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

通过 CNV、大脑激活和药物滥用的多层次脆弱性研究

• 批准号: 7764894
• 负责人: Jingyu Liu
• 金额: $ 20.63万
• 依托单位: THE MIND RESEARCH NETWORK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764894
• 关键词: Alcohol abuse; Alcoholic beverage heavy drinker; Alcohols; Base Sequence; Behavior; Behavior assessment; Behavioral; Biological; Biology; Brain; Brain imaging; Brain region; Characteristics; Comorbidity; Copy Number Polymorphism; DNA; Data; Data Set; Development; Diagnosis; Disease; Dopamine; Effectiveness; Equilibrium; Etiology; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Models; Genomics; Genotype; Glutamates; Goals; Knowledge; Marijuana; Marijuana Abuse; Marijuana Smoking; Measures; Methodology; Methods; Modeling; Monitor; Neurobiology; Nicotine; Noise; Norepinephrine; Outcome; Output; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Phenotype; Population; Prevention; Procedures; Research; Sample Size; Single Nucleotide Polymorphism; Smoker; Societies; Stratification; Structure; Substance abuse problem; Symptoms; Testing; Tobacco; Variant; behavior change; brain behavior; cost; endophenotype; experience; gamma-Aminobutyric Acid; genetic association; genetic risk factor; genome wide association study; genome-wide; improved; independent component analysis; insertion/deletion mutation; marijuana user; multilevel analysis; multimodality; neuropsychological; nicotine abuse; psychologic; public health relevance; simulation; theories; treatment planning

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. PUBLIC HEALTH RELEVANCE: People abuse substances such as drugs, alcohol, and tobacco for varied and complicated reasons, but it is clear our society pays a significant cost for the consequences. The understanding of the vulnerability to substance abuse in different developmental phases will greatly assist the diagnosis, prevention and treatment plans. The efficiency and effectiveness of prevention and treatment efforts can also be improved with increased knowledge about common pathways underlying disorders related to different substances.

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，推进对药物滥用脆弱性的研究。三种物质，尼古丁，酒精和大麻，将使用来自多项研究的多模态数据进行研究。CNV通过从1个碱基到几个碱基的DNA片段的缺失和插入，覆盖了大量的核苷酸序列变异。功能性磁共振成像（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。整合信息在不同阶段的渐进发展的物质障碍，一个多层次的脆弱性模型的物质滥用将被建立，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不同途径。对大脑如何与基因和行为相互作用的了解的增加将大大推进药物滥用障碍的诊断，并通过尽早监测和干预来协助预防计划。此外，了解药物滥用的共同途径将提高诊断、预防和治疗的总体效力。拟议的研究分为两个阶段。R21阶段将专注于开发多变量基因组关联分析方法，称为并行独立成分分析（伊卡）。通过仿真和真实的应用，与常用的单变量相关性检验相比，并行伊卡将获得基因组CNV阵列数据与fMRI脑激活之间的关系。将对来自饮酒者和吸烟者的数据实施平行伊卡方法，并且测试复制程序将验证所确定的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之间的共同途径。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向关系。然后，这些关系将被分解成一个多层次模型，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。在独立进行酒精、尼古丁和大麻滥用的多层次脆弱性研究后，提取它们之间的共同途径。 公共卫生关系：人们滥用药物、酒精和烟草等物质的原因多种多样，但很明显，我们的社会为此付出了巨大的代价。了解不同发育阶段对药物滥用的脆弱性将大大有助于诊断、预防和治疗计划。通过增加对不同物质引起的疾病的共同途径的了解，也可以提高预防和治疗工作的效率和效力。