EXPLORING GENETIC INFLUENCES ON ALCOHOL USE USING NOVEL STATISTICAL METHODS

描述（由申请人提供）：第二次修订的K01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，即发展一个独立的跨学科研究领域，研究基于表型和基因型信息的酒精相关问题和酒精使用障碍的风险亚型。在统计遗传学（与假设的产生和检验有关）、分子遗传学及其与酒精研究的结合方面寻求职业发展。这些培训目标将通过课程、讲习班、研讨会和会议来实现；通过广泛的指导和咨询高级调查员，他们的研究是直接相关的这个应用程序；通过合作的发展。这些活动将为研究计划提供基础，该计划将非传统的定量方法与中间表型方法相结合，利用信息量大但规模小（N<500）的研究数据，产生关于神经遗传对生理过程影响的概念和经验假设。更具体地说，该研究计划寻求在美国国立卫生研究院支持的两个正在进行的项目中增加遗传成分，这些项目检查多个动态相互关联的生物系统的协调功能，并提供与酒精使用相关的社会心理和心理生理特征的深入评估。基因组DNA是从跨越物质使用行为连续体的年轻成年参与者中收集的，GABA-A受体亚基基因的单核苷酸多态性将被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期间——将被用作初始的中间表型。这些初始目标可以识别出由于情绪唤醒调节能力差而具有高成瘾倾向的个体子集。总体目标是使用先进的统计数据作为一种新方法来识别问题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。从这些以发现为导向的早期研究中产生的假设随后将通过合作和从头开始的R01应用程序收集的独立样本进行测试。该应用程序将前沿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、干预和治疗方案更有效的方法。

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.