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Is there a genetic basis of alcoholism?
BIOL PSYCHIATRY 1992;32:955-957
955
EDITORIAL
Is There a Genetic Basis of Alcoholism? Alcoholism ranks among the most commonly occurring psychiatric disorders in the general population. Furthermore, it appears to have a higher probability of concurrence in families than most psychiatric disorders including the affective disorders (Merikangas et al 1985). Incidence of alcoholism in pedigrees selected for a high density of alcoholism reveals a segregation pattern that supports a major effect with or without additional multifactorial components (Aston and Hill 1990a). For males, adoption data suggest that this higher rate of presumed genetic transmission occurs even in the absence of exposure to the alcoholic p ~ n i (Goodwin et al 1973). Data gathered from male twin pairs (dizygous [DZ] and monozygous [MZ]) concordant or discordant for alcoholism have been more supportive of genetic etiologic factors than similar data obtained for women (Hill and Smith 1991) until recently when Kendler and colleagues (1992) announced that over 50% of the variance in alcoholism risk among female twin pairs could be explained by genetic factors. A disturbing trend, however, has been the tendency to assume that the higher rates of concurrence seen in alcoholic families are caused by entirely genetic factors. Clearly, the onset and maintenance of abusive drinking is dependent on the sociocultural background of the individual and the situational factors present that promote or prevent drinking. Because alcoholism is a complex disorder, its etiology and pathogenesis are most likely the result of both genetic and environmental factors of uncertain proportions (Hill et al 1986). With this in mind, does it make sense to search for an alcoholism susceptibility gene or genes? The answer to that question is a qualified yes. First, we need to specify what type of alcoholism we will study. Which form appears to have the greatest likelihood of being genetically mediated? Alcoholism appears in many forms and in association with a variety of psychiatric problems. The first step is to reduce the heterogeneity by studying some "pure" form of the disorder. Secondly, we need to recognize that there may be phenocopies. Not all alcoholics need to have a genetic propensity to the disorder. In fact, whole families may be phenocopies! Although a few alcoholism researchers would agree with the statement that "most of the variance in alcoholism outcome is attributable to genetic factors," many of the research designs employed to seek psychobiological predictors have made that assumption through designs that have contrasted "family history positive" and "family history negative" individuals. Apparently, the underlying assumption is that the presence of a single first-degree relative is evidence for a genetic predisposition. This is not so. To test the notion that there is considerable heterogeneity among pedigrees designated as "family history positive," we submitted two of our pedigrees to a quantitative analysis using the program MENDEL in collaboration with Dr. Stephen Matthysse. What we found was that the two pedigrees had vastly different likelihoods of frequency, if a sporadic family is defined as one in which factors other than genetic ones have etiological significance. In one case, the likelihood was less than 7% and in the other over 80%. This example underscores the need to take studies of alcoholism risk beyond categorical groups to quantified risk estimates. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
956
BIOL PSYCHIATRY 1992;32:955-957
Editorial
Thirdly, we need to recognize that although some genes have evolved specifically to take care of the metabolism of alcohol in both man and animals (e.g., alcohol dehydrogenase, aldehyde dehydrogenase) these genes may have little to do with the etiology of alcoholism. Rather, they may have more to do with nature's insurance that prehistoric man and animals did not eat themselves to death through fermented berries they could not handle metabolically. The key to understanding genetic mediation of alcoholism will come through the study of the transmission of intervening variables (e.g., temperament, information-processing capacity) that readily distinguish alcoholics from nonalcoholics, high-risk from low-risk individuals, and are trait rather than state marke~. Even if alcoholism is to some degree genetically mediated, the question arises what is being transmitted? The best candidates will be behavioral markers that jointly satisfy these criteria: (1) the marker distinguishes alcoholics from nonalcoholics, (2) the marker distinguishes high-risk from low-risk individuals, (3) the marker is not associated solely with alcohol use, but remains beyond the episode of drinking (vulnerability marker), and (4) the marker is heritable. We believe that specific aspects of temperament may qualify (Hill et al 1990b). In a review of over 30 twin studies, Nichols (1978) concluded that the mean correlation for MZ twins was 0.52 and 0.25 for DZ twins. The review also suggested that all measured aspects of personality appeared to be equally heritable. More recently, Ahem et al (1982) and Tellegen et al (1988) concluded that some domains of personality are more familial than others. Our findings support this notion. When correlations in personality were calculated for siblings for the two family types, alcoholic, and control, we found moderate correlations for specific traits (Hill et al 1990b). Interestingly, some traits were highly correlated in siblings from either family type (e.g., impulsivity), whereas other traits appeared to be highly correlated only within sibling pairs from the alcoholic pedigrees (e.g,, alienation). Moreover, when correlations between mates were evaluated it appeared that assortative mating for personality type was occurring. This suggests that susceptibility to alcoholism may arise through inbreeding for temperament. It may turn out that individuals temperamentally prone to be tense, restless, and impulsive or apprehensive are simply more likely to seek relief or relaxation from alcohol. We are also confident that particular neurobehaviorai markers recently found to reliably distinguish high-risk and low-risk individuals will qualify as risk markers based on the criteria outlined previously. Specifically, the P300 component of the event-related potential has been shown to distinguish alcoholics from nonalcoholics (Pfefferbaum et al 1979). Moreover, there is now a consensus that the amplitude of the P300 component is reduced in high-risk individuals (Begleiter et al 1984; Hill et al 1990a; Hill and Steinhauer in press; Steinhauer and Hill in press). Although there has been controversy concerning the reliability of the earlier finding (Polich and Bloom 1987; 1988), it is now clear that emergence of high/low risk differences is dependent on reducing experimental variance by administering tasks to children who have not yet begun to drink alcohol, controlling for gender differences, particularly as they relate to development, task difficulty, and modality of presentation (auditory or visual). These findings are particularly exciting in view of suggestions that event-related potentials may be strongly influenced by genes. Several laboratories have shown similarities of wave forms in genetically related individuals (Polich and Bums 1987; Steinhauer et al 1987). Recently, we have demonstrated a major genetic effect in the familial transmission of P300 using segregation analysis (Aston and Hill 1990b). In summary, there appears to be no specific genetic transmission of alcoholism in the
Editorial
BIOL PSYCHIATRY 1992;32:955-957
957
strict Mendelian sense, but there may well be a genetic diathesis for its development. However, the complexity of the endpoint phenotype (alcoholism) may obscure significant latent traits that are under genetic control. Shirley Y. Hill University of Pittsburgh Medical Center Department of Psychiatry Pittsburgh, Pennsylvania
References Ahem FM, Johnson RC, Wilson JR, McClearn GE, Vandenberg SG (1982): Family resemblances in personality. Behav Genet 12:261-280. Aston CE, Hill SY (1990a): Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics. Am J Hum Genet 46:879-887. Aston CE, Hill SY (1990b): A segregation analysis of the P300 component of the event-related brain potential. Am J Hum Genet 47(suppl): A127. Begleiter H, Porjesz B, Bihari B, Kissin B (1984): Event-related brain potentials in boys at risk for alcoholism. Science 225:1493-1496. Goodwin DW, Schulsinger F, Hermansen L, Guze SB, Winokur G. (1973): Alcohol problems in adoptees raised apart from alcoholic biological parents. Arch Gen Psychiatry 28:238-243. Hill SY, Smith TR (! 99 I): Evidence for genetic mediation of alcoholism in women. J Subst Abuse 3:!59-174. Hill SY, Steinhauer SR: Assessment of prepubertal and postpubertal boys and girls at risk for developing alcoholism with P300 from a visual discrimination task. J Stud Alcohol (in press). Hill SY, Zubin J, Steinhauer SR (1990). Personality resemblance in relatives of male alcoholics: A comparison with families of male control cases. Biol Psychiatry 27:1305-1322. Hill SY, Steinhauer SR, Zubin J (1986): Biological markers for alcoholism: A vulnerability model conceptualization. In Rivers PC (ed), Alcohol and Addictive Behavior, Nebraska Symposium on Motivation. Lincoln and London: University of Nebraska Press, pp 207-256. Kendler KS, Heath AC, Neale, MC, Kessler RC, Eaves l.J (1992): J Am Med Assoc 14:18771882. Merikangas KR, Leckman JF, Prusoff BA, Pauls DL, Weissman MM (1985): Familial transmission of depression and alcoholism. Arch Gen Psychiatry 42:367-372. Nichols RC (1978): Twin studies of ability, personality, and interest. Homo 29:158-173. Pfefferbaum A, Horvath TB, Roth WT, Kopell BS (1979): Event-related potential changes in chronic alcoholics. Electroencephalogr Clin Neurophysiol 47:637--647. Polich J, Bloom FE (1987): P300 from normals and adult children of alcoholics. Alcohol 4:301305. Polich J, Bloom FE (1988): Event-related brain potentials in individuals at high and low risk for developing alcoholism: Failure to replicate. Alcohol Clin Exp Res 12:368-373. Steinhauer SR, Hill SY: Auditory event-related potentials in children at high risk for alcoholism. J Stud Alcohol (in press). Steinhauer SR, Hill SY, Zubin J (1987): Event-related potentials in alcoholics and their first-degree relatives. Alcohol 4:307-314. Tellegen A, Lykken DT, Bouchard TJ Jr, Wilcox KF, Segal NL, Rich S (1988): Personality similarities in twins reared apart and together. J Pets Soc Psychol 54:1031-1039.
955
EDITORIAL
Is There a Genetic Basis of Alcoholism? Alcoholism ranks among the most commonly occurring psychiatric disorders in the general population. Furthermore, it appears to have a higher probability of concurrence in families than most psychiatric disorders including the affective disorders (Merikangas et al 1985). Incidence of alcoholism in pedigrees selected for a high density of alcoholism reveals a segregation pattern that supports a major effect with or without additional multifactorial components (Aston and Hill 1990a). For males, adoption data suggest that this higher rate of presumed genetic transmission occurs even in the absence of exposure to the alcoholic p ~ n i (Goodwin et al 1973). Data gathered from male twin pairs (dizygous [DZ] and monozygous [MZ]) concordant or discordant for alcoholism have been more supportive of genetic etiologic factors than similar data obtained for women (Hill and Smith 1991) until recently when Kendler and colleagues (1992) announced that over 50% of the variance in alcoholism risk among female twin pairs could be explained by genetic factors. A disturbing trend, however, has been the tendency to assume that the higher rates of concurrence seen in alcoholic families are caused by entirely genetic factors. Clearly, the onset and maintenance of abusive drinking is dependent on the sociocultural background of the individual and the situational factors present that promote or prevent drinking. Because alcoholism is a complex disorder, its etiology and pathogenesis are most likely the result of both genetic and environmental factors of uncertain proportions (Hill et al 1986). With this in mind, does it make sense to search for an alcoholism susceptibility gene or genes? The answer to that question is a qualified yes. First, we need to specify what type of alcoholism we will study. Which form appears to have the greatest likelihood of being genetically mediated? Alcoholism appears in many forms and in association with a variety of psychiatric problems. The first step is to reduce the heterogeneity by studying some "pure" form of the disorder. Secondly, we need to recognize that there may be phenocopies. Not all alcoholics need to have a genetic propensity to the disorder. In fact, whole families may be phenocopies! Although a few alcoholism researchers would agree with the statement that "most of the variance in alcoholism outcome is attributable to genetic factors," many of the research designs employed to seek psychobiological predictors have made that assumption through designs that have contrasted "family history positive" and "family history negative" individuals. Apparently, the underlying assumption is that the presence of a single first-degree relative is evidence for a genetic predisposition. This is not so. To test the notion that there is considerable heterogeneity among pedigrees designated as "family history positive," we submitted two of our pedigrees to a quantitative analysis using the program MENDEL in collaboration with Dr. Stephen Matthysse. What we found was that the two pedigrees had vastly different likelihoods of frequency, if a sporadic family is defined as one in which factors other than genetic ones have etiological significance. In one case, the likelihood was less than 7% and in the other over 80%. This example underscores the need to take studies of alcoholism risk beyond categorical groups to quantified risk estimates. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
956
BIOL PSYCHIATRY 1992;32:955-957
Editorial
Thirdly, we need to recognize that although some genes have evolved specifically to take care of the metabolism of alcohol in both man and animals (e.g., alcohol dehydrogenase, aldehyde dehydrogenase) these genes may have little to do with the etiology of alcoholism. Rather, they may have more to do with nature's insurance that prehistoric man and animals did not eat themselves to death through fermented berries they could not handle metabolically. The key to understanding genetic mediation of alcoholism will come through the study of the transmission of intervening variables (e.g., temperament, information-processing capacity) that readily distinguish alcoholics from nonalcoholics, high-risk from low-risk individuals, and are trait rather than state marke~. Even if alcoholism is to some degree genetically mediated, the question arises what is being transmitted? The best candidates will be behavioral markers that jointly satisfy these criteria: (1) the marker distinguishes alcoholics from nonalcoholics, (2) the marker distinguishes high-risk from low-risk individuals, (3) the marker is not associated solely with alcohol use, but remains beyond the episode of drinking (vulnerability marker), and (4) the marker is heritable. We believe that specific aspects of temperament may qualify (Hill et al 1990b). In a review of over 30 twin studies, Nichols (1978) concluded that the mean correlation for MZ twins was 0.52 and 0.25 for DZ twins. The review also suggested that all measured aspects of personality appeared to be equally heritable. More recently, Ahem et al (1982) and Tellegen et al (1988) concluded that some domains of personality are more familial than others. Our findings support this notion. When correlations in personality were calculated for siblings for the two family types, alcoholic, and control, we found moderate correlations for specific traits (Hill et al 1990b). Interestingly, some traits were highly correlated in siblings from either family type (e.g., impulsivity), whereas other traits appeared to be highly correlated only within sibling pairs from the alcoholic pedigrees (e.g,, alienation). Moreover, when correlations between mates were evaluated it appeared that assortative mating for personality type was occurring. This suggests that susceptibility to alcoholism may arise through inbreeding for temperament. It may turn out that individuals temperamentally prone to be tense, restless, and impulsive or apprehensive are simply more likely to seek relief or relaxation from alcohol. We are also confident that particular neurobehaviorai markers recently found to reliably distinguish high-risk and low-risk individuals will qualify as risk markers based on the criteria outlined previously. Specifically, the P300 component of the event-related potential has been shown to distinguish alcoholics from nonalcoholics (Pfefferbaum et al 1979). Moreover, there is now a consensus that the amplitude of the P300 component is reduced in high-risk individuals (Begleiter et al 1984; Hill et al 1990a; Hill and Steinhauer in press; Steinhauer and Hill in press). Although there has been controversy concerning the reliability of the earlier finding (Polich and Bloom 1987; 1988), it is now clear that emergence of high/low risk differences is dependent on reducing experimental variance by administering tasks to children who have not yet begun to drink alcohol, controlling for gender differences, particularly as they relate to development, task difficulty, and modality of presentation (auditory or visual). These findings are particularly exciting in view of suggestions that event-related potentials may be strongly influenced by genes. Several laboratories have shown similarities of wave forms in genetically related individuals (Polich and Bums 1987; Steinhauer et al 1987). Recently, we have demonstrated a major genetic effect in the familial transmission of P300 using segregation analysis (Aston and Hill 1990b). In summary, there appears to be no specific genetic transmission of alcoholism in the
Editorial
BIOL PSYCHIATRY 1992;32:955-957
957
strict Mendelian sense, but there may well be a genetic diathesis for its development. However, the complexity of the endpoint phenotype (alcoholism) may obscure significant latent traits that are under genetic control. Shirley Y. Hill University of Pittsburgh Medical Center Department of Psychiatry Pittsburgh, Pennsylvania
References Ahem FM, Johnson RC, Wilson JR, McClearn GE, Vandenberg SG (1982): Family resemblances in personality. Behav Genet 12:261-280. Aston CE, Hill SY (1990a): Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics. Am J Hum Genet 46:879-887. Aston CE, Hill SY (1990b): A segregation analysis of the P300 component of the event-related brain potential. Am J Hum Genet 47(suppl): A127. Begleiter H, Porjesz B, Bihari B, Kissin B (1984): Event-related brain potentials in boys at risk for alcoholism. Science 225:1493-1496. Goodwin DW, Schulsinger F, Hermansen L, Guze SB, Winokur G. (1973): Alcohol problems in adoptees raised apart from alcoholic biological parents. Arch Gen Psychiatry 28:238-243. Hill SY, Smith TR (! 99 I): Evidence for genetic mediation of alcoholism in women. J Subst Abuse 3:!59-174. Hill SY, Steinhauer SR: Assessment of prepubertal and postpubertal boys and girls at risk for developing alcoholism with P300 from a visual discrimination task. J Stud Alcohol (in press). Hill SY, Zubin J, Steinhauer SR (1990). Personality resemblance in relatives of male alcoholics: A comparison with families of male control cases. Biol Psychiatry 27:1305-1322. Hill SY, Steinhauer SR, Zubin J (1986): Biological markers for alcoholism: A vulnerability model conceptualization. In Rivers PC (ed), Alcohol and Addictive Behavior, Nebraska Symposium on Motivation. Lincoln and London: University of Nebraska Press, pp 207-256. Kendler KS, Heath AC, Neale, MC, Kessler RC, Eaves l.J (1992): J Am Med Assoc 14:18771882. Merikangas KR, Leckman JF, Prusoff BA, Pauls DL, Weissman MM (1985): Familial transmission of depression and alcoholism. Arch Gen Psychiatry 42:367-372. Nichols RC (1978): Twin studies of ability, personality, and interest. Homo 29:158-173. Pfefferbaum A, Horvath TB, Roth WT, Kopell BS (1979): Event-related potential changes in chronic alcoholics. Electroencephalogr Clin Neurophysiol 47:637--647. Polich J, Bloom FE (1987): P300 from normals and adult children of alcoholics. Alcohol 4:301305. Polich J, Bloom FE (1988): Event-related brain potentials in individuals at high and low risk for developing alcoholism: Failure to replicate. Alcohol Clin Exp Res 12:368-373. Steinhauer SR, Hill SY: Auditory event-related potentials in children at high risk for alcoholism. J Stud Alcohol (in press). Steinhauer SR, Hill SY, Zubin J (1987): Event-related potentials in alcoholics and their first-degree relatives. Alcohol 4:307-314. Tellegen A, Lykken DT, Bouchard TJ Jr, Wilcox KF, Segal NL, Rich S (1988): Personality similarities in twins reared apart and together. J Pets Soc Psychol 54:1031-1039.