE
Hokanson
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO.|Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO.
Marissa A
MA
Ehringer
D001741:Black or African American / Q000235:genetics / Q000706:statistics & numerical data; D006801:Humans; D009538:Nicotine / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000235:genetics*; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data
D011978:Receptors, Nicotinic; D009538:Nicotine