Abstract
Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.
Highlights
Alcohol use disorder (AUD) frequently causes harmful domestic and societal consequences
(5) In human genetic studies, it is often difficult to disentangle the role of environmental cofactors in determining AUD phenotypes
For gene discovery, many concerns of human genome-wide association studies (GWAS) are diminished in fly GWAS and other fly studies, which are amenable to higher sample number and greater statistical power
Summary
Alcohol use disorder (AUD) frequently causes harmful domestic and societal consequences. (6) Most human genetic studies are correlative by necessity, making it hard to differentiate cause and effects It is unclear if phenotypes such as altered gross and cellular structure and gene expression in the brains of AUD patients contribute to AUDs or are merely a byproduct of their existence [20,21,22,23]. Candidates are compared to human forward genetics data or used to guide hypothesis-driven reverse genetics studies, such as candidate gene association studies (CGAS) These complementary methods contribute substantially to our knowledge of the genes that predispose individuals to AUDs and/or contribute to AUD development and maintenance. We explain approaches used in humans and flies to discover, validate, and investigate candidate genes, summarize important findings contributed by each approach, and discuss their strengths and weaknesses
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