Genetics of Adolescent Alcohol Use and Disorders

by National Institute of Health

(Page 2 of 5)

Accumulating research indicates that complex behaviors result from the interplay between genes and environment over developmental time. Alcohol use is a prime example of a complex behavior in which gene expression and environment/ context reciprocally influence one another. For example, during adolescence, biological and physiological changes may promote risk-taking behavior, thereby influencing the way people decide to spend their time. The environments that a person selects may foster the use of alcohol, which in turn may result in acute physiological reactions that have the potential to trigger long-term biological changes. These changes then may affect the person's more immediate behavior as well as move unfolding developmental pathways toward adverse outcomes, including psychopathology (anxiety disorders). In this way, youthful patterns of alcohol initiation and escalation of use can become entry points for pathways that ultimately lead to abuse and dependence.

However, not all young people experience the same outcome from what may appear to be similar patterns of adolescent alcohol use. Studying such complexity is difficult, and adding to the difficulty of understanding these complex pathways at the biological level is the recognition that, unlike other drugs of abuse, alcohol does not appear to act through a specific receptor. Instead, alcohol modulates the function of multiple neurotransmitter systems and voltage-gated ion channels.

At the macro level, pathways that have been associated with the development of alcohol problems in general, and alcohol dependence more specifically, manifest themselves in the form of multiple behavioral and physiological characteristics, including disinhibition/ impulsivity, anxiety, variations in the intensity of response to alcohol, and several independent psychiatric disorders and alcohol-metabolizing patterns. These characteristics can influence the development of alcohol dependence through alterations in pathways that determine the rewarding effects of alcohol, tolerance to some of its intoxicating effects, pathologic effects on the brain, and the development of withdrawal symptoms. Genetically conferred characteristics contribute to the degree and/or rate of development of these changes.

Attempts have been made to categorize people based on the degree and rate that they develop dependence and to differentiate between the genetic contributions to various categories of alcohol dependence. Because the development of alcohol use, abuse, and alcoholism occurs on a continuum, and because recent data show that the highest prevalence of alcohol dependence in the population occurs between the ages of 18 and 25, this review focuses on efforts to identify genes contributing to those pathways that appear in childhood and adolescence. It must be emphasized, however, that many of the studies identifying heritable components which may contribute to alcohol abuse or dependence have been carried out in adults. The extent of their role, if any, in the development of alcohol problems in youth, therefore, remains to be determined. Additional genetic contributors to alcohol problems may be identified by future investigations, and some of these may be more specific to risk in children and adolescents.

Finding genes that contribute to the development of alcohol abuse and dependence in humans may be simplified by focusing on endophenotypes (i.e., intermediary connections between the manifestation of dependence and its biological underpinnings). To this end, human genetic studies have focused on families that have a high prevalence of members with alcohol dependence, on twin studies, and on studies assessing potential markers and/or contributors to risk. By performing genetic analyses on such populations, researchers have identified specific regions on individual chromosomes that correlate with risk for alcohol dependence. In some cases, individual candidate genes have been associated with these regions.

The goal now is to further refine those regions for which a specific gene has not yet been identified as responsible for the observed phenotype and to determine respective contributions of candidate genes to alcohol dependence. Research on how the identified genes interact with other genes and gene products and with the environment to result in alcohol dependence also is important. To date, functional polymorphisms in the alcohol-metabolizing enzymes alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase have been the most thoroughly documented for providing protective effects in specific populations. In addition, the Collaborative Study on the Genetics of Alcoholism has identified specific genes within identified regions that affect risk for alcoholism. These include gamma-aminobutyric acid (GABA) receptor subunits GABRA2 and GABRG3 and the muscarinic cholinergic receptor. GABRA2 has been independently confirmed.

Other promising candidates that have been implicated and are under investigation include the serotonin transporter 5-HTT; specific alleles of the neurotransmitter dopamine; catechol-O-methyltransferase; neuropeptide Y and the m opioid receptor (OPRM).

Animal Studies

In addition to studies with humans, studies using animal models, such as worms, flies, and rodents, permit researchers to model, in less complex systems, individual biological and behavioral components that may factor into alcohol problems, including dependence. The goal of this work is the convergence of findings from human and animal model studies to facilitate the design of pharmacological agents that can reduce, prevent, or ameliorate alcohol problems, including dependence and associated consequences.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.