A multilevel vulnerability study of substance abuse via CNV, brain activation and

描述（由申请人提供）：拟议研究的目标是通过对拷贝数变异（CNV）和大脑激活的复杂分析，弥合基因和行为之间的差距，从而推进药物滥用脆弱性的研究。三种物质，尼古丁，酒精和大麻，将使用来自多个研究的多模态数据进行调查。CNV通过删除和插入从1千碱基到数兆碱基的DNA片段，涵盖了大量的核苷酸序列变异。功能磁共振成像（fMRI）提供空间定位的神经生物学信息。行为和神经心理学评估提供有关症状和其他变量的信息。整合物质障碍发展不同阶段的信息，建立一个多层次的物质滥用脆弱性模型，以确定从基因到生物学，最后到行为的途径。还将研究不同类型药物滥用之间的共同和独特途径。大脑如何与基因和行为相互作用的知识的增加将大大促进药物滥用障碍的诊断，并通过尽早监测和干预来帮助预防计划。此外，了解药物滥用的共同途径将提高诊断、预防和治疗的总体有效性。本研究分为两个阶段。R21阶段将重点发展多变量基因组关联分析方法，称为平行独立成分分析（ICA）。与常用的单变量相关检验相比，基因组CNV阵列数据与fMRI脑激活之间的关系将通过模拟和实际应用通过并行ICA获得。平行ICA方法将应用于饮酒者和吸烟者的数据，并且测试复制程序将验证已确定的CNV-fMRI关联。R33阶段的目标是对药物滥用的脆弱性进行研究，包括从遗传到大脑到行为的多层次脆弱性模型以及不同类型药物滥用的共同途径。R33阶段的第一步是提取CNV、fMRI脑激活和行为评估之间的所有三方关系。然后，这些关系将被分解成一个多层次的模型，在这个模型中，连续的cnv -脑-行为连接和片段关系被识别出来。在独立开展酒精、尼古丁、大麻滥用的多层次脆弱性研究后，提取三者之间的共同路径。

DESCRIPTION (provided by applicant): The goal of the proposed research is to advance the study of vulnerability to substance abuse by bridging the gap between genes and behavior via sophisticated analyses of copy number variation (CNV) and brain activation. Three substances, nicotine, alcohol, and marijuana, will be investigated using multimodality data from multiple studies. CNV covers large amounts of nucleotide sequence variation, through deletion and insertion of DNA segments ranging from 1 kilobase to several megabases. Functional magnetic resonance imaging (fMRI) provides spatially localized, neurobiological information. Behavior and neuropsychological assessments provide information about symptoms and other variables. Integrating information at different phases of progressive development of a substance disorder, a multilevel vulnerability model of substance abuse will be established to identify pathways from genes to biology and finally to behavior. The common and distinct pathways among different types of substance abuse will also be studied. The increased knowledge of how the brain interacts with genes and behavior will significantly advance the diagnosis of a substance abuse disorder and assist prevention plans via monitoring and intervening as early as possible. In addition, the knowledge of common pathways among substance abuse will improve the overall effectiveness of diagnosis, prevention and treatment. The proposed research is divided into two phases. The R21 phase will focus on development of a multivariate genomic association analysis method, termed parallel independent component analysis (ICA). The relationship between genomic CNV array data and fMRI brain activation will be accessed via the parallel ICA through simulation and real application, compared with the often-used univariate correlation test. The parallel ICA method will be implemented to data from both drinkers and smokers, and a test- replication procedure will verify the identified CNV-fMRI associations. The goal of the R33 phase is to conduct a study of vulnerability to substance abuse, including a multilevel vulnerability model from genetics to brain to behavior and common pathways among different types of substance abuse. The first step in the R33 phase is to extract all three-way relations between CNV, fMRI brain activation, and behavioral assessments. Then, the relations will be factored into a multilevel model, where consecutive CNV-brain-behavior connections and segmental relations are identified. After independently conducting the multilevel vulnerability study on alcohol, nicotine, and marijuana abuse, the common pathways among them will be extracted.