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Sex Differences in the Genetic Risk for Alcoholism

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Sex Differences in the Genetic Risk for Alcoholism Sex Differences in the Genetic Risk for Alcoholism Carol A. Prescott, Ph.D. One of the characteristics influencing a person’s risk for alcoholism is his or her sex, and various factors may contribute to sex differences in risk. Adoption studies have provided some evidence of possible sex differences in the heritability of alcoholism, but overall the findings have been inconclusive. Twin studies have consistently supported the role of genetic risk factors in the heritability of alcoholism in men, and shared environmental factors also play a role in the familiality of alcoholism among women. In addition, sex differences exist in the patterns of transmission of alcoholism between family members. However, the genetic epidemiology research conducted to date on this issue has several limitations, some of which may be resolved by future molecular genetic studies. KEY WORDS: gender differences; genetic linkage; hereditary factors; risk factors; twin study; adoption study; epidemiological indicators; etiology; molecular genetics; AOD (alcohol and other drug) use susceptibility; AOD dependence potential; comorbidity; alcoholic beverage ne of the factors associated sources of genetic influences (i.e., sex- accounting for about half of the popu­ with a person’s risk for alco- specific transmission of genetic risk fac­ lation variation in liability to develop Oholism1 is his or her sex. In tors). Studies in many cultures have alcoholism (Prescott 2001). However, this article, the term “sex” is used in both found that the prevalence of alcoholism as will be described in this article, the its biological sense (i.e., as a variable and heavy drinking generally is higher evidence regarding the role of genetic based on genetic differences between among men than among women. Both cultural and biological explanations males and females) and its cultural CAROL A. PRESCOTT, PH.D., is an associ­ have been invoked to account for this meaning (i.e., in the sense of gender ate professor of psychiatry at the Virginia roles). Sex is associated with both bio­ difference, but the mechanisms remain Institute for Psychiatric and Behavioral logical risk factors (e.g., sex-specific unclear. Moreover, differences in preva­ Genetics and co-director of the Virginia hormone systems) and cultural risk fac­ lence may arise even if the mechanisms Adult Twin Study of Psychiatric and tors (e.g., social expectations about underlying alcoholism development do Substance Use Disorders, both at the how men and women use alcohol). An not differ between the sexes. In this Medical College of Virginia of Virginia understanding of the mechanisms case, the same genetic factors could Commonwealth University, Richmond, influencing sex differences in risk can predispose men and women to alco­ Virginia. help illuminate not only the differences holism, but other sex-specific genetic in men’s and women’s drinking behav­ and/or environmental factors could Preparation of this manuscript was sup- ior and related problems but also the influence whether alcoholism develops ported by Research Scientist Development biological and cultural bases for vari­ in a given person. Award K01–AA–00236 and National ability within each sex. The magnitude of genetic influ­ Institute on Alcohol Abuse and Sex differences in the factors under- ences on alcoholism risk may also be Alcoholism grant R01–AA–11408. lying the development of alcoholism sex specific. Evidence from twin and (i.e., its etiology) may be manifested as adoption studies of alcoholism in males 1Unless otherwise noted, the term “alcoholism” here refers differences in prevalence, in the magni­ has consistently supported the exis­ to all types of problematic alcohol use, including the tude of genetic influences, and in the tence of moderate genetic influences, clinical diagnoses of alcohol abuse and dependence. 264 Alcohol Research & Health Sex Differences in Genetic Risk factors in alcoholism in women has four times higher risk of being alco­ referred to reviews by McGue (1994) varied across studies. Such sex differ­ holics themselves than did relatives of and Prescott (2001). ences in the magnitude of genetic nonalcoholics (Cotton 1979). Studies influence could arise from the interac­ of intact families cannot determine, Adoption Studies tions between genes associated with however, whether this familiality arises alcoholism risk and other physiological because family members share genes or Adoption studies allow researchers to processes. For example, numerous because they share environments. This separate the effects of genetic and envi­ physiological differences between men question must be resolved using genetic ronmental factors because adoptees and women in the rate of alcohol epidemiology studies—studies using receive their genetic heritage from one absorption and metabolism are likely genetically informative samples, such as set of parents and their rearing environ­ to be genetic in origin and may influ­ twins or adoptees and their biological ment from another set. Given some ence the development of alcoholism. and adoptive relatives. assumptions (e.g., absence of intrauterine Another potential manifestation of The goal of genetic epidemiology effects on risk for developing alcoholism sex differences in alcoholism risk is the research is to understand sources of and no correlation between the adoptive presence of sex-specific etiological fac­ variability in the risk of developing a and biological family environments for tors. In this case, the risk that a relative factors that influence alcoholism risk), the of an alcoholic will develop alcoholism disorder such as alcoholism. It is usually assumed that alcoholism is a multifacto­ degree to which adoptees resemble their is greater when the relative and the biological relatives is a direct measure alcoholic are of the same sex than when rial disorder in which a combination of genetic and environmental factors con- of genetic influence. Conversely, the they are of different sexes. Sex-specific degree to which adoptees resemble differences in etiology could be caused tributes to the risk of developing the disorder. People differ in their level of their adoptive relatives is a measure of by genes that exhibit different levels of the influence of family environment. activity in men and women or which risk for the disorder, and individual risk probably arises from three sources: Five adoption studies of alcoholism are modified by other sex-specific in males and four in females have genetic or environmental factors to included adequate sample sizes to eval­ make male and female relatives less • Additive genetic variation (also called heritability), which is based on num­ uate genetic influences on alcoholism. similar. These sex-specific etiological Three of the studies were conducted in erous genes that exist in multiple differences also could arise from cul­ Europe and used government registries variants (i.e., alleles), each of which tural processes—for example, whether to identify adoptees whose biological girls are more likely to model their may have a different effect. A person’s parents had records of alcoholism treat­ drinking behavior after their mothers specific combination of alleles of ment or alcohol-related offenses. Two and boys after their fathers. those genes determines his or her other studies were conducted in Iowa This article explores the various genetic risk. The role of such among adoptees for whom alcoholism mechanisms that may contribute to sex genetic influences is usually not status was determined in adulthood differences in the genetic risk for alco­ measured directly but is inferred by using psychiatric evaluations as well as holism. After reviewing genetic epidemi­ comparing degree of similarity in a public records. In these two studies, the ology studies of alcoholism that assess characteristic or behavior among adoptees were classified as “family history genetic versus environmental contribu­ different classes of relatives. negative” if neither biological parent tions to alcoholism risk, the article eval­ showed evidence of alcoholism and as uates various explanations for apparent • Shared environment, which includes “family history positive” if at least one sex differences in heritability, summa­ all environmental factors that make biological parent showed evidence of rizes evidence for sex differences in pat- members of the same family similar alcoholism. terns of transmission, and discusses the to one another (and different from In all five studies of male adoptees, limitations of such research. The article members of other families), includ­ participants with a positive family his- then briefly addresses molecular genetic ing family environment; social class; tory were at significantly higher (i.e., studies before examining potential appli­ schools; and, for twins, the intra­ 1.6 to 3.6 times greater) risk for alco­ cations of research on sex differences. uterine environment. holism than were participants with a negative family history, suggesting a • Specific environment, which includes substantial genetic contribution to the Genetic Epidemiology all remaining environmental factors risk for alcoholism. The studies of Studies of Alcoholism not shared by family members. female adoptees, in contrast, obtained mixed results, with only two of the More than 50 family studies have The following sections discuss the four studies finding a significantly shown that alcoholism runs in families. findings of adoption and twin studies increased risk of alcoholism
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