Identification and Characterization of Novel Genetic Mechanisms in Alcohol Use Disorder and Excessive Drinking

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Project summary/abstract Alcohol use disorder (AUD) is associated with significant costs to both the individual and society. Genetic and environmental factors contribute to the risk of AUD and excessive drinking, and a better understanding of the specific risk genes will allow for novel strategies for prevention and treatment. Recent well-powered human genome wide association studies (GWAS) of AUD and alcohol consumption have begun to identify multiple novel candidate genes. As increasing numbers of genes are implicated, it will be imperative to have researchers trained to work at the interface between human and animal model research. This will allow for the translation of genetic findings across organisms for follow-up and characterization of novel genetic mechanisms. This proposal involves training in two converging strategies for translational genetic research in AUD and excessive drinking. Aim 1 will provide training in prioritizing genetic hits from human GWAS for follow-up in animal studies using new mutant mouse lines. The goal of Aim 1 is to move from identification of genes in GWAS to mechanistic characterization using mouse models. Mutant mouse lines developed based on GWAS hits will be evaluated on a variety of behavioral assays to identify which aspects of drinking behavior are altered by the genetic manipulation; the ultimate goal of these studies will be to develop an optimized behavioral framework for assessing gene effects on AUD-relevant behaviors. Behavioral assays will include a measure of initiation of acute binge-like drinking and drinking microstructure (Drinking in the Dark), escalation of drinking in post-dependent animals and negative affective changes in withdrawal (chronic intermittent alcohol vapor exposure model), and sensitivity to the positive and negative motivational effects of alcohol (alcohol effects on intracranial self-stimulation). Aim 2 will utilize a complementary translational genetic approach that seeks to discover genes using a genetically diverse mouse population. Specifically, mice from the LGxSM Advanced Intercross Line will be tested on a phenotypically-rich model of binge-like alcohol drinking (Drinking in the dark with lickometers) to characterize consumption, blood alcohol levels, and detailed characterization of drinking bout structure. The goal of this experiment is to identify novel genes associated with not only overall consumption, but also specific aspects of the drinking pattern. This aim will provide significant training in advanced statistical methods for bout analysis and in the quantitative genetics skills needed for mouse GWAS. Together, the studies proposed here will yield critical biological insights into the genetics of AUD and excessive drinking.