Understanding Complex Interactions Key to Preventing Alcohol Abuse

Like other mental illnesses, alcohol use disorders (AUDs) develop through interactions of multiple genetic vulnerabilities and environmental factors over a long period. By understanding these interactions, psychiatrists can devise and apply targeted, effective, and efficient prevention methods.

These were the messages of Marc Schuckit, M.D., in his Adolf Meyer Award lecture at APA's 2009 annual meeting in May in San Francisco. Schuckit is a professor of psychiatry at the University of California, San Diego, and director of the Alcohol and Drug Treatment Program and Alcohol Research Center at the Veterans Affairs San Diego Healthcare System.

His lecture, “How Alcoholism Develops: Identification of Genetic and Environmental Influences in a 25-Year Longitudinal Study,” examined groundbreaking research by him and his colleagues on the intricate dynamics between genes and environment that reveal much about AUDs as well as other mental illnesses.

Even before the advent of genetic testing, twin and family studies had pointed to a substantial genetic component in the development of AUDs. Genetic factors were estimated to account for about 60 percent of the risk of the disease, Schuckit told those in the packed lecture hall. “To fully understand how alcoholism develops, scientists have to investigate ... how the multiple genes conferring vulnerability interact with multiple environmental risk factors,” he said.

As with illnesses such as heart disease and schizophrenia, AUDs involve multiple risk factors, and each may be linked to multiple genes, Schuckit noted. He used heart attack as an analogy. Hypertension and high cholesterol levels are both risk factors, but each condition has its own set of genetic risk factors, which interact with environmental influences such as stress and diet. Risk factors for AUDs, such as high impulsivity, genes related to schizophrenia and bipolar disorder, and polymorphisms in alcohol metabolizing enzyme genes, have all been studied.

A key risk factor in Schuckit's research is a person's level of response (LR) to alcohol. LR is a genetically influenced characteristic, known as an endophenotype, that involves multiple genes. It is a measure of a person's sensitivity to alcohol. “If you're more sensitive to alcohol, you tend to drink less and have less risk for alcoholism,” he explained. People with different LRs feel different effects when their blood alcohol concentrations are the same.

Schuckit and colleagues have been conducting the San Diego Prospective Study (SDPS), a 25-year study of how AUDs develop. Since 1978, they have been following 453 young men starting when they were about 20 years old, half of whom had at least one parent with an AUD and half of whom were controls. These young men were tested for LR and other characteristics at baseline and then were followed every five years for 25 years. Over time, these men's spouses and children joined the study as well. With a remarkable follow-up rate of nearly 95 percent, the study provides a unique opportunity to examine how genes and environment interact over time.

The SDPS researchers found that low LR measured in adolescence is not only correlated with current drinking but also predicts the level of drinking and AUDs later in life. However, LR does not predict the risk of developing other psychiatric or substance use disorders, making it a unique risk factor for AUD.

Several genetic polymorphisms have been associated with low LR, including the serotonin transporter gene, gamma-aminobutyric acid (GABA) receptor alpha-6 subunit gene, KCNMA1 gene, and a nicotinic receptor gene.

Meanwhile, LR interacts with environmental factors such as peer influence, one's expectation for the effect of drinking, and stress. “Once you start getting into a pattern of heavy drinking,... you start picking or are only tolerated by heavy-drinking friends,” said Schuckit. Some people expect euphoria or increased sociability, he pointed out, while others expect to feel bad, and still others drink to cope with stress. Some of these expectations may encourage drinking, while the expectation of feeling ill from drinking can be protective.

In the SDPS, Schuckit's group found that a person's expectation from drinking and ability to cope with stress, but not peer drinking, significantly influenced the correlation between LR and AUD outcomes.

However, in the Avon Longitudinal Study of Parents and Children conducted by researchers at Great Britain's University of Bristol, LR's effect on outcomes was significantly mediated by peers in younger people around age 13. In other words, younger teens with low LR are more likely to have peers who drink more and to have worse outcomes.

What has been learned, Schuckit noted, is that prevention in adults with a high LR should target stress-coping skills and expectation for drinking, while addressing peer influence should probably be part of prevention in younger teens.

In summary, he said, he wanted clinicians to remember that “alcohol use disorders are genetically influenced.” This genetic component should be communicated to patients with AUDs and to their family members. “You may have the ability to do a bit of prevention by educating the patient's family about the genetic risk factors that they may carry,” he suggested. Furthermore, like most psychiatric disorders, “alcoholism relates to a whole range of risk factors, and very few if any of them relate to a person's moral fiber.”

“I'm hoping that five years from now, with the help of my friends, I will be able to start identifying kids based on their genotypes, before their first drink... and find out whether they have one of the risk factors for alcoholism,” said Schuckit. “Depending on their age, we can determine which interventions will make sense to try to diminish the impact of those genes.” ▪