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Integrating Genes, Environment, & Development in the Etiology of Substance Abuse

整合基因、环境、

基本信息

批准号：
8477159
负责人：
BRIAN M HICKS
金额：
$ 18.14万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2009-09-30 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477159
关键词：
Adolescence Age Alcohol or Other Drugs use Alcohols Alleles Award Behavior Behavioral Genetics Bioinformatics Candidate Disease Gene Chronic Disease Complex Consult Custom Data Dependence Development Developmental Process Diagnostic Diagnostic and Statistical Manual Economics Environment Environmental Exposure Environmental Risk Factor Epidemiology Etiology Exposure to Failure Family Family Study Genes Genetic Genetic Markers Genetic Polymorphism Genetic Predisposition to Disease Genetic Research Genotype Goals Health Health Care Costs Heritability Human Human Genome Intervention Light Longitudinal Studies Measures Mentors Methodology Methods Minnesota Molecular Outcome Participant Persons Phenotype Prevention Preventive Intervention Principal Investigator Process Productivity Psychiatry Psychometrics Public Health Quality Control Rehabilitation therapy Research Research Personnel Risk Risk Factors Role Sampling Scanning Smoker Substance Use Disorder Substance abuse problem Symptoms System Techniques Time Training Twin Multiple Birth Universities Variant Victimization Violence Youth addiction adolescent drug abuse base career design drug abuse education drug abuser effective therapy emerging adult experience follow-up genetic association genetic risk factor genome wide association study high risk improved indexing insight novel novel strategies programs skills sound

项目摘要

DESCRIPTION (provided by applicant): The overarching goals of this proposal are twofold: 1) to support the candidate in gaining additional training in the use of molecular and statistical genetic methods to identify risk alleles for substance use disorders (SUD), and 2) conduct a genome wide association study (GWAS) for a novel phenotype, a pre-morbid liability index for SUDs, and replication studies in two independent samples. The advantage of focusing on indicators of pre-morbid risk (i.e. prior to initiation of substance use) is that analyses are based on underlying rather than expressed risk and so may provide a more sensitive measure of genetic liability than manifest or "post-morbid" measures of SUDs. Focusing on pre-morbid liability also provides a sound theoretical framework to examine developmental processes associated with the emergence of SUDs such as exposure to environmental risk (gene-environment correlations) and sensitivity to environmental adversity (gene x environment interactions). The training portion of the proposal focuses on gaining skills in bioinformatics to identify candidate gene systems and select informative polymorphisms (e.g. SNPs) as well as expertise in statistical analyses to detect associations between genetic markers and complex phenotypes such as SUDs. The research plan entails conducting a GWAS of 61 OK SNPs on a measure of pre-morbid liability to SUDs on approximately 6000 participants. Replication studies of significant findings from the GWAS will then be conducted in two independent samples of high-risk youth. The research plan also includes studies examining mechanisms of G-E interplay that underlie the development of SUDs by utilizing a longitudinal twin design. The award will also assist the candidate in pursuing his long-term goal of becoming an independent researcher and is likely to yield important insights into the etiology of SUDs. PUBLIC HEALTH RELEVANCE: We propose a novel approach to identifying genes associated with substance abuse by focusing on risk factors present prior to initiation of substance use. Pooling multiple longitudinal samples (N~6000), we will conduct a genome wide association study on a novel measure of pre-morbid risk for substance abuse to identify specific risk genes.

描述（由申请人提供）：该提案的总体目标有两个：1）支持候选人获得使用分子和统计遗传学方法的额外培训，以识别物质使用障碍（SUD）的风险等位基因，2）针对新表型、SUD 病前责任指数和两个独立样本中的复制研究进行全基因组关联研究（GWAS）。关注病前风险指标（即开始使用药物之前）的优点是分析基于潜在风险而不是表达风险，因此可以提供比 SUD 的明显或“病后”测量更敏感的遗传责任测量。关注病前责任还提供了一个健全的理论框架来研究与 SUD 出现相关的发育过程，例如环境风险暴露（基因-环境相关性）和对环境逆境的敏感性（基因 x 环境相互作用）。该提案的培训部分侧重于获得生物信息学技能，以识别候选基因系统并选择信息多态性（例如 SNP），以及统计分析方面的专业知识，以检测遗传标记与复杂表型（如 SUD）之间的关联。该研究计划需要对约 6000 名参与者进行 61 个 OK SNP 的 GWAS，以衡量 SUD 的病前责任。然后，将对 GWAS 的重要发现进行重复研究，在两个独立的高危青少年样本中进行。该研究计划还包括利用纵向双胞胎设计研究 G-E 相互作用机制，该机制是 SUD 开发的基础。该奖项还将帮助候选人实现成为一名独立研究人员的长期目标，并可能对 SUD 的病因学产生重要的见解。公共卫生相关性：我们提出了一种新方法，通过关注开始使用药物之前存在的风险因素来识别与药物滥用相关的基因。我们将汇集多个纵向样本（N~6000），对药物滥用病前风险的新测量方法进行全基因组关联研究，以确定特定的风险基因。