EXPLORING GENETIC INFLUENCES ON ALCOHOL USE USING NOVEL STATISTICAL METHODS

描述（由申请人提供）：第二次修订的K 01申请的培训和研究计划将直接推进候选人的长期职业目标，即开发一个独立的跨学科研究路线，根据表型和基因型信息调查酒精相关问题和酒精使用障碍的风险亚型。在统计遗传学（与假设生成和测试有关），分子遗传学及其与酒精研究的整合中寻求职业发展。这些培训目标将通过课程、讲习班、研讨会和会议来实现;通过与其研究与本申请直接相关的高级研究人员进行广泛的指导和咨询;以及通过发展合作。这些活动将为研究计划提供基础，该研究计划将非传统定量方法与中间表型方法相结合，使用高信息量但小规模（N<500）的研究数据，生成关于神经遗传学对生理过程影响的概念性和实验性假设。更具体地说，该研究计划旨在为两个正在进行的NIH支持的项目增加遗传成分，这些项目研究多个动态相关生物系统的协调功能，并深入评估与酒精使用相关的心理社会和心理生理特征。基因组DNA正在从跨越物质使用行为连续体的年轻成年参与者中收集，GABA-A受体亚基基因的单核苷酸多态性将用作初始基因型目标。一个高度敏感的心率变异性指数-在休息时，在线索暴露和急性酒精挑战-将被用作初始中间表型。这些初始目标可以识别由于情绪唤醒调节不良而具有高成瘾倾向的个体的子集。总体目标是使用先进的统计学作为一种新的方法来识别有问题的酒精使用行为的多种风险途径，并提出新的有针对性的治疗方法。这些以发现为导向的早期研究产生的假设随后将通过合作和重新研究R 01应用收集的独立样本进行测试。该应用程序将尖端的统计策略应用于遗传和生理数据的分析，以一种新的方式探索饮酒行为的遗传基础。这种方法可能有助于识别酒精相关问题的风险亚型，并提出预防，干预和治疗计划更有效的方法。

DESCRIPTION (provided by applicant): The training and research plans of this second revised K01 application will directly advance the candidate's long term career goal of developing an independent, transdisciplinary line of research that investigates subtypes of risk for alcohol-related problems and of alcohol use disorders based on phenotypic and genotypic information. Career development is sought in statistical genetics (related to hypothesis generation and testing), molecular genetics, and their integration with alcohol studies. These training objectives will be accomplished through coursework, workshops, seminars, and conferences; through extensive mentoring and consulting with senior investigators whose research is directly relevant to this application; and through development of collaborations. These activities will provide the foundation for the research plan, which combines nontraditional quantitative methods with an intermediate phenotype approach to generate conceptually- and empirically-based hypotheses about neurogenetic influences on physiological processes using highly informative yet small scale (N<500) study data. More specifically, the research plan seeks to add a genetic component to two ongoing NIH-supported projects that examine the coordinated function of multiple dynamically-interrelated biological systems and that provide in depth assessment of psychosocial and psychophysiological characteristics related to alcohol use. Genomic DNA is being collected from young adult participants who span the continuum of substance use behaviors and single nucleotide polymorphisms in GABA-A receptor subunit genes will be used as initial genotype targets. A highly sensitive index of heart rate variability - at rest, during cue exposure and acute alcohol challenge - will be used as an initial intermediate phenotype. These initial targets may identify a subset of individuals with high addiction liability due to poor modulation of emotional arousal. The overall aim is to use advanced statistics as a novel approach to identifying the multiple pathways of risk for problematic alcohol use behaviors and suggesting new, targeted approaches to treatment. Hypotheses generated from these discovery-oriented, early-stage studies will subsequently be tested with independent samples gathered through collaborations and in de novo R01 applications. This application applies cutting-edge statistical strategies to the analysis of genetic and physiological data in an effort to explore the genetic basis of drinking behaviors in a new way. This approach may be useful for identifying subtypes of risk for alcohol-related problems and suggesting ways to make prevention, intervention and treatment programs more effective.