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Alcohol Alert

National Institute on Alcohol Abuse and Alcoholism No. 18 PH 357 July 1992


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.

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.


References

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In: Cox, W.M., ed. Why People Drink: Parameters of Alcohol as a Reinforcer. New York: Gardner Press, 1990. pp. 37-50. (8) Cloninger, C.R.; Bohman, M.; & Sigvardsson, S. Inheritance of alcohol abuse: Cross-fostering analysis of adopted men. Archives of General Psychiatry 36:861-868, 1981. (9) Begleiter, H., & Porjesz, B. Potential biological markers in individuals at high risk for developing alcoholism. Alcoholism: Clinical and Experimental Research 12:488-493, 1988. (10) Goedde, H.W., & Agarwal, D.P., eds. Alcoholism: Biomedical and Genetic Aspects. New York: Pergamon Press, 1989. (11) Crabbe, J.C., & Harris, R.A., eds. The Genetic Basis of Alcohol and Drug Actions. New York: Plenum Press, 1991. (12) Annoni, G.; Weiner, F.R.; Colombo, M.; Czaja, M.J.; & Zern, M.A. Albumin and collagen gene regulation in alcohol- and virus-induced human liver disease. Gastroenterology 98:197-202, 1990. (13) Cloninger, C.R., & Begleiter, H., eds. Genetics and Biology of Alcoholism: Banbury Report 33. New York: Cold Spring Harbor Laboratory Press, 1990. (14) McGue, M. "Genes, Environment, and the Etiology of Alcoholism." Paper presented at the Working Group on the Development of Alcohol-Related Problems in High-Risk Youth conference, Washington, DC, Nov. 14-16, 1991. (15) Pickens, R.W., & Svikis, D.S. Genetic influences in human substance abuse. Journal of Addictive Diseases 10:205-214, 1991. (16) Hrubec, Z., & Omenn, G.S. Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: Twin concordances for alcoholism and its biological endpoints by zygosity among male veterans. Alcoholism: Clinical and Experimental Research 5:207-212, 1981. (17) Pickens, R.W., & Svikis, D.S. The twin method in the study of vulnerability to drug abuse. In: Pickens, R.W., and Svikis, D.S., eds. Biological Vulnerability to Drug Abuse. National Institute on Drug Abuse Research Monograph Series No. 89. DHHS Pub. No. (ADM)88-1590. Washington, DC: Supt. of Docs., U.S. Govt. Print. 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Psychopathology in adopted-out children of alco holics: The Stockholm adoption study. In: Galanter, M., ed. Recent Developments in Alcoholism. Vol. 3. New York: Plenum Press, 1985. pp. 37-51. (24) Searles, J.S. The role of genetics in the pathogenesis of alcoholism. Journal of Abnormal Psychology 97(2):153-167, 1988. (25) Bohman, M.; Sigvardsson, S.; & Cloninger, C.R. Maternal inheritance of alcohol abuse: Cross-fostering analysis of adopted women. Archives of General Psychiatry 38:965-969, 1981. (26) Cloninger, C.R. Neurogenetic adaptive mechanisms in alcoholism. Science 236:410-416, 1987. (27) Schuckit, M.A. Biological vulnerability to alcoholism. Journal of Consulting and Clinical Psychology 55(3):301-309, 1987. (28) Hill, S.Y. Absence of paternal sociopathy in the etiology of severe alcoholism: Is there a type III alcoholism? Journal of Studies on Alcohol 53:161-169, 1992. (29) Gilligan, S.B.; Reich, T.; & Cloninger, C.R. Etiologic heterogeneity in alcoholism. 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(33) Comings, D.E.; Comings, B.G.; Muhleman, D.; Dietz, G.; Shahbahrami, B.; Tast, D.; Knell, E.; Kocsis, P.; Baumgarten, R.; Kovacs, B.W.; Levy, D.L.; Smith, M.; Borison, R.L.; Evans, D.D.; Klein, D.N.; MacMurray, J.; Tosk, J.M.; Sverd, J.; Gysin, R.; & Flanagan, S.D. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. Journal of the American Medical Association 266(13):1793-1800, 1991. (34) Bolos, A.M.; Dean, M.; Lucas-Derse, S.; Ramsburg, M.; Brown, G.L.; & Goldman, D. Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism. Journal of the American Medical Association 264:3156-3160, 1990. (35) Turner, E.; Ewing, J.; Shilling, P.; Smith, T.L.; Irwin, M.; Schuckit, M.; & Kelsoe, J.R. Lack of association between an RFLP near the D2 dopamine receptor gene and severe alcoholism. Biological Psychiatry 31:285-290, 1992. (36) Karp, R.W. D2 or not D2? 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