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.
Risky alcohol use is associated with numerous adverse consequences, and is known to be phenotypically heterogeneous, with heavy drinkers differing on their levels of externalizing or internalizing characteristics. Understanding the genetic and brain activation signatures associated with this phenotypic heterogeneity has the potential to identify new targets for specialized medication development.
