Abstract
Alcohol dependence (alcoholism) is a complex disorder attributed to the interaction of genetic and environmental factors that form a collage of "disease" predisposition, which is not identical for every alcohol-dependent individual. There is considerable evidence to demonstrate that genetic predisposition accounts for roughly half the risk in the development of alcohol dependence. Both family and population studies have identified a number of genomic regions with suggestive links to alcoholism, yet there have been relatively few definitive findings with regard to genetic determinants of alcoholism. This ambiguity can be attributed to a multitude of complications of studying complex mental disorders, such as clinical heterogeneity, polygenic determinants, reduced penetrance, and epistatic effects. Complex mental disorders are clinical manifestations described by combinations of various signs and symptoms. One approach to overcoming the ambiguity in studying the association between genetic risk factors and disease is to dissect the complex, heterogeneous disorder by using intermediate phenotypes--or endophenotypes--to generate more homogeneous diagnostic groupings than an all-encompassing definition, such as the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-derived term "alcohol dependence" or the commonly used term "alcoholism." The advantage of using endophenotypes is that the number of influential factors that contribute to these characteristics should be fewer and more easily identified than the number of factors affecting the heterogeneous entity of alcohol dependence (alcoholism). A variety of alcohol-related characteristics have been investigated in epidemiological, clinical, and basic research as potential endophenotypes of alcohol dependence. These include phenotypes related to alcohol metabolism, physiological and endocrine measures, neural imaging, electrophysiology, personality, drinking behavior, and responses to alcohol and alcohol-derived cues. This review summarizes the current literature, focused on human data, of promising endophenotypes for dissecting alcoholism.