Biometric and Measured Genetic Research on Smoking

该计划项目的长期目标是更好地了解有助于 使用尼古丁研究联盟作为载体，提高对吸烟和尼古丁依赖的易感性 协调和支持来自几个独立的NIH项目的研究活动。具体目标是(A) 确定高度可遗传的潜在因素(内表型)，以更多地表征吸烟行为的过程和原因 准确；(B)使用孪生遗传法估计遗传力(占变异的比例) 内表型；以及(C)测试内表型与特定候选基因的关联。系统调查 将在三个相关项目的背景下使用生物测定方法和测量的遗传方法进行研究：项目A。 尼古丁反应性的行为遗传学，将试图量化基因对尼古丁依赖吸烟的贡献 协调和不协调(同卵和异卵；MZ/DZ)双胞胎及其兄弟姐妹，重点关注最初对 尼古丁和慢性耐受性作为表型指标。项目B，行为表型和环境因素 烟草使用，检查了遗传和环境变异来源对吸烟的贡献 一系列心理测量学研究中的依赖、终生烟草使用里程碑和轨迹，以及复合表型 并对和谐和不和谐的MZ/DZ双胞胎进行行为遗传学研究，以确定内表型。项目C。 相关和不相关个人的吸烟候选基因将涉及-60个易感基因的检查 使用病例对照设计在(A)无关吸烟者和从不吸烟者中吸烟，以及(B)在吸烟者及其生物学上 父母使用亲子三人设计来确定与项目A和B中确定的内表型的遗传关联。 三个核心支持项目的活动：行政核心、尼古丁协调中心 研究联盟，负责沟通、集成和质量控制。分析化学核心 将对每个项目的生物样本(尼古丁、可替宁、羟基可替宁)进行分析。数据管理 分析核心将提供有组织的统计设计，表型和基因数据的仓储，以及先进的 基因分析。与健康相关。建议的计划项目构成了对如何 个体的生物、行为和环境因素汇聚在一起，相互作用，造成烟草依赖。 识别环境和行为风险因素以及更准确地表征表型和基因类型 因为吸烟是阐明吸烟潜在机制的关键下一步。这样的知识将 为吸烟的病因和进展提供新的见解，并应改善目前对吸烟的理解， 这在很大程度上仍然是描述性的。

The long-range objective of this Program Project is to engender a better understanding of the factors that contribute to heightened susceptibility to smoking and nicotine dependence, using a Nicotine Research Consortium as the vehicle for coordinating and sustaining research activity derived from several independent NIH projects. Specific aims are (a) to identify highly heritable, latent factors (endophenotypes) to characterize the course and causes of smoking behavior more accurately; (b) to use twin genetic methods to estimate the heritability (proportion of variance accounted for)of endophenotypes; and (c) to test endophenotypes for association with particular candidate genes. Systematic investigations will be carried out using both biometric and measured genetic approaches in the context of three related projects: Project A. Behavioral genetics of nicotine reactivity, will attempt to quantify the genetic contribution to nicotine-dependent smoking in concordant and discordant (monozygotic and dizygotic; MZ/DZ) twins and their siblings, focusing on initial sensitivity to nicotine and chronic tolerance as phenotypic indicators. Project B, Behavioral phenotypes and environmentalfactors for tobacco use,examines the contribution of genetic and environmental sources of variation for smoking along dimensions of dependence, lifetime tobacco use milestones and trajectories, and composite phenotypes in a series of psychometric studies and behavior genetic studies in concordant and discordant MZ/DZ twins, in order to identify endophenotypes. Project C. Candidate genesfor smoking in related and unrelated individuals, will involve an examination of -60 susceptibility genes for smoking in (a) unrelated smokers and never-smokers using a case-control design and (b) in smokers and their biological parents using a parent-child trio design to determine genetic association with endophenotypes identified in Projects A and B. Three cores support the activities of the projects: The Administrative Core, the coordinating center for the Nicotine Research Consortium, is responsible for communication, integration, and quality control. The Analytical Chemistry Core will conduct analyses of biological samples (nicotine, cotinine, hydroxy-cotinine) from each project. The Data Management and Analysis Core will provide organized statistical design, warehousing of phenotype and genotype data, and advanced genetic analyses. Health relatedness. The proposed Program Project constitutes a systematic investigation of how individual biological, behavioral, and environmental factors come together and interact to create tobacco dependence. Identification of environmental and behavioral risk factors and more accurate characterization of phenotypes and genotypes for smoking constitute crucial next steps in the elucidation of underlying mechanisms for smoking. Such knowledge will confer new insights about the etiology and progression of smoking and should improve the current understanding of smoking, which is still largely descriptive.