Recent developments on the genetics of alcohol use

Although researchers know that alcohol-use behavior and disorders are significantly genetic in nature, identification of the specific genes that contribute to an individual’s susceptibility for alcohol dependence has been difficult.   Many investigators have begun to examine alcohol dependence in relation to its component parts – called phenotypes – to better understand the genetic bases of alcohol use and dependence.   Proceedings of a symposium on the genetics of alcohol-related phenotypes at the Congress for the International Society for Biomedical Research on Alcoholism in Mannheim, Germany in October 2004 are published in the July issue of Alcoholism: Clinical & Experimental Research.

“The discoveries we discussed help to narrow the search for those genes that increase a person’s vulnerability for developing alcohol dependence and its physical consequences,” said Victor Hesselbrock, professor of psychiatry at the University of Connecticut School of Medicine and corresponding author for the proceedings.   “Clinically, there are several different types of alcoholism, each with a somewhat different etiology and sometimes a different response to treatment and eventual outcome.   Further, there is a variable pattern of physical consequences found among different populations of alcoholics.   The current findings provide some clues for understanding the biological bases of these differences.”

Some of the key proceedings were:

-   Polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) may explain individual differences in the concentration and elimination of alcohol and acetaldehyde in the blood after heavy drinking, and may also help to explain alcohol-related organ damage.

“When alcohol is consumed, there are two primary enzymes responsible for its metabolism: ADH and ALDH,” explained Hesselbrock.   “ADH is responsible for the initial metabolism of alcohol into acetaldehyde, and ALDH is responsible for metabolizing acetaldehyde into acetate and water.”   If acetaldehyde, a volatile and toxic compound, is not quickly converted and then eliminated from the body, it can cause considerable damage to the human body.

“Both enzymes are under genetic control, which determines ADH’s ability to metabolize alcohol and ALDH’s ability to metabolize acetaldehyde,” said Hesselbrock.  “Further, there is considerable individual variation in the expression of both ADH and ALDH.   Long story short, if a person is not able to rapidly metabolize acetaldehyde, different organ systems are exposed to higher levels of acetaldehyde for extended periods of time.  According to these findings, it is this extended exposure to acetaldehyde that is thought to be responsible for organ damage resulting from chronic alcohol use.”

-   Several chromosomal regions – particularly an area of chromosome two – were linked to suicidal behavior, conduct disorder symptoms, and alcohol dependence.   This suggests a “sharing” of genes for several different, but often related, types of behavior.

“Suicidal behavior, childhood problem behaviors, and alcohol dependence are all considered to be ‘externalizing behaviors,’ that is, behaviors an individual expresses outwardly towards others,” said Hesselbrock.  “Contrarily, internalizing behaviors are behaviors that are directed inward and include depression and anxiety.  For some time, scientists have thought that specific genes may be responsible for influencing specific behaviors.  While this is true for certain biological traits and some medical diseases, more recent studies are indicating that many genes influence a variety of behaviors.”

Hesselbrock said that individuals with alcohol dependence often display a variety of conduct disorder problems and suicidal behaviors.   “In other words, this study indicates that at least some of the genes that increase a person’s vulnerability for developing alcohol dependence may also contribute to their susceptibility for conduct disorder and suicidal behavior,” he said.

- Serotonin (5-HT) appears to be a key neurotransmitter in antisocial alcoholism and related phenotypes.   More specifically, the 5-HT 1B G 861 C polymorphism appears to play a role in antisocial behavior and alcohol dependence.  

“Serotonin is a chemical produced in the brain that has been shown to be related to many types of normal and abnormal behavior,” explained Hesselbrock.   “Aggressiveness, depression, drug use, migraine headache, pain sensitivity, and sleep disorders are examples of clinical conditions that are influenced by altered brain serotonin function.  However, there are several different families of serotonin receptors in the brain, and variations in serotonin affect different receptor systems producing different clinical outcomes.”

While previous human and animal studies have shown that serotonin is responsible for both aggressive behavior and increased alcohol consumption, said Hesselbrock, this study has demonstrated that the 5-HT 1B G 861 C gene – which controls one family of serotonin receptors, the 5HT1B group – occurs more frequently among antisocial alcoholics than non-antisocial alcoholics.  “Although not definitive,” he said, “this finding does indicate that the 5HT1B G 861 gene is associated with the development of antisocial alcoholism.”

Collectively speaking, said Hesselbrock, “these findings highlight the importance of the clinical phenotype for elucidating susceptibility genes.   While chronic drinking is common to all persons with alcohol dependence, there is considerable variation in other aspects of the clinical phenotype.  These findings help to narrow the search for those genes that contribute to alcohol dependence, suggesting also that some genetic contribution may be phenotype specific.”

Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.

Articles were written based on the following published research:

Higuchi, S.; Soyka, M.   (July 2005).   Recent developments in the genetics of alcohol-related phenotypes.   Alcoholism: Clinical & Experimental Research.   29(7): 1321-1324.