Tobacco use is a leading contributor to disability and death worldwide. Smoking behaviors, including onset of smoking, smoking persistence (current smoking versus past smoking), and nicotine dependence, cluster in families, and large twin studies indicate that this clustering reflects genetic factors. Using over 2.4 million Single Nucleotide Polymorphisms (SNPs), we have performed a genome wide association (GWA) study using nicotine dependent smokers as cases and non-dependent smokers as controls. In addition, we targeted over 300 candidate genes for genotyping in the same series of cases and controls. Nicotine metabolites were measured in the blood of a subset of 196 smokers from our genetic study. Our GWA findings implicate several novel genes, including Neurexin 1, (NRXN1) in the development of nicotine dependence as well as identify a known candidate gene, the Ii3 nicotinic receptor. Significant associations were also observed in 23 candidate genes, including several nicotinic receptor (nAChR) genes. The goal of the current study is to follow up these findings to identify specific functional alleles that influence risk for nicotine dependence and to use in vivo measures of nicotine metabolism to identify functional alleles in nicotine metabolizing enzymes that may influence risk for dependence. We will achieve these goals by 1) Genotyping the most significant SNPs from each stage of our prior study in an independent case control series;2) Performing fine mapping of genes that show evidence of replication and sequencing candidate genes, where necessary, to identify putative functional alleles;3) Sequencing genes encoding the major nicotine metabolizing enzymes in individuals from the top and bottom tenth percentiles of the plasma cotinine, N-oxidation and N-glucuronidation distributions. Putative functional alleles in each gene will then be genotyped in all 196 individuals in whom nicotine metabolism was measured to determine whether the alleles are associated with differences in nicotine metabolism and, in the case control series, to determine whether they affect risk for nicotine dependence. Lastly, functional studies will be performed to determine the mechanism by which they affect risk for nicotine dependence. Initial studies will focus on the CHRNA5 gene because our preliminary data in two independent studies suggest that a non-synonymous coding change (D398N) results in changes in the sensitivity of the receptor that lead to changes in risk for nicotine dependence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA089392-08
Application #
8092596
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
8
Fiscal Year
2010
Total Cost
$350,510
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wang, Kesheng; Chen, Xue; Ward, Stephen C et al. (2018) CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model. Int J Obes (Lond) :
Guerreiro, Rita; Ross, Owen A; Kun-Rodrigues, Celia et al. (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64-74
Chiu, Ami; Hartz, Sarah; Smock, Nina et al. (2018) Most Current Smokers Desire Genetic Susceptibility Testing and Genetically-Efficacious Medication. J Neuroimmune Pharmacol 13:430-437
Culverhouse, R C; Saccone, N L; Horton, A C et al. (2018) Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol Psychiatry 23:133-142
Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
Liu, Dungang; Zhang, Heping (2018) Residuals and Diagnostics for Ordinal Regression Models: A Surrogate Approach. J Am Stat Assoc 113:845-854
Glasheen, Cristie; Johnson, Eric O; Saccone, Nancy L et al. (2018) Is the Fagerström test for nicotine dependence invariant across secular trends in smoking? A question for cross-birth cohort analysis of nicotine dependence. Drug Alcohol Depend 185:127-132
Teitelbaum, A M; Murphy, S E; Akk, G et al. (2018) Nicotine dependence is associated with functional variation in FMO3, an enzyme that metabolizes nicotine in the brain. Pharmacogenomics J 18:136-143
Hancock, D B; Guo, Y; Reginsson, G W et al. (2018) Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. Mol Psychiatry 23:1-9
Cabana-Domínguez, Judit; Arenas, Concepció; Cormand, Bru et al. (2018) MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence. Transl Psychiatry 8:173

Showing the most recent 10 out of 268 publications