National Institute on Alcohol Abuse and Alcoholism No. 18 PH 357 July 1995
The Genetics of Alcoholism
The idea that alcoholism runs in families is an ancient
one. In recent decades, science has advanced this idea from the status of
folk-observation to systematic investigation (1-3). In the 1970s, studies
documented that alcoholism does run in families (4,5). But does alcoholism run
in families because a child learns to become an alcoholic from parents and the
home environment, or because a child inherits genes that create an underlying
predisposition for alcoholism? Or both? The studies did not resolve these
questions.
Why do we do genetic research? The discovery of a specific genetic
effect on the development of alcoholism would be beneficial for at least three
reasons. First, it would lead to the identification of some people at risk, who
could act to avoid developing alcohol-related problems (6,7). Second, it may
help us to understand the role of environmental factors that are critical in the
development of alcoholism (8). Third, it may lead to better treatments, based on
new understandings of the physiological mechanisms of alcoholism (9-11).
Although investigations of the inheritance of a vulnerability
to alcoholism are discussed here, a separate and distinct issue, not
addressed here, is the possibility that a vulnerability to organ damage
by alcohol is under some genetic control (12).
Researchers investigate possible genetic components of alcoholism
by studying populations and families as well as genetic, biochemical, and
neurobehavioral markers and characteristics (13,14). Two major methods of
investigating the inheritance of alcoholism are studies of twins and of adoptees
(15). Twin studies compare the incidence of alcoholism in identical twins with
the incidence of alcoholism in fraternal twins (16,17). If there is a genetic
component in the risk for alcoholism, then identical twins, who have identical
genes, would be expected to exhibit similar histories of developing alcoholism
(or not developing alcoholism). Fraternal twins, who are genetically different
individuals born at the same time, would be more likely to differ in their
tendencies to develop alcoholism. In general, researchers using the twin method
have found these expectations to be true.
For example, Pickens and co-workers (18) studied 169 same-sex
pairs of twins, both males and females, at least one of which had sought
treatment for alcoholism. The researchers found greater concordance of alcohol
dependence in identical twins than in fraternal twins. They also found greater
concordance of alcohol abuse (defined by DSM-III--Diagnostic and Statistical
Manual of Mental Disorders, Third Edition, of the American Psychiatric
Association) in identical male twins but not in identical female twins. Other
twin studies have produced more detailed information; for example, Partanen and
co-workers (19), in studying 902 male Finnish twins, found that less severe
drinking patterns were less heritable, and more severe drinking patterns were
more heritable.
Among the difficulties in designing twin studies is accounting for
unequal environmental conditions. Early studies assumed that the environments of
two fraternal twins were as similar to each other as were the environments of
two identical twins. Later studies showed that the environments of identical
twins are more alike than are the environments of fraternal twins, and recent
twin studies have taken this difference into account (14). The results of twin
studies are useful and have suggested the possibility of a genetic component in
inheritance (20); however, because focuses of the studies have varied, the
results are difficult to interpret.
&# 009;Adoption studies may employ a number of techniques. One
is to compare the histories of children of alcoholics who are adopted by
nonalcoholics and grow up in a nondrinking environment with the histories of
children of nonalcoholics similarly raised in a nondrinking environment (21-23).
If genetic factors play a role, then the adopted children of alcoholics should
preferentially develop alcoholism as adults.
Problems in designing and interpreting adoption studies result
from, among other things, the lack of detailed data on parents who give up
children for adoption, and environmental biases (as in the predominance of a
certain type of adopting family) (24).
In a pioneering study of adopted Danish children, Goodwin and
co-workers found some evidence for the expected trends (4,21). Cloninger and
co-workers subsequently performed a series of much larger studies of adoptees,
which also revealed these trends (8,25).
Cloninger and co-workers (23) hypothesized that so-called type II
alcoholics--characterized as having an early onset of drinking problems, usually
being male, and displaying personality disorders such as antisocial
behavior--had a more heritable form of alcoholism (26). However, other
researchers have argued that the scenario of inheritance is more complex, and
what is inherited is a mix of personality traits, such as those related to
antisocial behavior, rather than alcoholism itself (27). Genes might play a
direct role in the development of alcoholism, as in affecting the body's
metabolism of alcohol; or they might play a less direct role, influencing a
person's temperament or personality in such a way that the person becomes
vulnerable to alcoholism.
Different models for the way in which alcoholism runs in families
have been suggested by a limited number of family studies. Interpretation of
these studies has been complicated by the likelihood that alcoholism is a
heterogeneous condition, that is, a collection of different conditions that look
similar, but whose mechanisms and modes of inheritance may differ. Additional
studies are needed to sort out the mechanisms of transmission (28,29).
Population and family studies such as those cited above attempt to
establish the presence of a broad genetic influence on alcoholism. To
investigate specific genes, researchers have employed genetic marker studies. If
specific human genes are related to alcoholism, then genes lying close to them
on the same chromosome--and the traits they determine--may be inherited at the
same time that the risk of alcoholism is inherited. This phenomenon is called
linkage. An assortment of genes hypothesized to be linked to alcoholism has been
examined (30), but none has passed a rigorous test for linkage (31).
Still being studied is a marker referred to as the dopamine D2
receptor, which Blum and co-workers (32) found to be present more often in
alcoholics than in nonalcoholics (also see 33). In animal studies, the dopamine
D2 receptor had been associated with brain functions relating to reward,
reinforcement, and motivation. However, a number of researchers have been unable
to duplicate the results of Blum's study (34,35). Some researchers believe
dopamine D2 might modulate the severity of alcoholism, rather than serve as a
primary cause. The dopamine D2 association continues to be interesting, but it
does not seem to be transmitted in families in such a way that it is responsible
for alcoholism; its role, if any, has yet to be determined (36).
To search the human genome for specific genes related to
alcoholism, researchers employ two experimental techniques. The first, the
candidate gene approach, involves hypothesizing that particular genes are
related to the physiology of alcoholism and then individually testing these
genes for linkage (37). The second approach, scanning of the human genome,
involves characterizing, piece by piece, the entire length of DNA and finding ge
nes that relate to alcoholism, without proposing candidate genes.
Additionally, researchers use animal models to study the genetics
of alcoholism. These models have several advantages over human subjects. Using
animals, researchers can study larger numbers and more generations of subjects,
can arrange informative matings, can better manipulate the environment, and can
make measurements that would not be possible on humans. The main limitation of
using animals to study alcoholism is that there is no animal model of alcoholism
that encompasses the whole spectrum of alcoholic behaviors in humans.
Researchers nevertheless have studied alcohol-related behaviors in
animals that are believed to resemble aspects of human alcoholism. These include
consumption of and preference for alcohol, sedation induced by alcohol,
locomotor activation by alcohol (thought by some investigators to model the
euphoric effects of alcohol in humans), motor discoordination and hypothermia
induced by alcohol, withdrawal from alcohol, and tolerance to various effects of
alcohol (38). Researchers have succeeded in breeding lines of rodents with high
or low measures of most of these traits; this success demonstrates that the
traits are substantially genetically determined in rodents.
Researchers, using animals, have yet to identify a single gene
responsible for any alcohol-related behavior. They have established that all of
the above-mentioned traits are determined by multiple genes, and that the
individual traits are, for the most part, determined independently of each
other. One useful distinction revealed by studies using animals is that genes
determining the tendency to become tolerant to certain effects of alcohol are
different from genes determining the severity of withdrawal symptoms (even
though in a clinical setting these reactions are often seen together) (38).
Using the powerful genetic methods available in animals, investigators are
beginning to map genes responsible for some of the animals' alcohol-related
behaviors. The recent development of a scheme that makes it possible to predict
the location on the human genome of a similar gene mapped in a mouse will
provide an additional source of candidate genes for linkage studies in humans
(39). This approach also will help to distinguish those animal behaviors now
under study that will be most valuable for understanding human alcohol-related
behavior.
The Genetics of Alcoholism--A Commentary by
NIAAA Director Enoch Gordis, M.D.
Progress has been made in understanding genetic
vulnerability to alcoholism. We know, for instance, that more than one gene is
likely to be responsible for this vulnerability. We now must determine what
these genes are and whether they are specific for alcohol or define something
more general, such as differences in temperament or personality that increase an
individual's vulnerability to alcoholism. We must also determine how genes and
the environment interact to influence vulnerability to alcoholism. Based on our
current understanding, it is probable that environmental influences will be at
least as important, and possibly more important, than genetic influences.
Success in uncovering the genes involved in a vulnerability to alcoholism will
help us to recognize the potential for alcoholism in high-risk individuals, to
intervene at an early stage, and to develop new treatments for alcohol-related
problems. This is a productive area of research that will continue to yield
important answers to the basic questions of what causes alcoholism and how we
can prevent and treat it.
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