Tobacco use is a leading contributor to disability and death worldwide. Smoking behaviors, including onset ofsmoking, smoking persistence (current smoking versus past smoking), and nicotine dependence, cluster infamilies, and large twin studies indicate that this clustering reflects genetic factors. Using over 2.4 millionSingle Nucleotide Polymorphisms (SNPs), we have performed a genome wide association (GWA) studyusing nicotine dependent smokers as cases and non-dependent smokers as controls. In addition, wetargeted over 300 candidate genes for genotyping in the same series of cases and controls. Nicotinemetabolites were measured in the blood of a subset of 196 smokers from our genetic study. Our GWAfindings implicate several novel genes, including Neurexin 1, (NRXN1) in the development of nicotinedependence as well as identify a known candidate gene, the Ii3 nicotinic receptor. Significant associationswere also observed in 23 candidate genes, including several nicotinic receptor (nAChR) genes. The goal ofthe current study is to follow up these findings to identify specific functional alleles that influence risk fornicotine dependence and to use in vivo measures of nicotine metabolism to identify functional alleles innicotine 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 controlseries; 2) Performing fine mapping of genes that show evidence of replication and sequencing candidategenes, where necessary, to identify putative functional alleles; 3) Sequencing genes encoding the majornicotine metabolizing enzymes in individuals from the top and bottom tenth percentiles of the plasmacotinine, N-oxidation and N-glucuronidation distributions. Putative functional alleles in each gene will then begenotyped in all 196 individuals in whom nicotine metabolism was measured to determine whether thealleles are associated with differences in nicotine metabolism and, in the case control series, to determinewhether they affect risk for nicotine dependence. Lastly, functional studies will be performed to determine themechanism by which they affect risk for nicotine dependence. Initial studies will focus on the CHRNA5 genebecause 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 nicotinedependence.
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