Two large genetic studies of families with many alcoholic members have identified areas of five different chromosomes that may contain genes contributing to an individual's risk of alcoholism, researchers said last week.
Alcoholism, a pervasive public health problem whose cost is estimated at more than $150 million annually, has a strong tendency to run in families. Although it is common in the general population, brothers or sisters of alcoholics are at three to eight times greater risk of alcoholism than a person who has no family history of the condition. The identical twin of an alcoholic has about a 60 percent chance of also becoming alcoholic.
Studies of inheritance patterns long ago persuaded researchers that alcoholism, like diabetes and heart disease, was not caused by a single gene -- or even by genes alone. The fact that the identical twin of an alcoholic doesn't always develop the disease indicates that environment must also play a role.
"There's the likelihood of a handful of genes, each one responsible for part of the risk of the disease," said Enoch Gordis, director of the National Institute on Alcohol Abuse and Alcoholism.
About a decade ago, the NIAAA established six research centers around the country that began collecting blood samples, medical and psychiatric histories and other data on people from families with a very strong pattern of alcoholism. To qualify for the study, a family had to contain at least three first-degree relatives (siblings or parents and children) who were alcoholics. Individuals were recruited from alcohol-treatment facilities, and strict criteria were used to decide whether they had the condition.
Scientists at the centers isolate the chromosomes, which contain the DNA or genetic material, from blood cells of people in the study and use identifiable pieces of DNA called markers to analyze inheritance patterns for small stretches of each chromosome. This approach allows them to consider all 23 pairs of human chromosomes in short sections, and to begin to zero in on those sections that may harbor genes that increase (or decrease) a person's risk of becoming alcoholic. Each individual section, however, can contain hundreds of genes.
The Collaborative Study on the Genetics of Alcoholism (COGA) now includes more than 350 families and has collected data on about 10,500 people, said Henri Begleiter, a professor of psychiatry and neuroscience at the State University of New York, Brooklyn, and the study's chairman. It has received about $6 million annually in funding from NIAAA since 1989. The results reported last week come from 987 people in 105 families.
Meanwhile, two NIAAA scientists have pursued a similar approach in a smaller family study, involving 152 members of 32 interrelated families, done with the cooperation of members of an Indian tribe in the Southwestern United States that has very high rates of alcoholism. Eighty-five percent of the men and more than 50 percent of the women in the tribe become alcoholic at some time in their lives, said David Goldman, chief of the NIAAA's Laboratory of Neurogenetics. Goldman said researchers had agreed not to identify the tribe.
By comparison, the COGA study found that in the general population the lifetime risk of becoming alcoholic is about 17 percent for men and about 4 percent for women.
The laborious genetic analysis has begun to pay off, Gordis said, yielding "important findings about where in the genome the vulnerability to alcoholism likely lies."
The COGA study has found regions that may contain alcoholism-related genes on chromosomes number 1, 2, 4 and 7. The study on the Indian tribe identified two regions on chromosome 4 (one of which was the same as the region pinpointed in the COGA study) and one on chromosome 11.
Findings from both studies were published in this month's issue of the journal Neuropsychiatric Genetics.
"This is essentially the end of the first major phase," Gordis said. "The next move would be ... to use finer and finer markers and find the genes."
Some of the chromosome sections identified in the two studies are known to contain genes important for brain function and for the body's ability to break down and get rid of alcohol. For example, the region identified on chromosome 2 contains genes that control the brain's opioid system -- a group of narcotic-like chemicals released by nerve cells that can reduce pain and intensify pleasure. It also contains the gene for leptin, a chemical messenger that controls appetite and is related to obesity.
The region of interest on chromosome 11 contains genes for enzymes involved in manufacturing dopamine and serotonin, two important chemicals that relay messages in the brain, as well as the gene for the D4 dopamine receptor, a molecule on nerve-cell surfaces that binds to the chemical messenger.
The part of chromosome 4 identified in both studies contains genes that researchers believe may provide some protection against alcoholism. It has a cluster of genes required to manufacture an enzyme called alcohol dehydrogenase (ADH), which chemically converts ethanol (the alcohol in liquor, wine and beer) to acetaldehyde. Another enzyme then changes acetaldehyde to acetone, which is excreted.
Previous studies have shown that people with certain variant forms of these enzymes, most commonly Asians, develop uncomfortable facial flushing when they drink alcohol and tend to avoid it. Researchers suspect that genes for other variants of ADH may also be protective, even though they don't cause overt flushing.
Although the presence of these known genes in the identified regions is intriguing, Gordis cautioned that they may not turn out to be the ones contributing to development of alcoholism. "For every gene we have an idea about, there may be hundreds of others which nature has put there for an even-bigger reason," he said.
Alcoholism, also known as alcohol dependence, is an abnormal appetite for alcohol that leads to impaired control over drinking, a high tolerance for alcohol, physical withdrawal symptoms when it is removed, and compulsive drinking with neglect of normal activities. Alcohol abuse is a pattern of chronic misuse of alcohol that causes life problems but stops short of physical addiction.
Not everyone from a high-risk family develops alcoholism. "Even in high-density alcoholic families, not all children come out to be alcoholics," said Begleiter. "Thirty to 40 percent of these kids will end up developing the disease."
Gordis said that if researchers can identify alcoholism-related genes and discover their function, such knowledge should lead to better treatments and more specific strategies for preventing the disorder. But for now, people from families with a pattern of alcoholism are advised to avoid alcohol or to monitor their own drinking carefully, keeping in mind that they are at risk. In young adults who are starting to drink, Gordis said, having a higher-than-average tolerance for alcohol is often a warning of future problems.
"It's extremely important to emphasize aggressive vigilance in a high-risk family," said Theodore Reich, a professor of genetics and psychiatry at Washington University School of Medicine in St. Louis. Alcoholism and alcohol abuse "are best avoided and prevented rather than treated."