Genetics of Adolescent Alcohol Use and Disorders, Part 2

by National Institute of Health

(Page 3 of 5)

Adolescence

The recognition that the prevalence of alcohol dependence is highest in those ages 18 to 24 focuses attention on identifying the genetic contribution to alcohol initiation in childhood and adolescence; adolescent developmental pathways to alcohol dependence; and adolescent vulnerabilities to the consequences of alcohol abuse.

Very early starters (those who initiate alcohol use before age 12) often have several co-occurring problems that may include various externalizing and internalizing behaviors. Ongoing research is attempting to determine the order of causation and the potential underlying mechanisms that may be responsible for multiple problems as well as to identify early markers that might indicate some of those in need of early intervention. For example, what Cloninger classified as Type II alcoholism (characterized as male-limited, early onset, and occurring in sensation-seeking people and people with impaired impulse control) historically has been attributed to serotonergic dysfunction. Variation in the serotonin transporter gene promoter in humans has been associated with Type II alcoholism as well as with other neuropsychiatric diseases. Work in nonhuman primates has confirmed this relationship between excessive alcohol consumption and serotonin system genes in macaques; and, in addition, it has integrated research on the effects of early environmental stressors. In particular, this work has shown how environmental factors can influence gene expression to produce different patterns of behavior.

The gene that encodes the enzyme monoamine oxidase A also influences synaptic concentrations of serotonin. Among adolescent and young adult male rhesus macaques, studies suggest that MAOA gene promoter variation may confer risk for alcohol dependence. Given that this gene resides on the X chromosome (males only have a single copy and females have two), males may be particularly susceptible to alterations in its expression. In humans, a polymorphism in the transcriptional control region of this gene has been associated with antisocial behavior in alcohol-dependent males and with impulsivity, hostility, and a lifetime history of aggression in a community sample of men.

Environmental factors and genetic variations may result in similar phenotypes by affecting levels of specific gene products. For example, nonhuman primates that are removed from their parents at birth and reared with age-matched peers exhibit higher levels of anxiety and deficits in impulse control and are prone to violently aggressive behaviors. These animals also consume significantly higher volumes of alcohol and are more likely to drink to intoxication than are those reared with their parents under baseline nonstressful conditions. When stress is induced in mother-reared monkeys, however, they increase their alcohol consumption to that of their peer-reared counterparts. If peer-reared monkeys are given the serotonin reuptake inhibitor sertraline, alcohol consumption as well as anxiety and aggression are decreased. The level of the serotonin metabolite 5-hydroxyindoleacetic acid concentrations in the cerebrospinal fluid predicts subjects' response to sertaline, suggesting that a deficit in serotonin underlies these behaviors.

Consistent with the findings from adult twin studies, problematic use of alcohol in adolescence has been found to be more heritable than are initiation and more limited use. In a study specifically addressing adolescents, Rhee and colleagues applied a logistic regression model to data collected from sibling/twin/adopted adolescents ages 12-19. Their analysis resulted in the following conclusions: alcohol initiation arises from genetic and from shared and nonshared (uniquely experienced) environmental contributions. Alcohol use is minimally influenced by genetics but rather arises largely from environmental influences (shared, nonshared, and twin-shared experiences). Problem use of alcohol has a high heritability component and is significantly influenced by nonshared environmental influences (peer experiences, accessibility), but the contribution of shared environment (family) is small.

Whether the specific genes underlying the stages in the progression from initiation to problem alcohol use are different, and whether the influence of specific genes and their expression vary with age and/or context remains to be determined.

These findings are consistent with those from other studies of adolescents. Rose and colleagues also reported that the strength of genetic influence on adolescent drinking behavior appears to increase from modest levels in midadolescence to moderate levels by late adolescence. And these types of findings are not unique to alcohol use; in late adolescence, genetic influences on problem drinking appear to overlap extensively with genetic influences on other indicators of disinhibited behavior. Although this latter research suggests that abusive drinking in late adolescence may be driven substantially by inherited differences in a general disposition to undercontrolled behavior, it does not rule out the influence of alcohol-specific genetic effects (genetic influences on alcohol sensitivity), or the impact of contextual factors. Indeed, mounting evidence exists that genetic influences on complex behavioral outcomes such as drinking behavior reflect a complex interplay between inherited and environmental factors, the implications of which are only beginning to be explored for models of adolescent drinking.

Adolescence and In Vivo Alcohol Pharmacokinetics

Adolescence is associated with profound physiological changes that almost certainly have an impact on in vivo alcohol pharmacokinetics. There is scant direct evidence in humans of any differences between the pharmacokinetics of alcohol in adolescents compared with adults, and for good reason - no one would expose young people to alcohol for research purposes. Although data relevant to this point in humans is lacking, the ontogeny (i.e., development over the life span of an individual) of ethanol metabolism has been examined in laboratory animals. (Note, however, that what may be called "adolescence" in animals may not precisely correspond to the same developmental period in humans, especially when differences in the timing of adolescence in human males and females are considered.) These studies suggest general ontogenetic increases in alcohol dehydrogenase activity, ethanol elimination rates and the rate of ethanol metabolism. An exception to this pattern sometimes has been seen during adolescence, with adolescent animals occasionally reported to exhibit slightly higher levels of ethanol metabolism than more mature animals. Significant elevations in ethanol metabolism during adolescence are not always evident, however, and are insufficient to account for the attenuated sensitivity to certain ethanol effects seen in adolescent animals relative to their more mature counterparts. What can be expected in human adolescents with respect to specific aspects of pharmacokinetics as they relate to alcohol effects is based on inference from animal studies and from research on adults, elements of which are described in the following sections.

About the Author

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