We've come a long way in understanding the cunning, baffling disease known as alcoholism, and 12-step programs have helped millions of men and women recover.

Historically, alcoholic behavior was blamed on a character flaw or weakness of will. After all, couldn't people stop drinking if they really wanted to? While the stigma surrounding alcoholism continues, scientists have gained considerably more insight into how genes and environment interact to affect vulnerability to alcoholism--knowledge that is key to reducing the disease's exacting toll on individuals, families, and society.

As more genes are linked to the development of alcohol dependence and substance abuse, the findings will prove useful in developing tools for better gauging individual risk for the disease and identifying those with alcohol problems. Emerging genetic and environmental in-sights have also paved the way to the discovery of new therapies targeting specific genes or treatments tailored to individual backgrounds.

The Post spoke with John Nurnberger. M.D., Ph.D., director of the Institute of Psychiatric Research at Indiana University School of Medicine and a leading researcher on the genetics of alcoholism for decades.

Post: Could you tell us about your work with the Collaborative Study on the Genetics of Alcoholism (COGA), and how alcoholics and family members have helped?

Dr. Nurnberger: COGA is a study that has been continuously supported and funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) starting in 1989. Drs. Henri Begleiter from the State University of New York and Ted Reich at Washington University in St. Louis helped launch and direct the initial study, which involved six sites around the country: University of California San Diego. University of Iowa, University of Connecticut, SUNY Downstate Medical Center ha Brooklyn. Washington University ha St. Louis, and Indiana University in Indianapolis.

For the past 18 years, we have collaborated to identify families through persons diagnosed with alcohol dependence located at treatment facilities. Once we identified the individual, we would obtain permission to contact relatives of the person to discuss diagnoses in the extended family. We would then perform a brain wave study and take blood for DNA analysis.

In this way COGA established a huge database of information on 12,000 persons across the country. We organized the information to illuminate conditions that surfaced in families with a vulnerability to alcohol dependence and also to uncover the relationship of the brain electrical activity and DNA markers to those conditions.

Our group published a number of reports on findings from this sample over the years. We found that a variety of conditions go along with alcohol dependence ha families, including dependence on various drugs--marijuana, opiates, tobacco, stimulants, and sedatives. We also noted that a constellation of anxiety and depressive disorders tend to cluster with alcohol problems.

In addition, we observed particular electrical activity signatures ha the brain and specific single genes, such as those coding for GABRA2 (a receptor for a transmitter chemical that inhibits other signals). ADH4 (which breaks down alcohol ha the body), and CHRM2 (another brain transmitter receptor).

COGA remains very active in various ways: one, we're looking for additional genes in the families we have been studying; and two, we identified adolescents ha these families and are following them over time. This is a special high-risk population, and we're trying to determine risk and protective factors that impact young people growing up in families with multiple alcohol-dependent relatives, We are now at a point where some young people in the group are experiencing problems with alcohol but others are not, providing insights into how genes interact with family experience.

In doing the adolescent study, one interesting finding is that the pattern related to specific genes is unexpected. For example, in young people with genetic variations in the GABRA2 neurotransmitter receptor gene, we expected to see alcohol problems and we didn't. Instead, we observed conduct disorder. While you have to study adults to see the alcohol problem, in kids it's more behavior problems. When you look at persons who have the ADH4 gene variant, they begin drinking very early. When you observe persons with the CHRM2 gene variant, they experience depression and anxiety at greater rates as children. Later, they may develop alcohol problems.

Post: What other insights have emerged?

Dr. Nurnberger: A number of developments parallel the work we are doing. Some involve the identification of specific medications that reduce the risk of alcohol dependence, including naltrexone and acamprosate, which are used to reduce craving and risk of relapse.

Post: Are 12-step programs like Alcoholics Anonymous still cornerstones of treatment?

Dr. Nurnberger: Over the years Alcoholics Anonymous has been the most successful single treatment available for alcohol dependence. It still is. The A.A. Twelve Step Program has been adapted for many situations. For example, when adolescents and people with dual diagnoses, such as depression or anxiety, need help with substance abuse problems, A.A. is used. A series of psychotherapies are also under investigation--for example, motivational enhancement.

Alcohol treatment is actually much more successful than people realize. People tend to get a negative picture regarding addiction and the prognosis for people with addiction. It's unwarranted, because many treatments are successful both short- and long-term. People with an effective course of treatment tend to do well for about a year or so initially. A number will then slip back into problems with alcohol, but they seek treatment again, and eventually those who keep trying will be able to maintain their sobriety. Alcoholism has to be thought of as a chronic condition that requires long-term treatment. With that attitude and the ability to support long-term monitoring and treatment, people can recover very successfully from these disorders.

Post: Can someone with a vulnerability to alcoholism also inherit a predisposition to bipolar disorder, depression, or another disorder?

Dr. Nurnberger: Yes. They both need to be treated. That's been one of the difficulties in the past. In someone with depression and alcohol dependence, if you just treat the depression without the alcohol problem, It won't be effective and vice versa: if you just treat the alcohol problem without thinking about the depression, that's likely also not to be effective. There is an increased risk of alcohol dependence in persons with bipolar illness or depression. About half of people with major depression or bipolar illness will experience problems with alcohol dependence or substance abuse. The risk is about three times over the general population.

Post: Are we at a point where we tailor treatment to best address an individual's specific genetic profile?

Dr. Nurnberger: Not yet. There are not too many instances in which a genetic test would be of particular value as part of an individual's medical exam for alcohol dependence. But things may change rapidly in the next few years.

Post: In your recent article in Scientific American, you wrote, "Genetics is never destiny." What can physicians and members of high-risk families do with the emerging information about vulnerability to alcoholism or substance abuse?

Dr. Nurnberger: We are trying to understand the biochemical pathways to vulnerability so that new treatments can be designed. Just because a condition is related to genetics doesn't mean it can't be treated or altered. Genetic vulnerabilities are simply that--vulnerabilities. While you can't alter the DNA code you're born with, you can alter the way the genes are expressed and how your body makes proteins from that DNA. In fact, medications can change gene expression, as can exercise. In effect, you can help turn off or turn on various genes by what you do, what medications you take, and the foods that you eat. It's very important for people to realize that. because there is a prominent notion that "you've got a gene for this or that, therefore the condition is inevitable." That's not at all the case.

We have to think differently about how genes actually work. In the body, gene expression Is a very malleable process. We are trying to understand what the specific genes are that relate to alcohol dependence and how they work. We know some of them already, such as the GABRA2, the ADH4, and the CHRM2 that I mentioned.

Post: Will your research findings apply to other addictions, such as smoking?

Dr. Nurnberger: Yes. There is a genetic profile for tobacco dependence, as well as for alcohol dependence. The two conditions overlap quite a bit. Some of the overlap relates to a general predilection to addiction, and some has to do with specific aspects of nicotine or alcohol. We're beginning to understand the interaction. New evidence regarding the treatment response for people with tobacco dependence is very interesting with regard to the ability of genetic tests to predict treatment response to bupropion (Wellbutrin), one of the agents used to help people stop smoking. It may be that bupropion treatment is very good for persons with certain gene variants, while another treatment modality will help persons with other gene variants.

Post: In the course of meeting these families, has increased self-awareness of genetic risk helped individuals make more informed choices?

Dr. Nurnberger: In our clinic, the information has helped persons with bipolar illness; that's where I have the greatest exposure to individuals over time. The knowledge makes a difference in the way people think about themselves and their vulnerabilities. If they know that they are vulnerable to a certain substance, they may not stay away from it initially. Over time and with experience, they learn.

Post: Are you enrolling participants and families, and if so, what criteria are involved and whom should they contact?

Dr. Nurnberger: While we are not enrolling persons in the alcohol study, because we already have all needed subjects, we continue to enroll individuals in our ongoing bipolar study. For the bipolar study, persons can contact Carrie Smiley at (317) 274-8844.

Post: Are we overcoming the stigma associated with these disorders?

Dr. Nurnberger: Psychiatric illness has been stigmatized, Some think it shameful that people with any disorder might have to see a psychiatrist. There's no reason to think this. The brain is an organ Just like the heart, Things go wrong with the brain based on genetics, just like they might go wrong in the heart or liver based on genetics. As we understand more about the treatments people need, the stigma associated with who they are because of genetic vulnerability to anxiety, depression, or addiction will decrease. People will see that no matter what gene variant they were born with (and we all have some), they can do--or not do--things to make life better.

Post: What percentage of vulnerability to alcohol dependence is related to genetics?

Dr. Nurnberger: For alcohol dependence, about 50 percent is related to genetic factors and the other half to environmental factors, such as availability of alcohol and cultural factors. In comparison, the heritability of bipolar illness is about 80 percent, while the heritability of major depression is about 60 percent. Alcohol dependence is less heritable, but still substantially influenced by genetics. In general, there is rarely a situation where there's a 100 percent chance that someone is going to inherit the disorder, except in a single-gene condition, such as Huntington's disease. Most of the diseases we study and treat are conditions of complex inheritance, where there is an increased or a decreased risk.

Post: Could you discuss the connection between variations in basic physiology and individual susceptibility to alcohol problems?

Dr. Nurnberger: There is actually a protective effect in many persons from East Asian populations who have variant forms of the enzyme aldehyde dehydrogenase (ALDH2]. These persons tend to build up acetaldehyde--a byproduct of the metabolism of alcohol--which causes them to have low tolerance for alcohol. After one or two drinks, they may get a flushed feeling, feel uncomfortable. develop a rapid pulse, experience nausea or reddening of the skin. Persons with this variant have a much lower risk of developing alcohol dependency because they just don't tolerate the alcohol very long. We don't see this in the general U.S. population. but we do see more subtle effects related to variants of the alcohol dehydrogenase (ADH) enzyme, and some of these variants appear protective as well--a finding that emerged in the last few years.

Post: What is the clinical difference between alcohol dependence and alcohol abuse?

Dr. Nurnberger: Alcohol dependence is a more severe condition. We diagnose alcohol abuse if a person has one persistent symptom--driving while intoxicated or using alcohol in a way that it interferes with work or gets a person in trouble socially. If the symptom persists over time, that would be enough for a diagnosis of alcohol abuse.

Alcohol dependence, on the other hand. is a more pervasive characteristic. The diagnosis requires three or more symptoms that include loss of control, tolerance and withdrawal, giving up important activities In order to drink, and persistent drinking despite medical consequences. If the problems occur together over the course of a year or longer, we would call that alcohol dependence.

Post: Are brain electrical activity patterns different between alcoholics and nonalcoholics? If so, could we include an EEG as a useful clinical tool in the diagnosis of alcoholism?

Dr. Nurnberger: We use the electrical activity of the brain to provide information for research purposes, but not really for clinical purposes. Brain imaging could at some point be used for clinical purposes. But we are primarily trying to understand whether there is a difference in the electrical activity of the brain in persons vulnerable to alcohol dependence. We studied persons with alcohol problems and their relatives--those who drank and those who didn't. We found consistent differences in attention, response to stimuli like sounds and lights, and the predominant frequency of brain wave activity. It appears that persons vulnerable to alcohol dependence have measurable brain differences in terms of the electrical activity. For one, there appeared to be decreased attention to important stimuli in persons vulnerable to alcohol dependence. It also appeared as though there was decreased evidence of inhibition in the cortex area of the brain, which could be related to increased impulsivity. We believe it relates to the activity of GABA, a major inhibitory neurotransmitter in the brain. Like many of our findings, the hope is that these observations may one day translate into a target for intervention.

Post: In studies of children of alcoholics who were adopted by non-drinking families, does alcohol tend to emerge less often, harking back to the role of the environment?

Dr. Nurnberger: While we haven't done adoption studies in Indiana. studies have been done. primarily in Scandinavian countries that have central records of adoption and psychiatric hospitalization that investigators can access. It does appear that the chance for alcohol dependence is greater in adopted-away children of alcoholics, even if they are not brought up in families with the alcoholic person. One still faces increased risk from the genes.

Post: What is your overall hope by identifying genetic influences on vulnerability?

Dr. Nurnberger: Identifying genetic influences helps us on the road to self-knowledge and leads to strategies for optimal health and a productive life. The field is opening up In front of us. We will witness very real changes in the next couple of decades.