The Collaborative Genetic Study of Nicotine Dependence

描述(申请人提供)：此申请是尼古丁依赖的合作遗传学研究的5年续期。通过全基因组关联和候选基因研究，我们成功地确定了与尼古丁依赖发展有关的基因，如α5尼古丁胆碱能受体亚单位CHRNA5。该计划的目标是进一步识别导致吸烟和尼古丁依赖的开始和持续的基因、环境特征和生物学机制。 项目1建立在上一个资助期奠定的基础之上。该项目将使用表型改进和复杂的遗传建模来分析现有数据，包括尼古丁代谢内表型。这个项目的目标是了解基因如何影响尼古丁依赖的易感性和相关特征。 项目2将使用遗传和功能方法的组合来进一步识别特定的风险等位基因。我们将在一个独立的病例对照系列中对我们先前研究中最重要的SNPs进行基因分型。显示复制证据的基因将经过精细绘制，那些具有最令人信服的关联证据的基因将在体内和体外进行检查，以确定风险等位基因的功能后果。这将对尼古丁依赖的生物学机制提供相当大的帮助。 项目3通过整合CHRNA5的小鼠遗传模型，在程序中增加了一个翻译部分。这将确定和描述尼古丁暴露的强化和厌恶特性，以及CHRNA5/Alpha5促进尼古丁成瘾的基本神经生物学机制。 项目4考察了了解戒烟和复发的核心问题。在过去的资助期间招募的尼古丁依赖病例的后续行动将是从社区样本中对成瘾吸烟者进行的第一次纵向研究。我们将测试戒烟和复发的候选基因；测试基因的相互作用；以及测试候选基因和与戒烟和复发相关的内表型之间的关联。 我们的协同计划项目使用了一种强大的跨学科方法，为减少烟草消费和降低随后的发病率和死亡率提出了新的战略。

DESCRIPTION (provided by applicant): This application is for a 5-year renewal of the Collaborative Genetic Study of Nicotine Dependence. Through a genome wide association and candidate gene study, we successfully identified genes contributing to the development of nicotine dependence, such as the alpha5 nicotinic cholinergic receptor subunit, CHRNA5. The goals of this program are the further identification of genes, environmental features, and biological mechanisms that contribute to the onset and persistence of smoking and nicotine dependence. Project 1 builds upon the foundation laid in the past funding period. This project will use phenotypic refinement and sophisticated genetic modeling to analyze existing data, including the nicotine metabolism endophenotype. The goal of this project is to understand how genes affect the susceptibility to develop nicotine dependence and correlated characteristics. Project 2 will use a combination of genetic and functional approaches to further identify specific risk alleles. We will genotype the most significant SNPs from our previous study in an independent case control series. Genes that show evidence of replication will undergo fine mapping and those with the most compelling evidence of association will be examined in vivo and in vitro to determine functional consequences of the risk alleles. This will shed considerable light on the biological mechanisms underlying nicotine dependence. Project 3 adds a translational component to the program by incorporating mouse genetic models of Chrna5. This will identify and characterize reinforcing and aversive properties of nicotine exposure and basic neurobiological mechanisms through which Chrna5/alpha5 contributes to nicotine addiction. Project 4 examines questions central to understanding smoking cessation and relapse. The follow-up of nicotine dependent cases recruited during the past funding period will be the first longitudinal study of addicted smokers from a community based sample. We will test candidate genes for smoking cessation and relapse; test gene interactions; and test association between candidate genes and endophenotypes involved with cessation and relapse. Our synergistic program project uses a powerful trans-disciplinary approach to suggest novel strategies for reducing tobacco consumption and decreasing the morbidity and mortality that follow.