"Prior research has shown that a significant proportion of the risk for having a low response to alcohol is genetic," said Kirk C. Wilhelmsen, principal investigator at the Ernest Gallo Clinic and Research Center and first author of the study. "In other words, most of what accounts for the variation among us in terms of our response to alcohol probably comes from genes. But the research doesn’t tell us how many genes are involved, or how the genes work to cause this effect."

"All behavior, thinking and feeling are controlled by the actions of molecules in the brain," added Ivan Diamond, professor and Vice Chairman of the department of neurology at the University of California, San Francisco. "Brain molecules can be changed by experiences in our environment, diseases, drugs and genes. Genes control the proteins which regulate the molecules that carry out all of the functions in the brain. If we could identify genes that confer risk for alcoholism or allow alcoholism to develop, then we could begin to understand which molecules are behaving abnormally or which molecules are responsible for contributing to alcoholism."

Diamond, who is also the founding director of the Ernest Gallo Clinic and Research Center, said that identification of chromosomes and eventually, specific genes, is a logical step in ongoing research. "About 25 years ago, Dr. Marc Schuckit started to measure responses to alcohol in young college students," he said. "None of these young men were alcoholics when they were tested. Many years later, however, he discovered that those young men who exhibited a low response to a drink of alcohol were more likely to become alcoholics in the future. Therefore, it seems that a diminished response to alcohol appears to predict the development of alcoholism in some people. If you are easily intoxicated by small amounts of alcohol, it is unlikely that you will ever become an alcoholic. On the other hand, if you can ‘hold your liquor’ at an early age, you have a greater risk of becoming an alcoholic years later."

For the current study, researchers initially chose participants from students attending two San Diego universities: each was between 18 and 29 years of age, had an alcohol-dependent parent, a personal history of drinking but not alcohol dependence, and a full sibling with similar characteristics. Full siblings (n=139 pairs) and available parents were then genotyped for 811 satellite markers. Subjects were given eight minutes to consume a beverage (20% by volume solution of 0.75 ml/kg of 95% alcohol for women and 0.90 ml/kg for men) from a closed container, designed to disguise the alcohol taste and the amount consumed. Measurements of body sway and both positive and negative subjective feelings were collected at baseline and then at 15 minutes, 30 minutes, and every half-hour thereafter during the three-hour testing session.

"We found there were three locations that had the largest evidence for genes that affect the level of response to alcohol," said Wilhelmsen. These were chromosomes 10, 11 and 22.

"Identification of chromosome locations for genes … that may affect someone's risk for becoming an alcoholic is important because this may lead to the identification of specific genes that determine how alcohol makes us feel, give us new insight into how the brain works, and help us understand why some people become addicted to alcohol," said Diamond.

"We still don’t know which genes or how many genes are involved," said Wilhelmsen. "What we do know is that there are some genes with big effects on the level of response to alcohol, and we know the approximate chromosome location. In terms of a puzzle, we now not only know which pieces contain the critical clues, we also know that probably the puzzle is solvable."

Next, Wilhelmsen and his colleagues will investigate if individual variations of these genes correlate with level of response to alcohol. "Each region that we’ve implicated typically contains about 200 to 300 genes," he said. "Because of the human genome project, we know a lot about some of the genes in this region, but some of the genes we know very, very little about. If we’re lucky, one of the genes that we think we understand something about will prove to play a role. However, if we’re unlucky, we’ll end up doing a systematic search of all the genes that are in the regions that have been implicated."

"A lot of studies have shown that the earlier people start to drink regularly," said lead author Scott F. Stoltenberg, assistant research scientist at the Department of Psychiatry, University of Michigan Alcohol Research Center, "the more likely it is that they will eventually develop alcohol problems. So if you can put off a person’s initiation into regular drinking into their 20s or so, they’re a lot less likely to develop these kinds of problems."

It’s no secret that early use of alcohol, cigarettes and other drugs can ‘set the stage’ for long-term health and behavioral problems. Although alcohol is thought to be the most commonly used psychoactive substance during adolescence, its use has a complicated relationship with the use of other substances such as tobacco and illegal drugs. Furthermore, numerous studies have found a strong association between early use of these substances and later-in-life alcohol-use disorders, depression, and multiple health-risk behaviors that include violence and suicide plans.

Why does this happen? "There are probably two answers," said Victor Hesselbrock, professor of psychiatry at the University of Connecticut School of Medicine. "First, developing a substance-use disorder requires a certain amount of exposure to the substance. You can’t become an alcoholic, a heroin addict, a cocaine addict, or addicted to cigarettes unless you use that substance a significant amount. The earlier you start, the more exposure you have to the drug. Second, there are problem-behavior children. They have what we call conduct disorder; these are the kids who have trouble with their parents, they’re unresponsive to discipline, they’re a problem in school, they’re unruly, they get into trouble in the neighborhood and for whatever reason, they start using these substances at an early age."

The generational study, published in the December issue of Alcoholism: Clinical & Experimental Research, looked at three "cohorts" or groups of people: those born before 1930 (referred to as "old); those born between 1930 and 1949 (referred to as "middle"); and those born after 1949 (referred to as "young"). Those considered "young" began regular use of alcohol at an earlier age than the other two groups. They were also more likely to develop drinking problems before the age of 25, called "early-onset alcoholism." In addition, this same group was more likely to exhibit elements of what is called "anti-social alcoholism," such as fighting while drinking, involvement with the police and drunk driving. Another finding of interest concerned women: age of first regular alcohol use among women declined more dramatically than it did among men, suggesting a related increase in problem drinking among women. Finally, the study found that a strong family history of alcohol problems was highly correlated with younger ages of regular drinking, early-onset alcoholism and alcohol-related antisocial behavior.

"In the study of alcoholism and other disorders," explained Hesselbrock, "you find something called a ‘secular trend.’ When people about 15 years ago spoke of early-onset alcoholism, it meant before the age of 25. The more we study this, the more we see that age march down. Right now, early-onset alcoholism probably begins before the age of 21."

Early-onset alcoholism is one of the defining features of anti-social alcoholism. "Generally these are the people that you would have met in high school," said Stoltenberg, "probably not in college because a lot of these folks don’t go to college. They get arrested, they drive while drunk; generally they’re thought to be very impulsive. ‘Impulsivity,’ or the lack of impulse control, has a lot to do with whether or not a person can keep themselves from doing whatever comes into their head." In other words, anti-social behavior involves a range of behaviors that tend to get people into trouble; early-onset alcoholism facilitates anti-social behavior in those individuals who already have impulse-control problems, most likely by further weakening impulse control.

"This paper not only confirms that the age of onset for alcohol problems and alcoholism is marching down, getting younger and younger," said Hesselbrock. "It also shows that the risk for women of developing these disorders, particularly women who are problem-behavior oriented, is probably not that different from men’s."

The study, funded by the National Institute of Alcohol Abuse and Alcoholism, also found support for a genetic tendency for alcoholism. Both Hesselbrock and Stoltenberg spoke of an unknown number of genes - six to eight, 10 or more - that each has an influence vis-à-vis vulnerability or susceptibility to alcohol disorders that can be ‘shared’ with other disorders such as depression and nicotine dependence.

"No single gene causes alcoholism," noted Stoltenberg.

Hesselbrock added that "genes do not predetermine, they only increase risk."

Yet not even a body of genes, let alone a solitary gene, entirely explains the conundrum. "When you talk about these cohort effects," explained Stoltenberg, "you’re talking about social changes rather than genetic changes. Clearly an individual with a dense family history of alcoholism has a much greater risk for alcohol problems than an individual without that history. In the couple of generations involved in this study, however, there’s no genetic change going on, so the effects have to be due to social or environmental changes."

The prevalence of drinking and age of first regular alcohol use among women are prime examples of social changes, noted Stoltenberg. "Maybe men and women have the same biological predisposition to behave this way," he said, "but 50 years ago it wasn’t socially acceptable for women to go into bars and drink. Certainly they weren’t considered ‘good girls.’ Now it’s a lot more acceptable for women to go out and drink like men."

Those considered "young" in the study would be almost 50 years old today. Stoltenberg said that even though "it’s hard to extrapolate from one cohort to another, I wouldn’t be surprised if the rates of these kinds of behaviors are going to be even higher in groups in their 20s and 30s right now."