Integrating Genetics, Brain Imaging and Phenotypic Subtypes in Binge Drinkers

 风险饮酒是大学生的一个主要健康问题，在过去的一个月里，40.1%的大学生报告酗酒（一次5杯或更多），14.4%的大学生报告酗酒（5杯或更多）。危险的酒精使用被认为是基因、生物过程和其他表型特征之间复杂相互作用的结果。这是进一步复杂化的表型异质性的发展中的酒精使用。发展研究提出了两种途径，以危险的酒精使用，其特点是外化和内化的特点，分别。然而，区分这些途径的潜在生物学过程尚未完全了解，从而导致难以开发有效的治疗方法。如果不了解潜在的生物学，个性化的药物干预和治疗将是不可能的。神经影像学研究已经使用功能磁共振成像评估了奖励敏感性、情绪反应性和行为抑制，并分别证明了外在化和内在化亚型的关联。此外，以前的遗传学研究已经发现了特定多态性与这些外化和内化亚型之间的关联。最后，大脑激活模式本身也被证明是一种可遗传的特征。因此，我们假设，外化和内化酗酒者的特点是生物学差异（在大脑和基因组水平）和大脑激活的差异将介导遗传变异对表型特征的影响。我们将通过以下具体目标来解决这一假设：1）确定酗酒者的外化和内化特征之间的遗传关系，2）测试外化和内化酗酒者在对测量情绪反应性，奖励敏感性，和行为抑制和3）测试大脑激活是否介导遗传风险和外化/内化特征之间的关系。为了实现这些目标，我们将使用大量（N~ 7，500）基因分型的年轻成人样本（NIAAA-R37 AA 011408，PI Kenneth Kendler）进行一系列基因型分析，评估外化和内化亚型之间常见变异、遗传途径、基因网络和罕见变异的差异。在这些狂饮年轻人的一个子集（N=60）中，将在评估行为抑制、奖励敏感性和情绪反应性的任务上测量大脑激活。最后，我们将测试这些任务中大脑激活的变化是否介导了酗酒者遗传风险和外化/内化特征之间的关系。该项目的发现将为更好地理解经典的外化和内化酒精使用亚型之间的潜在生物学提供坚实的基础。这种潜在的生物学知识有可能阐明新的亚型特异性预防和干预目标，这是NIAAA的一项重大举措。

 DESCRIPTION (provided by applicant): Risky alcohol use is a major health concern among college students, with 40.1% reporting binge drinking (5 or more drinks in one occasion) and 14.4% reporting heavy drinking (binge drinking on 5 or more occasions) in the past month. Risky alcohol use is thought to be the result of a complex interplay between genes, biological processes, and other phenotypic characteristics. This is further complicated by the phenotypic heterogeneity in the development of alcohol use. Developmental studies have suggested two pathways to risky alcohol use, characterized by externalizing and internalizing characteristics, respectively. However, the underlying biological processes that differentiate these pathways are not fully understood, thereby contributing to the difficulty developing efficacious treatments. Without knowledge of the underlying biology, personalized pharmacological interventions and therapeutic treatments will not be possible. Neuroimaging studies have assessed reward sensitivity, emotion reactivity, and behavioral inhibition using fMRI and separately demonstrate associations in externalizing and internalizing subtypes. In addition, previous genetic studies have found associations between specific polymorphisms and these externalizing and internalizing subtypes. Finally, brain activation patterns have been shown to be a heritable trait themselves. Therefore, we hypothesize that externalizing and internalizing binge drinkers are characterized by biological differences (at the brain and genome levels) and differences in brain activation will mediate the effect of genetic variation on the phenotypic characteristics. We will address this hypothesis through the following Specific Aims: 1) determine the genetic relationship between externalizing and internalizing characteristics in binge drinkers, 2) test whether externalizing and internalizing binge drinkers show differences in brain activation in response to tasks measuring emotion reactivity, reward sensitivity, and behavioral inhibition and 3) test whether brain activation mediates the relationship between genetic risk and externalizing/internalizing characteristics. In order to achieve these Aims, we will use a large (N~7,500) genotyped young adult sample (NIAAA-R37 AA011408, PI Kenneth Kendler) to conduct a series of genotypic analyses assessing differences in common variants, genetic pathways, gene networks, and rare variants between the externalizing and internalizing subtypes. In a subset of these binge drinking young adults (N=60), brain activation will be measured on tasks assessing behavioral inhibition, reward sensitivity, and emotion reactivity. Finally, we will test whether variation in brain activation on these tasks mediates the relationshi between genetic risk and externalizing/internalizing characteristics in binge drinkers. The findings of this project will provide solid groundwork to better understand the underlying biology between the classic externalizing and internalizing alcohol use subtypes. This knowledge of the underlying biology has the potential to elucidate new subtype specific targets for prevention and intervention, a major initiative of the NIAAA.