Multigeneration Study of Nicotine Dependence Phenotypes

吸烟受到遗传因素的强烈影响，但已证明很难确定影响吸烟行为的特定基因。在阐明吸烟的遗传基础方面取得进展的主要障碍可能是难以确定吸烟行为（或表型）的最相关方面。我们将在新英格兰家庭研究的前五年开展的工作的基础上，开发表型，使我们能够描述家庭对吸烟行为的影响（遗传和环境）。已经完成的数据收集和这里提出的数据收集将产生至少500个核心家庭， 父母和至少2个成年后代。我们已经确定了大约900个有两个幸存父母和至少两个后代的家庭，并从其中560个家庭中评估了一个或多个成员。另外1200项评估将完成总共500个所寻求类型的四边形。我们将收集终生吸烟轨迹、尼古丁依赖、相关人格特征、物质使用和共病精神障碍的详细测量结果， 遗传物质我们将使用多变量结构方程对我们的吸烟行为细粒度测量进行建模，以阐明吸烟相关性状的“家族结构”，我们预计这些细粒度测量相对于更基本的吸烟测量将显示出更大的“家族性”。我们将研究选择性交配对家庭聚集的影响，并研究家庭吸烟行为脆弱性的阶段性模型，这些模型取决于先前的行为。我们将 调查吸烟行为的不同阶段以及烟草和其他物质使用之间的共同和不同责任。我们将评估关键环境条件作为尼古丁依赖的潜在风险因素和/或吸烟行为中兄弟姐妹相似性的调节因子的影响。在这项长期前瞻性研究的丰富环境变量中，我们强调了母亲在怀孕期间吸烟， 家庭社会经济特征、父母精神病理学和幼儿行为和认知功能。使用TTURC-1中开发的广泛的吸烟相关行为电池，我们将使用项目反应理论和潜在类别分析识别新的替代吸烟表型（数量性状和/或“亚型”），并评估其家族和非家族决定因素。未来的分子遗传学分析将强调最大限度地确定家族替代表型。

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.