Biometric and Measured Genetic Research on Smoking

描述(由申请人提供)： 该计划项目的长期目标是利用尼古丁研究联盟作为协调和维持NIH几个独立项目的研究活动的媒介，更好地了解导致吸烟和尼古丁依赖增加的因素。具体目标是(A)确定高度可遗传的潜在因素(内表型)，以更准确地描述吸烟行为的过程和原因；(B)使用双生子遗传学方法估计内表型的遗传力(占变异的比例)；以及(C)测试内表型与特定候选基因的关联。将在三个相关项目的背景下使用生物测定和测量遗传学方法进行系统调查：项目A，尼古丁反应性的行为遗传学，将试图量化协调和不协调(同卵和异卵；MZ/DZ)双胞胎及其兄弟姐妹对尼古丁依赖吸烟的遗传贡献，重点是作为表型指标的最初对尼古丁的敏感性和慢性耐受性。项目B，烟草使用的行为表型和环境因素，审查了吸烟的遗传和环境变异源对吸烟的贡献，包括依赖维度、终生烟草使用里程碑和轨迹，以及在和谐和不和谐的MZ/DZ双胞胎中进行的一系列心理测量研究和行为遗传学研究中的复合表型，以确定内在表型。项目C是相关和不相关个人中吸烟的候选基因，将涉及到在(A)无关吸烟者和从不吸烟者中使用病例对照设计和(B)在吸烟者及其亲生父母中使用亲子三重设计来确定与项目A和B中确定的内表型的基因关联的~60个吸烟易感基因的检查。三个核心支持项目的活动：管理核心，尼古丁研究联盟的协调中心，负责沟通、整合和质量控制。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。数据管理和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遗传分析。与健康相关。拟议的计划项目构成了对个人生物、行为和环境因素如何结合在一起并相互作用以造成烟草依赖的系统调查。识别环境和行为危险因素以及更准确地描述吸烟的表型和基因类型是阐明吸烟潜在机制的关键下一步。这些知识将对吸烟的病因和发展提供新的见解，并应改善目前对吸烟的理解，目前仍在很大程度上是描述性的。

DESCRIPTION (provided by applicant): 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 environmental factors 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 genes for 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.