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.
Marc Schuckit, M.D.: "Alcoholism relates to a whole range of risk
factors, and very few if any of them relate to a person's moral fiber."
Schuckit was the recipient of APA's 2009 Adolf Meyer Award.
Credit: David Hathcox
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
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
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
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
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." ▪