Integrating Genetics, Brain Imaging and Phenotypic Subtypes in Binge Drinkers

整合酗酒者的遗传学、脑成像和表型亚型

基本信息

批准号：
8983592
负责人：
Megan Cooke
金额：
$ 3.44万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2017-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8983592
关键词：
Accounting Address Alcohol abuse Alcohol consumption Alcohol or Other Drugs use Alcoholic beverage heavy drinker Alcoholism Alcohols Amygdaloid structure Anxiety Area Award Behavioral inhibition Biological Biological Process Biology Brain Brain imaging Characteristics Complex Consumption Data Dependence Development Emotions Equipment Esthesia Family history of Functional Magnetic Resonance Imaging Genes Genetic Genetic Polymorphism Genetic Risk Genetic Variation Genetic study Genome Genotype Goals Health Heavy Drinking Heterogeneity Impulsivity Individual Knowledge Lead Measures Mediating Mental Depression National Institute on Alcohol Abuse and Alcoholism Neurologic Participant Pathway interactions Pattern Pharmaceutical Preparations Pharmacotherapy Population Prefrontal Cortex Preventive Intervention Reaction Reporting Research Research Personnel Rewards Risk Running Sampling Series Solid Techniques Testing Therapeutic Intervention Training Twin Studies Variant Ventral Striatum Work adverse outcome antisocial behavior binge drinker binge drinking blood oxygen level dependent college coping drinking effective intervention experience externalizing behavior genetic variant genome wide association study neuroimaging problem drinker public health relevance rare variant response skills therapeutic target trait university student young adult

项目摘要

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.

描述（由申请人提供）：危险饮酒是大学生的一个主要健康问题，40.1% 的大学生报告酗酒（一次饮酒 5 次或以上），14.4% 的大学生报告酗酒（5 次或以上酗酒）。过去一个月，酒精使用风险被认为是基因、生物过程和其他表型特征之间复杂相互作用的结果，而发展中的表型异质性使这一情况变得更加复杂。发育研究表明，危险饮酒有两种途径，分别具有外化和内化特征，然而，区分这些途径的潜在生物过程尚未完全了解，因此在不了解的情况下，导致难以开发有效的治疗方法。潜在的生物学、个性化药物干预和治疗方法是不可能的，神经影像学研究已经使用功能磁共振成像评估了奖赏行为敏感性、情绪反应性和抑制，并分别证明了外化和内化亚型之间的关联。具体的最后，大脑激活模式本身就是一种可遗传的特征，因此，我们发现外化和内化酗酒者的特征是生物学差异（在大脑和基因组水平上）和大脑差异。激活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）确定酗酒者外化和内化特征之间的遗传关系，2）测试是否存在。外化和内化酗酒者在应对测量情绪反应性、奖励敏感性和行为抑制的任务时表现出大脑激活差异，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，我们将使用大型（N~7,500）基因型年轻人样本（NIAAA-R37 AA011408，PI Kenneth Kendler）进行一系列基因型分析，评估共同点的差异在这些酗酒年轻人的子集中（N = 60），将通过评估行为抑制、奖励敏感性和情绪反应性的任务来测量大脑激活。最后，我们将测试这些任务的大脑激活变化是否介导酗酒者的遗传风险和外化/内化特征之间的关系。该项目的发现将为更好地理解经典外化和内化酒精之间的潜在生物学提供坚实的基础。使用亚型的基础生物学知识有可能阐明新的亚型特定预防和干预目标，这是 NIAAA 的一项重大举措。