Cross-species investigation of gene networks for ethanol-related behaviors

Virginia Commonwealth University, Richmond VA

Investigators

Linked publications, trials & patents

Abstract

Project Summary – Overall Alcohol use disorders (AUDs) represent a major public health burden. Genetic risk factors contribute significantly to the susceptibility to develop AUDs and are likely to be a result of many variants that each contribute modestly to risk. Genetic studies in animal models and humans to date have made slow progress in identifying individual genetic risk variants. This proposal for a P50 Alcohol Research Center presents a novel and highly integrated overall design in which we focus both on gene discovery and on functional analysis of the biological bases underlying risk for AUDs. This application is a renewal of our currently funded P50 that supports the VCU Alcohol Research Center (VCU-ARC), which was first funded with a P20 Developmental Center grant in 2009, and has been continuously funded since. We have a rich history of collaborative studies, and we have made significant progress over the past 14 years. Here we seek to both continue aspects of our current studies and to extend our work into new areas. Our approach continues to be innovative and significant due to three novel features: 1) A focus on gene networks contributing to AUD-related phenotypes and ethanol response behaviors; 2) A cross-species genetic and genomics analysis to validate candidate genes and networks and examine the underlying biology affecting ethanol response behaviors; and 3) A highly integrative and collaborative Center design with rapid data sharing across projects through a cross-species analysis pipeline to provide ranked gene lists, networks, and biological processes for further experimental validation in the component projects. We request five years of support for five Research Projects performing genetic studies in worms, flies, mice, and humans. Two projects will pursue new areas of study, and three others will extend their current projects with novel areas of investigation. Two projects will be in human genetics using state-of-the-art statistical approaches to leverage the power of large genome-wide association and exome sequencing studies on phenotypes significantly associated with AUDs. Three projects will use animal model organisms to develop and test hypotheses about the biological underpinnings of the effects of genes on alcohol response behaviors. All projects will be supported by an Administrative Core containing statistical and modeling support and a Behavior Core containing both a high- throughput invertebrate genetic screening function as well as a high-resolution analysis of the effects of candidate genes on mouse behavior. The scientific work proposed in these Projects and Cores is clearly greater than the sum of its parts, due to the highly interactive structure of the VCU-ARC components. The VCU-ARC is well positioned to continue to make major contributions to the advancement of our understanding of the etiology of AUDs and subsequently their prevention and treatment.