) The proposed project addresses: a) the effect of in utero exposure (IUE) to nicotine and other prenatal and childhood conditions on the risk of nicotine dependence in adulthood; and b) the familial aggregation of nicotine dependence and related phenotypes. Building on current research in this area, findings from the proposed study will advance the field of nicotine research in at least two important ways. Firstly, the proposed study will use prenatal and early childhood measures collected prospectively in a large community sample, enabling statistically powerful analyses of multiple and alternative early risks for adult nicotine dependence. Secondly, through a hybrid design we examine hypotheses and anticipate future studies of gene:environment interactions in the etiology of adult nicotine dependence. We focus primarily on a specific environmental risk, in utero exposure (IUE) to nicotine both based on the strength of the existing human and animal study data and for parsimony of effort. We have developed a sampling and measurement strategy intended both to distinguish the role of IUE from other salient characteristics of pregnant women who smoke and from known sequelae of IUE that may explain or mediate any observed link between IUE and later nicotine dependence. In so doing, we are able to simultaneously investigate the predictive utility of a range of hypothesized prenatal, childhood and familial risks for adult nicotine dependence. We propose to accomplish these aims through a, multidisciplinary, multi- method longitudinal investigation. The proposed project integrates: 1) a natural history study of the smoking trajectories and associated behaviors through mid-life of subjects whose mother did and did not smoke during pregnancy; 2) a family study of sibling pairs, discordant for maternal smoking during pregnancy; 3) a sibling study of current or ex-regular smokers to investigate the familial aggregation of nicotine dependence and related phenotypes; and 4) a baseline assessment of current smokers targeted for a randomized smoking cessation trial. The resulting 40-year prospective study will: 1) determine whether nicotine dependence is elevated among adult offspring exposed in utero to nicotine; 2) investigate the mechanisms for this potential association; 3) identify prenatal, child and familial risks f adult nicotine dependence; and 4) examine patterns of familial aggregation to identify potential mechanisms for familial clustering and identify the components of nicotine dependence that may be familial. These data will provide an empirical basis for conducting future studies of susceptibility genes for nicotine dependence.
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