Elsevier

Alcohol

Volume 16, Issue 1, July 1998, Pages 33-45
Alcohol

Articles
The D2 Dopamine Receptor Gene: A Review of Association Studies in Alcoholism and Phenotypes

https://doi.org/10.1016/S0741-8329(97)00175-4Get rights and content

Abstract

The role of the D2 dopamine receptor (DRD2) gene in alcoholism and other substance use disorders has come under intense investigation since the minor TaqI A (A1) allele of the DRD2 gene was first reported to be associated with alcoholism. In a meta-analysis of 15 US and international studies of European (non-Hispanic) Caucasians, consisting of 1015 alcoholics (more severe and less severe) and 898 controls (unassessed and assessed for alcoholism), alcoholics had a higher prevalence (p < 10−7) and frequency (p < 10−5) of the A1 allele than controls. The prevalence of the A1 allele was 1.5-fold higher in more severe than less severe alcoholics (p < 10−4), whereas unassessed controls had a twofold higher prevalence of the A1 allele than assessed controls (p < 10−4). Whereas more severe alcoholics had a threefold higher A1 allelic prevalence than assessed controls (p < 10−10), A1 allelic prevalence was virtually identical in less severe alcoholics and in unassessed controls. The A1 allele has also been associated with other drug problems including cocaine, nicotine, and polysubstance abuse. Furthermore, the minor TaqI B (B1) allele of the DRD2 gene has been associated with alcoholism and psychostimulant (cocaine, amphetamine) abuse. Beyond association studies, phenotypic differences exist between genotypes containing the TaqI A minor (A1A1 and A1A2) and major (A2A2) alleles of the DRD2. These different phenotypes have been identified through a number of approaches, including pharmacological, neurophysiological, neuropsychological, stress, personality, metabolic, and treatment studies. In conclusion, the present review suggests that the type of alcoholics and the nature of controls used are among critical factors in DRD2 association studies in alcoholism. Intronic mutations in both the 3′(TaqI A) and 5′(TaqI B) regions of the DRD2 associate with alcoholism and other drug use disorders. The identification of phenotypes of DRD2 genotypes suggests that the observed intronic DRD2 mutations may have functional consequences that predispose individuals to a variety of substance use disorders.

Section snippets

The drd2 gene: alcoholism and other substance use disorders

Eight months after our first study (13) appeared in press, a group at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) published a report (17) that, while finding a higher prevalence of the A1 allele in alcoholics compared to their controls, claimed a lack of significant involvement of the DRD2 gene in alcoholism. However, it should be noted that there were important differences between our study and theirs. In our study, the prevalence of the DRD2 A1 allele was compared between

Phenotypic expression of drd2 genotypes

If the described mutations in the DRD2 gene associate with alcoholism and other substance use disorders, then such mutations should have neural correlates. In the absence of such correlates, it may be reasonably assumed that the said mutations have no functional significance. However, besides the differentiation of the clinical severity of alcohol and other drug use disorders, based on A1+ (A1/A1 and A1/A2 genotypes) and A1 (A2/A2 genotype only) allelic classification, a growing number of

Comments

The DRD2 has been one of the most intensively studied genes in alcoholism and other substance use disorders. The initial controversy surrounding the DRD2 association with alcoholism appears to be resolving as a large number of studies are beginning to address and to clarify the various issues raised about the nature of this association.

Conclusions

  • 1.

    Combined analysis of Caucasian studies reveals an association of the DRD2 A1 allele with alcoholism. This association is most robust when more severe alcoholics are compared with assessed controls. However, no association is found when less severe alcoholics are compared with unassessed controls. These findings suggest that two factors are critical in this association: the type of alcoholics and the nature of controls used.

  • 2.

    Considering that the present analysis consisted of a large number of

Acknowledgements

The author thanks Adele C. Smithers and The Christopher D. Smithers Foundation for their generous financial support and is grateful for the dedicated involvement of many scientific colleagues.

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