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

描述（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，以及2）对新表型进行全基因组关联研究（GWAS），SUD的发病前责任指数，和两个独立样本的重复研究。侧重于发病前风险指标（即开始使用药物之前）的优势在于，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“发病后”措施更敏感的遗传责任措施。关注病前责任也提供了一个合理的理论框架，以检查与SUD的出现相关的发展过程，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。该研究计划需要对大约6000名参与者进行61个OK SNP的GWAS，以衡量SUD的发病前责任。然后，将在两个独立的高危青年样本中进行GWAS重大发现的复制研究。该研究计划还包括研究G-E相互作用的机制，该机制是利用纵向双胞胎设计开发SUD的基础。该奖项还将帮助候选人追求成为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来识别与药物滥用相关的基因，通过关注在开始使用药物之前存在的风险因素。汇集多个纵向样本（N~6000），我们将对一种新的物质滥用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.