Beyond Association: Predictive Modeling of Nicotine Dependance

烟草使用，主要是吸烟，是世界上可预防死亡的最大来源，仅在美国就造成了超过1.6亿美元的健康相关经济损失。尼古丁依赖是吸烟者继续吸烟的主要原因，并且大多数无辅助戒烟尝试在一周内失败。众所周知，尼古丁依赖具有遗传成分，但它是一种复杂的性状，即，没有单一的基因是尼古丁依赖的原因。因此，研究人员和资助机构投入了相当大的努力和支持，通过全基因组扫描来确定该性状的遗传基础，使我们在确定尼古丁依赖的全球遗传预测因子方面处于独特的地位。本研究提出通过实现两个特定目标来实现NIDA资助的尼古丁依赖性协作遗传研究（COGEND）全基因组数据的承诺：（1）使用称为贝叶斯网络的尖端计算方法来识别尼古丁依赖复杂性状的遗传变异集，以及（2）在完全独立的人群中验证预后模型。这一提议代表了一个更广泛的研究计划的第一步，该计划旨在发现尼古丁依赖背后复杂的相互作用网络。该计划的最终结果将提供一种临床工具，该工具将准确评估依赖风险，允许个性化预防措施，阐明依赖的分子过程，并为尼古丁成瘾的药物治疗提名新的靶点。尼古丁依赖给个人和社会带来了巨大的负担。遗传因素至少是造成这种情况的一部分原因，NIDA已经资助了一项名为COGEND的研究，该研究检查了尼古丁依赖者和非尼古丁依赖者的40，000多个遗传变异。我们建议使用尖端技术来分析这个大型数据集，以确定尼古丁依赖的有效预测模型，这将有助于我们预测，诊断和治疗这种疾病。

DESCRIPTION (provided by applicant): Tobacco use, primarily cigarette smoking, is the greatest source of preventable mortality in the world and costs over $160 million in health-related economic losses in the U.S. alone. Nicotine dependence is the primary reason that smokers continue smoking and that most unassisted quit attempts fail within a single week. It is known that nicotine dependence has a genetic component, but that it is a complex trait, i.e., no single gene is responsible for nicotine dependence. Thus, researchers and funding agencies have devoted considerable effort and support to identifying the genetic underpinnings of the trait through whole genome scans, putting us in a unique position to identify global genetic predictors of nicotine dependence. This study proposes to realize the promise of the NIDA-funded Collaborative Genetic Study of Nicotine Dependence (COGEND) whole genome data through the accomplishment of two specific aims: (1) to identify the set of genetic variations underlying the complex trait of nicotine dependence using a cutting-edge computational method called Bayesian networks and (2) to validate the prognostic model in an entirely independent population. This proposal represents the very first step of a broader research program aimed at discovering the complex network of interactions underpinning nicotine dependence. The ultimate result of this program will provide a clinical tool, which will accurately assess the risk of dependency, allow for individualized preventive measures, elucidate the molecular processes of dependence and nominate novel targets for the pharmaceutical treatment of nicotine addiction. Nicotine dependence places an enormous burden on individuals and society. Genetic factors are responsible for at least some part of the condition, and the NIDA has already funded a study, called COGEND, that examined over 40,000 genetic variations in people who were nicotine dependent and who were not nicotine dependent. We propose to use cutting-edge techniques to analyze this large dataset to identify a valid predictive model of nicotine dependence that will help us predict, diagnose, and treat this condition.