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

描述（由申请人提供）：本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识别物质使用障碍（SUD）风险等位基因的额外培训，2)进行基因组全关联研究（GWAS），研究新表型，SUD的发病前责任指数，并在两个独立样本中进行复制研究。侧重于发病前风险指标（即开始使用药物之前）的好处是，分析是基于潜在风险而不是表现风险，因此可能提供比明显或“发病后”sud措施更敏感的遗传责任措施。关注病前责任也为研究与sud出现相关的发育过程提供了一个健全的理论框架，例如暴露于环境风险（基因-环境相关性）和对环境逆境的敏感性（基因-环境相互作用）。该提案的培训部分侧重于获得生物信息学方面的技能，以识别候选基因系统和选择信息性多态性（例如snp），以及统计分析方面的专业知识，以检测遗传标记和复杂表型（如sud）之间的关联。该研究计划需要对大约6000名参与者进行61个OK snp的GWAS，以衡量对sud的发病前责任。然后将在两个独立的高风险青年样本中对GWAS的重要发现进行复制研究。研究计划还包括利用纵向双胞胎设计来研究影响sud发展的G-E相互作用机制。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的病因学产生重要见解。公共卫生相关性：我们提出了一种新的方法，通过关注物质使用开始之前存在的风险因素来识别与药物滥用相关的基因。汇集多个纵向样本（N~6000），我们将对一种新的药物滥用发病前风险测量方法进行全基因组关联研究，以确定特定的风险基因。

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.