Letter to the Editor

An Association Between a FunctionalPolymorphism at the DRD2 Gene andthe Liability to Substance Abuse

To the Editor:

In 1997, this journal published a paper by Goldmanet al. presenting an analysis of a functional polymor-phism (ser → cys substitution) in the DRD2 gene in aNative American population. No association was foundfor either substance abuse/dependence or alcohol de-pendence. Since this polymorphism causes consider-able variation in the receptor function, the paper’snegative conclusion, if valid, is obviously a strong ar-gument against any further DRD2-related substanceabuse research.

It should be noted, however, that the Native Ameri-can population where the Goldman et al. data wereobtained has an extremely high frequency of alcoholdependence (155 out of 186 males and 121 out of 251females in the sample) and substance abuse/dependence (73 females and 97 males). The effect of theDRD2 gene would be difficult to detect in such a popu-lation if it was not a major contributor to liability varia-tion, considering the powerful background influence ofother genetic and/or environmental factors that re-sulted in the high prevalence of the disorder. Indeed,the comparison of genotypic distributions presented inthe paper did not reveal differences between substanceabusers and nonaffected individuals (x2 4 3.19, P 40.203).

Since, however, it is the cys allele that impairs theDRD2 function, and this effect, if any, is expected to bemost strongly expressed in the cys/cys genotype, it maybe more informative to compare the frequencies of thisparticular genotype in affected and nonaffected sub-jects. In fact, since the hypothesized association is func-tional, i.e., mediated by the receptor phenotype (nota-bly, the alleles are named after their phenotypic ex-pressions), the actual relationship being tested is theone between the two phenotypes, receptor and liability.If the ser allele is dominant, then splitting the ser/-phenotypic class into two, according to the genotypes itcontains, decreases the power of analysis.

From Table III in the Goldman et al. report, the fre-quency of cys/cys genotype in substance abusers ismore than twice that in the nonaffected subjects (0.053vs. 0.022). This difference is marginally significant (x2

4 2.91; one-sided P 4 0.04; the use of one-sided crite-rion is justified because the direction of expected dif-ference is known). This is consistent with the associa-tion hypothesis and, due to the direct influence of thepolymorphism on the receptor function, with the caus-ative relationship between the DRD2 gene and the riskfor substance abuse in the sample studied. It is possiblethat the very high frequencies of the cys allele and thecys/cys genotype in this Native American population—reported to be 5 and 27 times higher, respectively, thanin the Caucasian population—contribute to the differ-ences in the alcoholism and substance abuse preva-lence between these populations.

The relationship could be more pronounced in apopulation with a lower frequency of the disorder. Thefact that the sample (especially males) was almost uni-formly alcohol-dependent and, consequently, the se-vere truncation of the liability variance may have dra-matically diminished power to detect any contributionto the liability variation. It is thus not surprising thatno association could be found for alcoholism. The asso-ciation is, however, found for substance abuse, forwhich the sex ratios in cases and controls did not differand the frequency of the disorder was generally lower.One should also take into account that, at least in thesubstance abuse analysis, the control sample appar-ently contained alcoholics. This could further decreasethe power of analysis. Furthermore, the female andmale data presented in the paper were pooled, whereasthe relationship may be moderated by sex (e.g., bestronger in females), as observed, for example, in theDRD5 study (Vanyukov et al., 1998). Combining malesand females in the DRD2 analyses, in case of alcoholdependence, resulted in the comparison of the predomi-nantly male sample of affected individuals (155 malesand 121 females) with the overwhelmingly femalesample of nonaffected subjects (31 males and 130 fe-males). Separation by sex in the association analyses ofsubstance use disorders is also necessary consideringthe differences in the prevalences of the disorder and inthe composition of the phenotypic variance in malesand females [e.g., Pickens et al., 1991]. In summary,

*Correspondence to: Michael M. Vanyukov, Ph.D., Center forEducation and Drug Abuse Research (CEDAR), Departments ofPsychiatry and Human Genetics, University of Pittsburgh, 3811O’Hara Street, Pittsburgh, PA 15213. E-mail: mmv@pop.pitt.edu

Received 7 August 1998; Accepted 9 November 1998

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:590–591 (1999)

© 1999 Wiley-Liss, Inc.

the data used to infer the paper’s definitive conclusionof “[n]o role for presence or homozygosity of the func-tionally impaired D2 receptor allele . . . in . . . sub-stance abuse . . .” may, in fact, support the oppositeview.

REFERENCES

Goldman D, Urbanek M, Guenther D, Robin R, Long JC. 1997. Linkageand association of a functional variant [Ser311Cys] and DRD2 markersto alcoholism, substance abuse, and schizophrenia in SouthwesternAmerican Indians. Am J Med Genet 74:386–394.

Pickens RW, Svikis DS, McGue M, Lykken DT, Heston LL, Clayton PJ.1991. Heterogeneity in the inheritance of alcoholism: a study of maleand female twins. Arch Gen Psychiat 48:19–28.

Vanyukov MM, Moss HB, Gioio AE, Hughes HB, Kaplan BB, Tarter RE.1998. An association between a microsatellite polymorphism at theDRD5 gene and the liability to substance abuse: pilot study. BehavGenet 28:75–82.

Michael M. Vanyukov*Center for Education and Drug Abuse ResearchDepartments of Psychiatry and Human GeneticsUniversity of Pittsburgh, Pittsburgh, Pennsylvania

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