Rapid advancement of genetic knowledge has provided a wealth of data demonstrating a significant contribution of genes to the development of alcoholism but has suggested little in the way of clinical applicability. Twin and adoption studies suggest that 50% to 60% of the development of alcoholism is due to heritable factors, and linkage and association studies have identified chromosomal regions and individual genes that likely contribute to the development of this condition. Most of these genes are related to neurotransmitter systems and to alcohol metabolizing enzymes. We briefly review the evidence for this before discussing intermediate phenotypes of alcoholism under genetic control, pharmacogenetic aspects of alcoholism treatment, and the possibility of future clinical applications based on these areas.
(Can J Psychiatry 2006;51:461-467)
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* Heritable factors play a large role (50% to 60%) in the development of alcoholism, with multiple genes each having a small effect.
* Intermediate characteristics may provide more easily definable traits with which to study the genetics of alcoholism and to identify at-risk populations and individuals.
* Genetic knowledge of the mechanisms of alcoholism may inform treatment choices through better understanding of clinical subtypes and pharmacogenetics.
* While genetics significantly contribute to the development of alcoholism, the role of the environment and of gene-environment interactions cannot be ignored.
* Many genes combine to reach a threshold of clinical liability. No single gene is likely to be identified as the "alcoholism" gene.
* Clinical applicability of these data is presently speculative; further investigations with defined outcomes are needed to assess the use of this knowledge in the management of alcoholism.
Key Words: alcoholism, genetics, pharmacogenetics, endophenotype, alcohol metabolism
Abbreviations used in this article
ADH alcohol dehydrogenase
ALDH aldehyde dehydrogenase
ASPD antisocial personality disorder
CD conduct disorder
COGA Collaborative Study on the Genetics of Alcoholism Diagnostic Interview Schedule for DSM-III-R
LL long variant
LR level of response
SS short variant
SSRI selective serotonin reuptake inhibitor
Despite the explosion of genetic knowledge in substance use disorders and psychiatry in general, there are few clinical applications of this information. Nevertheless, it is conceivable to envision future clinical practice that uses existent knowledge and technology. Genetics in psychiatry carries the promise of use in various facets of practice. Screening, diagnosis, prognosis, and treatment are all areas wherein genetic data are applied routinely in some areas of medicine.
We present major methodologies used in genetic research and principal findings (which demonstrate a heritable component to alcoholism), followed by a discussion of intermediate phenotypes or endophenotypes-characteristics thought to have more consistent genetic underpinnings. We also discuss genetic influences in the potential pharmacologie management of alcoholism.
Review of the Literature
The body of literature discussing the genetics of alcoholism is vast and steadily increasing. A search of the PubMed database up to December 1,2005, yielded 4491 articles; of these, 1931 were published in the last 10 years. Therefore, this article does not purport to be an exhaustive review of the subject or a critique of the varied and complex methodologies used throughout this field. We paid particular attention to general review articles dealing with the genetics of alcoholism (see 1-7) and to articles where a potential clinical application was relevant. …