HUMAN GENETIC VARIATION IN SMOKING AND ADDICTION RISK

吸烟和成瘾风险的人类基因变异

基本信息

批准号：
7905034
负责人：
NANCY L SACCONE
金额：
$ 42.4万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905034
关键词：
15p 15q Accounting Adult Affect African American Alcohol or Other Drugs use Alleles American Amino Acids Architecture Arts Atherosclerosis Cessation of life Chromosomes Cocaine Dependence Communities Comorbidity Complex DNA Sequence Data Data Set Development Disease Environment Epidemiology European Framingham Heart Study Gene Cluster Genes Genetic Genetic Epistasis Genetic Markers Genetic Risk Genetic Variation Genome Genotype Goals Health Human Genetics Individual Joints Linkage Disequilibrium Maintenance Malignant Neoplasms Medical Methods Morbidity - disease rate Nicotine Nicotine Dependence Nicotinic Receptors Pathway interactions Phenotype Population Population Attributable Risks Predisposition Public Health Research Personnel Resources Risk Role Sample Size Sampling Single Nucleotide Polymorphism Smoke Smoking Smoking Behavior Substance Addiction Testing Time Tobacco Tobacco use United States Variant Work addiction base case control cholinergic cigarette smoking cohort gene interaction genetic variant genome wide association study genome-wide mortality novel population based prevent public health relevance trait

项目摘要

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.

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识别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中的作用。在胆碱能烟碱受体亚基基因簇 CHRNA5-CHRNA3-CHRNB4 中，多项独立研究现已证实两组不同的尼古丁成瘾风险变异。目标 1 将使用带有吸烟数据的基于社区的基因分型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特征。为了进一步基于 CHRNA5-CHRNA3-CHRNB4 中已证实的发现，在目标 2 中，我们将对欧洲裔美国人和非洲裔美国人中包含该簇的更大的强连锁不平衡区域进行 DNA 测序，以识别新的遗传变异。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并测试它们与尼古丁依赖的关联。目标 3 通过整合多项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识别额外的遗传风险变异和基因间相互作用。在目标 4 中，我们将检查已确定的吸烟基因座和对其他物质成瘾的基因座之间的关系。通过测试吸烟风险位点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常见影响和特定影响。总而言之，该项目将进一步加深我们对与吸烟相关的已知基因变异所带来的风险的理解，并使我们能够发现基因组中其他导致吸烟和相关疾病风险的新基因位点。公共卫生相关性：吸烟和尼古丁成瘾造成了沉重的公共卫生负担。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遗传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。