Alcohol is a common “addictive” substance. As a psychoactive compound, it can elicit a spectrum of behavioral effects, which include gregariousness, aggression, loss of executive function, and cognitive deficits. While pharmacokinetic factors (absorption, distribution in the tissues, and rate of metabolism, primarily in the liver) contribute to the intensity and duration of ethanoPs actions, the behavioral manifestations are a consequence of the effects of ethanol on the brain. The spectrum of behavioral effects is attributed to the ability of ethanol to inhibit or activate multiple neural pathways, and how one responds to alcohol will ultimately depend on how the neural pathways are organized in an individual, and the extent to which certain pathways are inhibited or activated. It is known that there is substantial variability in the response to alcohol, and differences in cognitive evaluation of ethanol's effects are likely to play a significant role in the predisposition to alcohol abuse and dependence.
Although the diagnoses for alcohol use disorders are based on a range of reported symptoms, they are typically treated as a binary outcome (affected or unaffected). As early as the 1960s, it was conceptualized that alcoholism was not a single entity and that various types of alcoholism existed. Jellinick originally identified five “species” of alcoholism characterized by psychological and physiological dependence.1
Researchers have utilized and refined such typological schemes in order to identify more etiologically homogeneous subtypes as a means for studying, diagnosing, and treating alcoholism.2-4
As with all complex diseases, alcoholism can be thought of as a clinical outcome that has been generated by a combination of many risk factors, and the alcohol-dependent population represents a spectrum of individuals displaying different sets of symptoms and severity of disease. Genetic factors that affect susceptibility to alcohol dependence may be involved in only certain components of the spectrum of alcohol dependence, such as alcohol metabolism, personality, cognitive function, and neurophysiology.5
An approach for identifying alcohol susceptibility genes is to focus on the particular components of the dependence spectrum, ie, intermediate phenotypes that influence susceptibility to alcohol dependence, also known as endophenotypes. With reference to genetic theories in schizophrenia research, Gottesman and Shields6
originally defined endophenotypes as internal phenotypes, not obvious to the unaided eye, which can fill the gap between the gene and the available descriptors of disease. More recently, Tsuang et al7
established the following criteria for evaluating endophenotypes8
Specificity. The endophenotype is more strongly associated with the disease of interest relative to other psychiatric conditions.
State-independence. The endophenotype is stable over time and not merely indicative of the disease process or its treatment.
Heritability. Variance in the endophenotype is associated with genetic variance.
Familial association. It is more prevalent among the relatives of ill probands compared with the appropriate control group.
Cosegregation. The endophenotype is more prevalent among the affected relatives compared with the unaffected relatives of affected probands.
Biological and clinical plausibility. The endophenotype bears some conceptual relationship to the disease.
The advantage of using endophenotypes is that the number of genetic and environmental factors that contribute to these should be easier to identify because the number of factors influencing each is fewer than the number affecting the undifferentiated clinical syndrome.9
Endophenotypes have been utilized extensively when nonhuman animals have been used to study alcohol use-related phenomenon. Animal models have proven to be an ideal tool for identifying genetic and environmental factors that influence alcohol-related traits due to the ability to conduct studies under controlled environmental and genetic conditions. Furthermore, animal models provide an opportunity to assess quite specific alcohol-related endophenotypes, such as alcohol preference, sensitivity, tolerance, and dependence. For example, selected lines of mice produced from breeding animals for certain endophenotypes have been widely used in mapping quantitative trait loci (QTL), an analytical method utilized to identify regions of the genome influencing a specific trait by comparing genetic markers that are shared by lines or strains displaying extremes in quantitative endophenotypes. Several selected lines that differ with respect to various alcohol-related traits have been developed to identify genetic differences contributing to differences in the effects of alcohol. This area of research has recently been reviewed.10
Although animal models provide for “proof of concept,” which indicates that the definition and utilization of endophenotypes can lead to a better understanding of the etiology of the endophenotype and provide a means for identifying which genetic factors would be of interest to study in humans, not all observations in the nonhuman animal are necessarily applicable to humans. Thus, it is essential to conduct studies with human populations in order to elucidate the pathophysiology of human disease. Recent research efforts with humans have focused on the identification and incorporation of endophenotypes to study risk factors for alcoholism. Schuckit recently proposed that the majority of genetically related markers of alcoholism risk were represented by five relatively independent overarching categories (endophenotypes), which include level of response, neuronal or behavioral disinhibition, independent axis I major psychiatric disorders, the opioid system, and alcohol-metabolizing enzymes.11
A variety of additional traits have been investigated in epidemiological research as potential endophenotypes for alcohol dependence. These include endophenotypes related to endocrine measures, electrophysiology, personality, and drinking behavior.