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，即发展一条独立的、跨学科的研究路线，根据表型和基因信息调查酒精相关问题和酒精使用障碍的亚类风险。在统计遗传学(与假设生成和检验相关)、分子遗传学及其与酒精研究的整合方面寻求职业发展。这些培训目标将通过课程作业、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人员(其研究与这一应用直接相关)；以及通过发展合作来实现。这些活动将为研究计划提供基础，该计划将非传统的量化方法与中间表型方法相结合，使用信息量很大但规模较小的研究数据，生成关于神经遗传学对生理过程影响的概念性和经验性假说。更具体地说，该研究计划试图在NIH支持的两个正在进行的项目中增加一个基因部分，这两个项目检查多个动态相互关联的生物系统的协调功能，并对与饮酒有关的心理社会和心理生理特征进行深入评估。基因组DNA是从跨越药物使用行为连续体的年轻成年参与者身上收集的，GABA-A受体亚单位基因的单核苷酸多态将被用作初始基因分型目标。心率变异性的一个高度敏感的指标--在休息时、在线索暴露期间和急性酒精挑战期间--将被用作初始中间表型。这些最初的目标可以确定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数据作为一种新的方法来确定有问题的酒精使用行为的多条风险途径，并建议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产生的假设随后将通过合作和新R01应用程序收集的独立样本进行测试。这一应用将尖端的统计策略应用于遗传和生理数据的分析，努力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与酒精相关的问题的风险亚类，并提出使预防、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.