Study of Addiction: Genetics and Environment

描述(申请人提供)：酒精和非法药物成瘾是美国可预防死亡的第三大原因。众所周知，遗传因素在成瘾的发展中起着重要作用，其中许多因素似乎有助于成瘾的普遍倾向。然而，环境因素也起着重要作用，有大量证据表明，许多环境因素可能会改变遗传风险因素的影响。因此，使用基因-环境方法来处理成瘾性疾病是至关重要的。 我们建议在病例对照设计中使用近3000名无关的欧洲血统受试者进行一项全面的全基因组关联研究，并分析遗传关联和基因与环境的相互作用。病例包括1,333名以DSM-IV酒精依赖为主要表型，并经常合并其他药物成瘾的受试者。对照组包括1647名曾饮酒但从未对酒精、尼古丁或其他非法物质上瘾的受试者。这种控制状态的方法将确保遗传发现与物质依赖有关，而不是与物质使用的开始有关。通过涉及三项关于成瘾障碍的主要研究的交叉研究合作，使大量的受试者成为可能：酒精中毒遗传学合作研究(COGA)、可卡因依赖家族研究(FSCD)和尼古丁依赖的合作遗传学研究(COGEND)。所有这些研究都参与了NIAAA和NIDA的基因库。 我们这项建议的主要目标是通过基因与环境倡议(GEI)测序中心进行大规模的基因分型，标准化和协调所有研究中的表型和环境变量，并执行一套逻辑和顺序的分析，其中将纳入协变量和环境特征，以测试遗传关联、基因-环境和基因-基因相互作用。最后，我们将在超过1300名受试者(760例病例和485名对照)的非裔美国人群体中复制和扩展这项全基因组关联研究的结果。其他独立的和具有遗传信息的数据集，包括COGA收集的两个数据集和合作研究人员持有的三个大型数据集，为进一步调查基因发现提供了机会。 这项研究将首次系统地解决使用全基因组关联方法成瘾的遗传和环境影响；新的特点包括整合多个大规模数据集，仔细考虑控制状态的定义，以及在几个独立样本中复制的机会。

DESCRIPTION (provided by applicant): Addiction to alcohol and illicit drugs is the third leading cause of preventable death in the United States. It is well known that genetic factors play a major role in the development of addiction, and many of these factors appear to contribute to a generalized liability for addiction. However, environmental factors also play important roles, and there is abundant evidence that a number of environmental factors may alter the effect of genetic risk factors. Hence, it is critical to approach addictive disease using a gene-environment approach. We propose to undertake a comprehensive genome-wide association study using nearly 3,000 unrelated subjects of European descent in a case-control design and to analyze genetic associations and gene x environment interactions. Cases include 1,333 subjects with the primary phenotype of DSM-IV alcohol dependence, and often with other comorbid drug addiction. Controls comprise 1,647 subjects who have used alcohol, but have never been addicted to alcohol, nicotine, or other illicit substances. This approach to control status will ensure that genetic findings are related to substance dependence, rather than the initiation of substance use. The large number of subjects is made feasible by a cross-study collaboration involving three major studies of addictive disorders: the Collaborative Study on the Genetics of Alcoholism (COGA), the Family Study of Cocaine Dependence (FSCD), and the Collaborative Genetic Study of Nicotine Dependence (COGEND). All these studies participate in the NIAAA and NIDA Genetic Repositories. Our primary goals of this proposal are to undertake large-scale genotyping through the Genes and Environment Initiative (GEI) sequencing center, to standardize and harmonize phenotypic and environmental variables across all studies, and to perform a logical and sequential set of analyses that will incorporate covariates and environmental features for the testing of genetic association, gene-environment and gene-gene interactions. Finally, we will seek to replicate and extend findings from this genome-wide association study in an African-American population with over 1300 subjects (760 cases and 485 controls). Other independent and genetically informative datasets, including two data sets collected by COGA, and three large data sets held by collaborating investigators, provide the opportunity to further investigate genetic findings. This study will be the first to systematically address both genetic and environmental effects in addiction to using a genome-wide association approach; novel features include the integration of multiple large-scale data sets, a carefully considered definition of control status, and the opportunity for replication in several independent samples.