The search for genes contributing to the low level of response to alcohol: Patterns of findings across studies

Background: Alcoholism is a complex genetically influenced disorder in which multiple phenotypes [e.g., disinhibition, alcohol-metabolizing patterns, and the low level of response (LR) to alcohol] contribute to the risk. A low LR to alcohol is one of the more thoroughly studied risk phenotypes; data indicate that LR relates to the risk status, predicts future alcoholism, and has a heritability as high as 60%. This article reviews data from animal and human studies regarding the LIZ to alcohol, searching for a convergence of results that might lead to the identification of relevant genes. Methods: A literature search was performed regarding animal and human genetic studies focusing on genes that might affect. the LR to alcohol as a risk factor for alcoholism. The goal was to synthesize these results and highlight potential patterns. Results: Focusing on both genetic linkage and association studies, a number of chromosomal regions and genes potentially relevant to findings across two or more sources were identified. The genes of potential interest fell into several categories, including second-messenger systems (e.g., G proteins, adenylyl cyclase, and protein kinases); neurotransmitters or drug-related receptors (e.g., gamma-aminobutyric acid-A, glutamate, serotonin, and cannabinoid and opioid receptors); genes that affect alcohol metabolism; and genes that might relate to an overlap in the risk for alcoholism and some psychiatric conditions (e.g., catechol-O-methyltransferase regarding schizophrenia and bipolar disorder). Conclusions: The review identifies several genes that may contribute to a low LR to alcohol and, thus, to an increased risk for alcohol use disorders. The chromosomal regions and genes highlighted here may form the basis for more focused genetic studies of alcohol use disorders, with the goals of developing more specific and effective prevention and treatment approaches.