Genetic and Environmental Risks for Smoking Characteristics and Cessation

描述（由申请人提供）：我请求通过K 08奖获得支持，以完成我从一名经过临床委员会认证、接受过流行病学研究培训的精神科医生到一名独立的戒烟遗传和环境因素转化研究员的转变。为了实现这一目标，我需要在先进的遗传学，戒烟科学和纵向研究方法方面的进一步培训和经验，使我能够进行未来的戒烟遗传学前瞻性研究。我将在高级遗传学（Laura Bierut博士、Alison Goate博士、John Rice博士和Robi Mitra博士）、戒烟科学（Timothy Baker博士和加里·斯旺博士）和纵向研究（Naomi Breslau博士、Eric约翰逊博士、Laura Bierut博士和Timothy Baker博士）等领域的专家指导下进行研究。将通过以下关于尼古丁依赖的拟议研究推进培训目标，尼古丁依赖是一个严重的公共卫生问题。一些与尼古丁依赖和戒烟相关的遗传变异已经用现代遗传学方法鉴定，但仅占少量遗传变异。我们的初步结果表明，全面的尼古丁依赖表型和前瞻性戒烟措施有更大的灵敏度，以检测遗传关联。本研究旨在填补研究文献中的空白，方法是：（1）在两个现有的互补数据集中使用全面的新表型进行尼古丁依赖的全基因组关联研究（GWAS）分析（群体与治疗样本），（2）GWAS分析的前瞻性戒烟表型，和（3）对尼古丁依赖受试者进行试点纵向随访研究，以复制研究目的2中戒烟的遗传发现，并结合环境、共病和治疗因素检查已确定的遗传风险。我们希望发现与尼古丁依赖和戒烟的精细表型特征相关的新的遗传变异。与戒烟相关的遗传风险可能不同于尼古丁依赖，这种区别将有助于将遗传风险转化为结果研究。了解遗传风险如何影响临床结果以及是否会受到治疗和共病因素的影响，不仅可以阐明尼古丁依赖的病因，为预防创造机会，还可以为个体化戒烟治疗提供必要的证据，以增加成功戒烟的可能性。这将是未来R01应用于戒烟试验的大规模前瞻性研究的基础。总之，在这个奖项结束时，我将成为一名专注于戒烟的精神病遗传学专家。通过我在先进的遗传学方法、戒烟科学和纵向分析方面的培训，沿着我在纵向数据收集和分析方面的实践经验，我将在华盛顿大学建立一个独特的戒烟研究项目，并开展一项独立的职业生涯，进行大规模的戒烟试验，这将为尼古丁依赖和相关疾病的治疗做出重要贡献。

DESCRIPTION (provided by applicant): I request support through the K08 award to complete my transition from a clinical board-certified psychiatrist with prior research training in epidemiology to an independent translational researcher in genetic and environmental factors for smoking cessation. To achieve this goal, I need further training and experience in advanced genetics, cessation science, and longitudinal research methods, to enable me to conduct future prospective studies on genetics of smoking cessation. I will be guided by experts in the fields of advanced genetics (Drs. Laura Bierut, Alison Goate, John Rice, and Robi Mitra), cessation science (Drs. Timothy Baker and Gary Swan), and longitudinal research (Drs. Naomi Breslau, Eric Johnson, Laura Bierut, and Timothy Baker). The training goals will be advanced through the following proposed research on nicotine dependence which is a serious public health problem. Some genetic variants associated with nicotine dependence and smoking cessation have been identified with modern genetic methods, but account for only a small amount of genetic variance. Our preliminary results suggest comprehensive nicotine dependence phenotypes and prospective cessation measures have greater sensitivity to detect genetic associations. This study aims to fill gaps in the research literature by conducting (1) Genome Wide Association Study (GWAS) analyses of nicotine dependence using comprehensive novel phenotypes in two existing, complementary datasets (population vs. treatment sample), (2) GWAS analyses of prospective smoking cessation phenotype, and (3) a pilot longitudinal follow up study of nicotine dependence subjects to replicate the genetic findings of smoking cessation from study aim 2, and to examine identified genetic risks jointly with environmental, comorbid, and treatment factors. We hope to uncover novel genetic variants associated with refined phenotypic characteristics of nicotine dependence and smoking cessation. Genetic risks associated with smoking cessation may be different from those for nicotine dependence, and this distinction will be useful in translating genetic risk to outcome research. Knowledge of how genetic risks influence clinical outcomes and whether they are modified by treatment and comorbid disorder factors will not only clarify the etiology of nicotine dependence to create opportunity for prevention, but also provide needed evidence for individualized cessation treatments to increase the probability of successful quitting. This will be the foundation for future R01 applications for large scale, prospective studies of smoking cessation trials. In summary, by the end of this award, I will become an expert in psychiatric genetics with a focus on smoking cessation. Through my training in advanced genetic methods, cessation science, and longitudinal analyses, along with hands on experience in longitudinal data collection and analyses, I will establish a unique smoking cessation research program at Washington University and launch an independent career conducting large scale smoking cessation trials that will make important contributions to the treatment of nicotine dependence and related disorders.