1Washington University, St. Louis, MO, USA
Alcohol is one of the most commonly used and misused substances. The World Health Organization (WHO) estimated that over 3 million deaths every year are attributable to alcohol use. Because of the high global burden from alcohol use disorder, it is important to understand the biologic (including genetic) underpinnings that lead to this disorder.
The development of alcohol use disorder requires the initiation of alcohol use, the conversion from experimental use to established regular use, and then the development of addiction. Each step in this developmental cascade is influenced by environmental and genetic factors. Insights into understanding the genetic influences to each step can now come from large-scale genetic analyses of tens of thousands (or more) people with measured aspects of alcohol use and alcohol use disorder.
Systematic large-scale studies of alcohol use disorders now confirm the known genetic contributions to alcohol use disorders in alcohol metabolizing genes. New discoveries are likely to be made as the datasets mature and reach critical numbers. Yet, a significant fraction of the genetic variance continues to remain unexplained. The heritability of alcohol use disorder is approximately 50%, yet the confirmed genetic contributions explain only a small fraction of this heritability. Three main explanations for the missing variance exist: many genes of small effect contribute to the disorder, rare variation remains unmeasured, and complex interactions between genes and environment obscure genetic findings. It is likely that all of these explanations contribute to the missing genetic variance, and more rigorous large-scale and systematic studies will be needed to untangle this Gordian knot.