HUMAN GENETIC VARIATION IN SMOKING AND ADDICTION RISK

描述（由申请人提供）：烟草使用，主要是通过吸烟，是美国和世界上可预防死亡的最大原因。其他物质成瘾会增加公共卫生负担。该项目的总体目标是确定改变吸烟和尼古丁依赖风险的基因变异，并评估它们在确定其他物质依赖风险方面的作用。在胆碱能尼古丁受体亚基基因簇CHRNA5-CHRNA3-CHRNB4中，两组不同的尼古丁成瘾风险变异现已在多个独立研究中得到证实。目的1将使用基因分型、社区为基础、吸烟数据的纵向样本来检验这些强有力的遗传发现。目标是确定这些风险变异的更广泛的健康影响和流行病学概况。为了进一步建立在CHRNA5-CHRNA3-CHRNB4中已证实的发现的基础上，在Aim 2中，我们将对欧裔美国人和非裔美国人中包含该集群的强连锁不平衡的较大区域进行DNA测序，以确定新的遗传变异。然后，我们将在两个人群的样本中对这些变异进行基因分型和测试，以确定它们与尼古丁依赖的关系。目的3通过整合几个大型全基因组关联研究（GWAS）的基因型和吸烟数据，扩展了我们对吸烟的研究。目标是在这个强大而独特的组合样本中确定额外的遗传风险变异和基因-基因相互作用。在目标4中，我们将研究吸烟基因座与其他物质成瘾基因座之间的关系。通过测试吸烟风险基因座与其他物质成瘾风险的关联，我们可以评估这些基因对物质依赖易感性的共同与特殊影响。总之，这个项目将进一步加深我们对吸烟相关基因变异所带来的风险的理解，并将使我们发现基因组中其他地方的新基因位点，这些基因位点会导致吸烟风险和相关疾病。公共卫生相关性：吸烟和尼古丁成瘾造成严重的公共卫生负担。最近的快速进展已经开始建立影响吸烟风险的基因位点。更多地解释这一极其重要的公共卫生问题背后的基因结构，将为继续努力预防和控制吸烟和其他物质成瘾提供信息。

DESCRIPTION (provided by applicant): Tobacco use, primarily through cigarette smoking, is the largest cause of preventable mortality in the United States and the world. Other substance addictions cause added public health burdens. The overall objectives of this project are to identify genetic variants that alter risk for smoking and nicotine dependence, and to evaluate their role in determining risk for other substance dependence. In the cholinergic nicotinic receptor subunit gene cluster CHRNA5-CHRNA3-CHRNB4, two distinct groups of nicotine addiction risk variants have now been confirmed in multiple independent studies. Aim 1 will examine these strong genetic findings using genotyped, community-based, longitudinal samples with smoking data. The goal is to determine the broader health implications and epidemiological profile of these risk variants. To further build on the confirmed findings in CHRNA5-CHRNA3-CHRNB4, in Aim 2 we will DNA sequence the larger region of strong linkage disequilibrium containing this cluster in both European-Americans and African-Americans to identify novel genetic variants. We will then genotype and test these variants for association with nicotine dependence in samples from both populations. Aim 3 extends our study of smoking by integrating genotypic and smoking data across several large genome-wide association studies (GWAS). The goal is to identify additional genetic risk variants and gene-gene interactions in this powerful and unique combined sample. In Aim 4 we will examine the relationships between loci identified for smoking and for addiction to other substances. By testing smoking risk loci for association with risk for other substance addiction, we can evaluate the common versus specific effects of these genes on susceptibility to substance dependence. Altogether, this project will further our understanding of the risks conferred by variation in established genes involved in smoking, and will allow us to uncover new genetic loci elsewhere in the genome that contribute to risk for smoking and associated morbidities. PUBLIC HEALTH RELEVANCE: Smoking and nicotine addiction create profound public health burdens. Recent and rapid progress has begun to establish genetic loci that influence risk for smoking. Explaining more of the genetic architecture that underlies this extremely important public health problem will inform continued efforts to prevent and control smoking and other substance addiction.