Nicotine Dependence to Smoking Cessation: Sequencing Common and Rare Variants

描述（由申请人提供）：在过去的5年里，技术革命以惊人的速度推动了遗传研究，并确定了对吸烟行为的明确遗传贡献。我们的小组是第一个报告尼古丁依赖与染色体15q25.1区域的关联，该区域包括CHRNA 5-CHRNA 3-CHRNB 4胆碱能尼古丁受体亚单位基因。尼古丁依赖、肺癌和慢性阻塞性肺疾病的最强遗传关联研究结果随后集中在该区域。我们的研究和一些荟萃分析令人信服地表明，CHRNA 6-CHRNB 3受体亚基和尼古丁代谢基因CYP 2A 6中的SNP也与重度吸烟和尼古丁依赖相关。该项目的目标是进一步确定和表征尼古丁依赖的遗传发现，并整合这些关联如何有助于成功戒烟。具体目标1是对已鉴定的变异体进行分类、表征和测试，并对烟碱受体基因和烟碱代谢基因进行精细定位。这一目标将建立在遗传疾病研究中心（CIDR）的定制靶向测序的基础上，对近3,000名尼古丁依赖或非依赖受试者的尼古丁受体和尼古丁代谢基因的变异进行编目。具体目标2是在大规模研究中评估尼古丁依赖的遗传相关性，包括我们自己的复制样本，并通过参与荟萃分析和联盟。具体目标3是在大规模研究中评估戒烟的遗传相关性。我们将积极开展并参与评估戒烟相关表型的荟萃分析和联盟，我们还将建立与Timothy Baker博士的合作，他沿着了来自辉瑞伐尼克兰临床试验（Chantix（R））的表型和遗传数据。该项目将继续加速发现控制尼古丁依赖发展的分子途径的变化，并扩展我们对戒烟的理解。通过利用我们以前开发的资源和合作，这项研究将沿着基因组科学的前沿迈出重要的下一步，并将该领域推向了解尼古丁依赖和戒烟遗传学的下一个层次。

DESCRIPTION (provided by applicant): A revolution in technology has moved genetic studies forward at a remarkable pace over the last 5 years, and clear genetic contributions to smoking behavior have been identified. Our group was the first to report the association of nicotine dependence with the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotine receptor subunit genes. The strongest genetic association findings for nicotine dependence, lung cancer and chronic obstructive pulmonary disease then converged to implicate this region. Our studies and several meta-analyses have convincingly shown that SNPs in the CHRNA6-CHRNB3 receptor subunits and nicotine metabolizing gene CYP2A6 are also associated with heavy smoking and nicotine dependence. The goal of this project is to further identify and characterize genetic findings for nicotine dependence and to integrate how these associations contribute to successful smoking cessation. Specific Aim 1 is to catalogue, characterize, and test identified variants and fine map nicotinic receptor genes and nicotine metabolizing genes. This aim will build upon custom targeted sequencing from the Center for Inherited Disease Research (CIDR) to catalogue variation in the nicotinic receptors and nicotine metabolizing genes in almost 3,000 nicotine dependent or non-dependent subjects. Specific Aim 2 is to evaluate genetic associations for nicotine dependence in large-scale studies, including our own replication sample and through participation in meta-analyses and consortia. Specific Aim 3 is to evaluate genetic associations for smoking cessation in large-scale studies. We will actively generate and participate in meta-analyses and consortia assessing smoking cessation related phenotypes, and we will also build upon our collaboration with Dr. Timothy Baker, who has data from smoking cessation trials along with phenotypic and genetic data from the Pfizer clinical trial of varenicline (Chantix(R)). This project will continueto accelerate the discovery of variation in molecular pathways that govern the development of nicotine dependence and extend our work toward the understanding of smoking cessation. By capitalizing on the resources and collaborations we have previously developed, this study will take an important next step along the cutting edge of genomic science and move the field to the next level of understanding the genetics of nicotine dependence and smoking cessation.