Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol-related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be.

This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Schuckit's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.

OBJECTIVE: This article reviews developments in research on genetic influences on alcohol and other drug use and disorders over the past 7 decades. METHOD: The author began with a review of the flow and content of articles published in the three iterations of the journal since 1940 and then used a PubMed search of genetics of alcohol and other drug-related topics to gain a broad overview of developments in this field. RESULTS: The literature demonstrates the rapid metamorphosis of genetic research from the ideas of Mendel to an understanding that the substance use disorders are complex, genetically influenced conditions where genes explain up to 60% of the picture. Most genes operate through additional intermediate characteristics, such as impulsivity and a low sensitivity to alcohol, some of which are substance specific and others related to substances in general. Using linkage, association, genome-wide association, and other modern methods, investigators have identified a diverse range of genetic variations that affect substance-related phenomena. CONCLUSIONS: Genetic studies regarding alcohol and other drug use and problems have grown dramatically in the past 75 years. We currently have a much more sophisticated understanding of these influences, and the rapid development of new methods has the promise of continuing what has been a solid contribution of important findings in recent years.