Smoking is strongly influenced by genetic factors, but it has proven very difficult to identify specific genes influencing smoking behavior. The major impediment to progress in explicating the genetic basis of smoking may be difficulty specifying the most relevant aspects of smoking behavior (or phenotypes) to study. We will build upon work carried out during the first five years of the New England Family Study to develop phenotypes that will allow us to characterize familial influences (both genetic and environmental) on smoking behavior. Already completed data collection and that proposed here will yield a minimum of 500 nuclear families comprising 2 parents and a minimum of 2 adult offspring. We have already identified about 900 families with two surviving parents and at least two offspring and assessed one or more members from 560 of these. An additional 1200 assessments would complete a total of 500 quads of the type sought. We will collect detailed measures of lifetime smoking trajectory, nicotine dependence, related personality traits, substance use and co-morbid psychiatric disorders, and genetic material. We will explicate the """"""""familial architecture"""""""" of smoking-related traits using multivariate structural equation nodeling of our fine-grained measures of smoking behavior that we expect will show greater 'familiality', relative to more basic measures of smoking. We will examine effects of assortative mating on familial aggregation and examine staged models of familial vulnerability for smoking behaviors that are contingent on prior behaviors. We will investigate common and distinct liability both within various stages of smoking behavior and between tobacco and other substance use. We will evaluate the influences of key environmental conditions as potential risk factors for nicotine dependence and/or moderators of sibling similarity in smoking behaviors. Among the rich set of environmental variables in this long-term prospective study, we have highlighted maternal smoking during pregnancy, family socioeconomic characteristics, parental psychopathology, and early childhood behavioral and cognitive function. Using the extensive battery of smoking-related behavior developed in TTURC-1, we will identify novel, alternative smoking phenotypes (quantitative traits and/or 'subtypes') using item response theory and latent class analyses and assess their familial and non-familial determinants. There will be an emphasis on identifying maximally familial alternative phenotypes for future molecular genetic analyses.
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