Approximately 20% of adult deaths in the U.S. are attributable to cigarette smoking. Smoking cessation greatly reduces the risk of disease and premature death and increasing cessation is key to decreasing tobacco-attributable disease. Understanding gene x environment interactions predictive of smoking cessation would allow for treatment matching to increase smoking cessation and decrease tobacco-related morbidity and mortality. Tobacco dependence and cessation are complex behaviors influenced principally by nicotine. It has been estimated that 25-50% of the variability in smoking initiation and cessation results from genetic factors. This proposal focuses on genetic markers in three prime pathways (dopamine, serotonin, and nicotine metabolism) using data collected from initial participants in the NCI's Community Trial for Smoking Cessation (COMMIT) to examine genetic and environmental factors involved in smoking cessation. Begun in 1988, COMMIT is the largest randomized community-based trial on smoking ever conducted and thus presents an excellent opportunity for molecular genetics studies. In 2001, 7,329 respondents completed this investigative team's follow-up survey and 6,728 consented to participating in future research studies. This project proposes linking DNA data obtained from mouthwash rinse samples obtained through the mail from all remaining cohort members with past and newly collected survey data on smoking behavior, indicators of depression, and ethnicity in order to assess gene x environment factors related to smoking cessation. The investigative team helped initiate the COMMIT study and has an extensive track record of multidiseiplinary tobacco research. Our primary aim is to examine patterns of tobacco use in relation to genetic factors including the following genes: DRD2 and DRD4 (dopamine receptor); SLC6A3 (dopamine transporter); DBH, COMT, MAOA (dopamine metabolism); 5-HTT (serotonin transporter), and CYP2A6, CYP2B6, and CYP2D6 (nicotine metabolism). Additional genes will be reviewed and nominated for analysis by our internal review as well as by our external advisory committee. Outcomes include smoking cessation and relapse, amount smoked, and other indicators of nicotine dependence. Specific gene x environment interactions include genetic markers and indicators of depression and pharmacotherapy utilization while examining cessation outcomes. A secondary aim is to analyze how genetic factors modify smoking cessation by other covariates including demographics, past smoking behavior, and tobacco control policies, as well as to examine how genetic factors may be associated with cigarette product characteristic selection.