Why do some people become addicts while others do not? Why can some teenagers take a drink of alcohol and not crave more while others know from the instant of their first drink that alcohol is going to cause them problems for the rest of their life?

The most obvious reason is that the susceptibility to addictive behaviors is an inborn or genetic trait. Studies of the frequency of alcoholism in children of alcoholics adopted away from their alcoholic parents at birth provide some of the most powerful evidence that our genes play an important role in the development of subsequent alcoholism.

Dr. Donald Goodman was one of the pioneers in this field. On the basis of such an adoption study he found that the frequency of alcoholism, in adopted-out sons of alcoholic fathers, was just as great when they were placed with non-alcoholic parents as with alcoholic parents. This meant that this form of alcoholoism was predominantly a genetic disorder.

However, it is one thing to know that certain genes play a critical role in our risk to develop alcoholism or other addictions, and another to find those genes. One approach is to ask if there are any genetic disorders of childhood that predispose to the development of addictive behaviors in adults. If the answer to this is 'yes', then finding the genes that cause such disorders might simultaneously find the gene that causes alcoholism and other addictive behaviours.

In fact, the answer to this question is 'yes', and the childhood disorder is attention deficit hyperactivity disorder or ADHD.

Attention Deficit Hyperactivity Disorder

ADHD was once called 'hyperactivity' or 'minimal brain damage' (MBD). Children with this disorder have a range of symptoms, including inability to concentrate, seeming not to listen when parents or teachers talk to them, having difficulty organizing their work, acting impulsively, having difficulty waiting their turn, being unable to sit still or stay in their seat, being constantly on the go, and other related behaviors. These symptoms cluster into groups labeled inattention, impulsivity and hyperactivity.

ADHD is the most common childhood behavioral disorder, affecting 5% to 8% of boys and 2% to 4% of girls. While the symptoms may improve with age, most studies show that about half of the children continue to have significant symptoms into adulthood. This is termed adult ADHD or ADHD residual type. Both adoption and family studies show that ADHD is common in the relatives of ADHD children, i.e., like alcoholism, ADHD is a genetic disorder.

Many, but not all, long-term studies of children with ADHD have also shown that, as they enter their teenage and early adult years, significantly more of them develop problems with alcoholism or drug addiction than do children without ADHD. In one study a group of Swedish children were examined in childhood and then restudied as adults.¹ Those who became alcoholics showed a much higher frequency of symptoms of ADHD as children than the adults who did not become alcoholics. Other studies show that when the relatives of ADHD children are examined, a much higher percentage of them have problems with alcoholism and depression than relatives of non-ADHD children.

These studies suggest that one of the genes causing alcoholism is the same gene that causes ADHD. Put differently, carriers of the ADHD-alcoholism gene express it as ADHD when they are children and as alcoholism and/or depression when they are teenagers.

Children with ADHD also have a high incidence of learning disorders and anxiety. When a gene causes more than one disorder it is termed a 'spectrum disorder.' Thus, the spectrum of the ADHD-alcoholism gene is ADHD, alcoholism, drug addiction, depression, learning disorders, and anxiety.

Tourette Syndrome

In 1980 we began to study what was then thought to be a rare hereditary disorder, Tourette syndrome or TS. TS is characterized by the presence of motor tics such as rapid eyeblinking, head jerking, facial grimacing, mouth opening, shoulder shrugging and other involuntary muscle jerks. Patients also have vocal tics such as throat clearing, grunting, sniffing, squeaking, barking, or other involuntary vocal noises. Between 10% and 30% also have involuntary swearing, but this is not necessary for the diagnosis. Although the diagnosis of TS requires the presence of both motor and vocal tics, some subjects have only motor or only vocal tics. These are considered genetic variants of TS and are called chronic moter tic disorder or chronic vocal tic disorder.

Soon after we began studying TS it became apparent that it was much more common than was generally thought. The diagnosis simply requires that these tics be present almost every day for at least one year. Because the tics are suppressible for minutes to hours, patients frequently do not display these symptoms in the doctor's office. Thus, a careful history, beginning in childhood and covering every year to their present age, is a critical part of the evaluation. In a two year study of three Los Angeles schools, we found that 1 in 90 schoolboys had Tourette syndrome.²

The second feature of Tourette syndrome that was striking to us was the wide range of other behavioral problems that many patients displayed. The most prominent was ADHD. Of the TS patients that seek medical help, 50% to 85% had a family history of TS or of chronic motor or vocal tics. Since TS is clearly a genetic disorder, this suggested that the TS gene was one of the major causes of ADHD.

Other behavioral problems that were common in TS patients and their relatives included obsessive-compulsive behaviors, learning disorders, dyslexia, conduct and discipline problems, anxiety, depression, autism, sleep disorders, short temper, and addictive behaviors including alcoholism and drug abuse, especially in the men, and compulsive eating with obesity, especially in the women.³

Our studies of over 1,800 TS families have shown that relatives with these associated disorders are simultaneously present on both the mother's and father's side. These findings led us to suspect that in order to develop TS a child had to inherit a TS gene from both his parents. This suggested a recessive form of inheritance. However, the family histories also indicated that carriers of a single TS gene could also have symptoms, including alcoholism. This is termed dominant inheritance. Thus, the form of inheritance of TS seemed to have characteristics of both. We have termed it 'semirecessive semidominant' inheritance. ⁴

The distinction between dominant and semirecessive semidominant inheritance is far from trivial. If TS was inherited as just a dominant trait, and 1 in 90 boys had the disorder, the frequency of gene carriers in the general population would be closer to 20%. If many of these carriers were at increased risk to develop addictive behaviors, this would provide one factor accounting for the high prevalence of alcoholism and drug addiction in our society.

Chemical Deficiency

Serotonin is one of the major chemicals in the brain involved in communication between individual nerves, i.e., it is a neurotransmitter. Serotonin is especially common in the part of the brain controlling emotions, called the limbic system, and in the part of the brain necessary for paying attention, for being motivated to do things, and for thinking before acting, located in the prefrontal lobes. Defects in serotonin have been postulated as causing all of the disorders listed above, including alcoholism and drug addiction. Because of this we suspected that Tourette syndrome might be caused by a genetic defect in how the body produces serotonin.

To test this we examined the blood levels of serotonin in 1,440 TS and ADHD patients, their parents, and controls. This showed that there was a significant decrease in serotonin levels in patients with both TS and ADHD, as well as in their parents.⁵ Since serotonin is made from tryptophan, a normal componenet of protein in the diet, we also examined tryptophan levels. They were also significantly decreased. This caused us to suspect that the gene causing TS, and many cases of ADHD and alcoholism, might be tryptophan oxygenase. This gene breaks down tryptophan. If a mutation made this gene do its job too well, tryptophan would be broken down too fast and there would be too little left over to make normal amounts of serotonin. Too little serotonin in the brain could lead to all of the behavioral problems associated with TS, including the addictive behaviors.

To study this further, we cloned the human tryptophan oxygenase gene and found it was located on the long arm of chromosome number 4, in band 3.1.⁶ Tempting evidence that we are on the right track has come from a study by Dr. S. Hill and colleagues of 35 families containing more than one male with early-onset alcoholism. Using a method called linkage analysis, she found preliminary evidence that the gene for early onset, hereditary alcoholism might be in the same band as tryptophan oxygenase, 4q3.1,^7,8 suggesting they could be one and the same gene.

Dopamine in TS, ADHD and Alcoholism

Dopamine is a second major neurotransmitter in the brain. While it is particularly improtant in controlling muscle movement, like serotonin it is also present in the limbic system and prefrontal lobes and thus plays a role in emotions, attention and motivation. It is also important in the reward pathway or pleasure centers of the brain. In order for neurotransmitters to work, they have to bind to receptors. For dopamine, five different types of receptor genes have been described.

In March of 1990 Blum Noble and colleagues reported that a mutation of the dopamine D₂ receptor gene (D₂A1) was present in 69% of severe alcoholics, versus 20% of non-alcoholic controls. Since defects in dopamine metabolism have also been implicated in TS, this led us to wonder whether the D₂A1 mutation was unique to alcoholism or whether it might be associated with TS and ADHD as well. Eventually we examined over 850 patients with a wide range of disorders, and compared them with controls. We found that in a total of 374 controls, 25% carried the D₂A1 mutation. By contrast the D₂A1 mutation was present in 40% to 55% of patients with TS, ADHD, alcoholism, autism and post-traumatic stress disorder (PTSD).⁹ PTSD is a behavioral disorder common in Vietnam veterans who experienced severe combat conditions. The D₂A1 mutation was not increased in frequency in patients with depression, panic attacks, obesity or Parkinson's disease. The studies to date suggest that the more severe the alcoholism or the TS, the more likely it is that the D₂A1 mutation was not the major gene causing any of these disorders. "These genes are yet to be discovered. In genetics we speak of the degree of expression of a gene. If a gene is fully expressed the symptoms are more severe. The D₂A1 mutation appeared to be playing a role in modifying the degree of expression of these yet to be discovered genes. The D₂A1 mutation appears to be related to addictive and impulsive behaviors and susceptability to stress.

A theory that incorporates all of these observations is illustrated in Figure 1. It is known that serotonin and dopamine metabolism are tightly interlinked in the brain, forming an axis in which defects in serotonin and hypersensitivity to dopamine have the same effect on aggressive and impulsive behaviors.¹ We believe that defects in the dopamine D receptor caused by the D₂A1 allele result in hypersensitivity to dopamine in other parts of the brain. Any upset in this balance causes a variety of behavioral problems. We suggest that a common gene affecting serotonin metabolism, such as the Tourette syndrome gene, causes the major tilt of this axis, but modifying genes, such as the D₂A1 allele, adds further tilting. This genetic background then interacts with environmental factors and a large dose of random unpredictability, i.e., chaos, to produce a wide variety of behavioral disorders in almost any combination.

These observatons begin to open the door to our understanding of TS, ADHD, addictive and other behaviors.

First, it is the first time that specific genetic abnormalities have been identified in connection with these disorders. These findings confirm the suspicion that genetic factors do play an important role.

Second, these findings show that mutations that directly affect specific receptors may affect behavior and that specific defects in dopamine receptors may play a role in addictive behaviors.

Third, they show that entities such as childhood ADHD may be genetically caused and not due to poor parenting or other environmental factors.

Fourth, they support the concept of spectrum disorders, i.e., a specific gene or genes causing an interrelated group of behavioral disorders, previously thought to be separate intities. TS, ADHD, alcoholism, drug abuse, conduct disorder, autism, and PTSD are part of this spectrum. Given the same genetic make-up, environmental factors and random chance may determine which of these disorders, if any, a person may develop.

Fifth, these findings may open the way to new concepts of treatment of addictive behaviors. The more that addictions are seen as biochemical and genetically caused defects, the more likely it is that biochemcal approaches, such as medications to replace the defective chemicals, will come to play a role in their treatment.

[Additional details about the role of TS and ADHD in addictions and other behaviors can be found in Comings, D.E. Tourette Syndrome and Human Behavior. 828pp, Hope Press, P.O. Box 188, Duarte, CA, 91009. It can be ordered by calling 1-800-321-4039.]