Researchers now state with confidence that genetics plays a major role in the development of alcoholism; the environment, however, also plays a part.

A comprehensive overview, including the current state of research on etiology and where research is headed, was presented by Marc A. Schuckit, M.D., a professor of psychiatry at the University of California, San Diego (UCSD), last month at APA’s 2000 annual meeting in Chicago. Schuckit’s fast-paced, complex lecture was intently followed by the standing-room-only crowd of over 800.

Schuckit began by asking the question, How does medical science know that any disorder is inherited? Three primary questions are looked at, he explained. First, is the disorder familial? Second, are identical twins of people who have the disorder at higher risk of developing the disorder than fraternal twins? And, third, do children of an alcoholic parent who were adopted and thus not raised by the alcoholic parent have an increased risk of developing the particular disorder?

"The answer to all three of these questions," said Schuckit, "is very strongly yes within the alcohol field."

Environment, according to Schuckit, certainly plays a significant role, accounting for about 40 percent of the risk, while genetics accounts for the remaining 60 percent. The difficulty for researchers and clinicians studying alcoholism is that the genetic pathway that puts someone at risk to develop alcoholism is heterogeneous. Some people might have increased risk for alcoholism through one genetic mechanism, while a different group has increased risk through an entirely different mechanism. Schuckit told the crowd the question is complex and will take a great deal of time, effort, and ingenuity to move toward clinically meaningful answers.

An important area of research, being studied by several research groups, including Schuckit and his colleagues at UCSD, is the phenomenon known as "low response" to alcohol. Alcohol, when given to an average individual, causes characteristic changes in the blood chemistry of that individual. A "low responder," when given alcohol, experiences less of a physiological change. For example, low responders show smaller changes in prolactin and cortisol levels when exposed to alcohol.

This phenomenon is often referred to as "tolerance." It may be characterized by a patient saying "I have always held my liquor well," "I drank more than anyone else, but I didn’t look like it," or, the favorite boast of many alcoholics, "I could drink anyone under the table." Research has now shown that these patients could do so because the alcohol they drank had less of a physiological effect on their system than it would on the average individual’s system. This finding applies to both impaired judgment and reflex response.

Schuckit and his colleagues at UCSD started studying low response nearly 15 years ago. Their initial work involved 454 children of known alcoholic fathers who were in their late teens or early 20s and already known to drink alcohol, but none of whom was alcohol dependent at the beginning of the study. The subjects were followed for 10 years. Their cortisol levels, prolactin levels, and EEG recordings were taken before and after alcohol consumption. The protocol was repeated in a control group of children of nonalcoholics.

The children of alcoholics were frequently found to have less change in their prolactin and cortisol levels and less change in their EEG tracings than the controls. The research had revealed the tendency toward low response in the children of alcoholics.

"It was important to determine," Schuckit said, "whether this phenomenon of low response was an indicator of increased risk for the development of alcoholism in these children of alcoholics."

The group of 454 children of alcoholics was followed up 10 years later with nearly 100 percent participation; only three of the original subjects did not agree to participate.

Schuckit looked at the subgroup of children that were low responders to see how many of them had become alcoholics. The researchers interviewed each of the participants and people who knew the participants and analyzed blood samples of each of the participants.

Schuckit found a link between low response to alcohol at age 20 and alcoholism at age 30. However, there was no significant correlation between low response and the development of any other substance dependence or abuse or to the development of any psychiatric disorder.

After linking low response and alcoholism, Schuckit had two questions. Can we find some of the genes that contribute to the low response to alcohol? Secondly, how are the genes relating to the environment? Schuckit believes it will be the environmental factors that prove to be the key to prevention.

Some work has already been done in trying to locate the specific genes responsible. The "LL" allele of the serotonin receptor as well as a particular subunit of the GABA-a receptor have been associated with low response. Indeed, Schuckit and his group found that in one study population, people with both of these genetic markers were all low responders and all alcoholics. These results are awaiting independent replication.

"The genetic family of findings," Schuckit summarized, "will lead us to which specific genes are contributing, and that may lead us to more information on how to prevent and how to treat. But remember, the risk for alcoholism is only half genetic."

Schuckit and his colleagues are now looking prospectively at the 555 sons and daughters of the original 454 participants they started with 15 years ago. Through the parents they are learning about gestation and early-life behavior problems. From the age of 13, the children are interviewed.

What Schuckit plans to investigate prospectively is the age of onset of drinking, early problems with drinking, level of response to alcohol, and eventual development of alcoholism.

"The clinical punchline is," said Schuckit, "that we are looking for two things. By studying the original sample and their offspring, we may be able to come up with ways of prevention. And then there’s treatment. We may be able to identify that there may be subgroups of alcoholics for which different treatments are preferentially useful."