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：
8305010
负责人：
NANCY L SACCONE
金额：
$ 38.84万
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/8305010
关键词：
15p 15q Accounting Adult Affect African American Alcohol or Other Drugs use Alleles American Amino Acids Architecture 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 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

15p 15q Accounting Adult Affect African American Alcohol or Other Drugs use Alleles American Amino Acids Architecture 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 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

展开

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，是美国和世界可预防死亡率的最大原因。其他物质成瘾造成了增加的公共卫生负担。该项目的总体目标是确定改变吸烟和尼古丁依赖风险的遗传变异，并评估其在确定其他物质依赖风险中的作用。在胆碱能受体亚基基因簇CHRNA5-CHRNA3-CHRNB4中，现在已经在多个独立的研究中证实了两组尼古丁成瘾风险变体的两组。 AIM 1将使用具有吸烟数据的基因分型，基于社区的纵向样本来检查这些强大的遗传发现。目的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。为了进一步建立在CHRNA5-CHRNA3-CHRNB4中的确认发现，在AIM 2中，我们将DNA序列在欧洲裔美国人和非裔美国人中均包含该群集的强连接不平衡的较大区域，以鉴定新的遗传变异。然后，我们将基因型并测试这些变体，以与两个人群的样品中的尼古丁依赖性关联。 AIM 3通过在几个大基因组关联研究（GWAS）中整合基因型和吸烟数据来扩展我们对吸烟的研究。目的是在这个功能强大且独特的组合样本中确定其他遗传风险变异和基因基因相互作用。在AIM 4中，我们将研究吸烟和成瘾其他物质的基因座之间的关系。通过测试吸烟风险基因座与其他物质成瘾的风险相关，我们可以评估这些基因对物质依赖性易感性的常见和特定影响。总而言之，该项目将进一步了解吸烟中既定基因的变化所带来的风险，并使我们能够在基因组中其他地方发现新的遗传基因座，从而有助于吸烟和相关的病态。公共卫生相关性：吸烟和尼古丁成瘾造成了巨大的公共卫生负担。最近和快速的进步已经开始建立影响吸烟风险的遗传基因座。解释更多基于这个极为重要的公共卫生问题的遗传建筑将为预防和控制吸烟和其他物质成瘾而持续努力。