Abstracts: The Dopamine D2 Receptor Gene (DRD2)
Comings, D. E., Comings, B. G., Muhleman, D. , Dietz, G., Shahbahrami, B., Tast, D. , Knell, E., Kocsis, P.,Baumgarten, R., Kovacs, B. W., Levy, D. L., Smith, M., Borison, R. L., Evans, D.D., Klein, D. N., MacMurray, J., Tosk, J., Sverd, J., Gysin, R. and Flanagan, S. D. (1991) The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. J.Am.Med.Assn., 266: 1793-1800.
1. Objective. Blum et al reported the 1 allele of the Taq I polymorphism of the dopamine D2 receptor gene was present in 69% of alcoholics compared to 20% of controls. By contrast, Bolos et al. reported no significant difference in the prevalence of the 1 allele in alcoholics versus controls, and no evidence that the D2 gene was linked to alcoholism. We hypothesized that these seemingly conflicting results might be because increases in the prevalence of the 1 allele may not be specific to alcoholism. Thus we examined other disorders frequently associated with alcoholism, or believed to involve defects in dopaminergic neurotransmission.
2 Design. Case comparison study. To minimize the effect of racial differences in gene frequencies, the study was restricted to non-Hispanic Caucasians.
3. Setting. Ambulatory and hospitalized patients.
4. Results. Among all known controls (N = 314), 24.5% carried the 1 allele. Of the 69 controls known to be non-alcoholic, 14.5% carried the 1 allele. The prevalence of the 1 allele was significantly increased in patients with Tourette syndrome (44.9%, n=147), attention deficit hyperactivity disorder (46.2%, n=104), autism (54.5%, n=33), alcoholism (42.3%, n=104), and post-traumatic stress disorder (45.7%, n=35). After correction for multiple comparisons (requiring p <0.0009 for significance) all remained significant except PTSD. The prevalence of the 1 allele was not significantly increased in patients with depression, panic attacks, Parkinson's disease, or obesity. The prevalence of the 1 allele in drug addiction and schizophrenia was only significant when compared to non-alcoholic controls and no correction was made for multiple comparisons.
5. Conclusions. These results suggest the 1 allele of the dopamine D2 receptor gene is associated with a number of behavior disorders where it may act as a modifying gene rather than the primary etiological agent.
Comings, D.E., Flanagan, S.D., Dietz, G., Muhleman, D., Knell, E., & Gysin, R. (1993). The dopamine D2 receptor (DRD2) as a major gene in obesity and height. Biochem.Med.Metabolic Biol., 50: 176-185.
Dopamine plays a major role in the regulation of appetite and growth hormone. Dopaminergic agonists suppress appetite and dopamine D2 receptor antagonists enhance it. We examined the hypothesis that allelic variants of the DRD2 locus may be associated with weight and height. Sarkar and Sommer described two DRD2 polymorphisms that could be haplotyped by PCR. For weight, the mean Z score (National Center for Health Statistics) for 208 subjects without haplotype 4 was 0.086 versus 0.557 for 280 subjects with haplotype 4, P = 0.0003. Two separate sets of subjects were studied and these results were significant for both, providing an internal replication. For height,the mean Z score for 164 subjects without haplotype 4 was 0.1677 versus 0.6885 for 219 subjects with haplotype 4, P < 0.00001. These and other data suggest that the 4 haplotype is in linkage disequilibrium with allelic variants of the DRD2 gene that play a major role in the regulation of weight (obesity) and height, and may serve as a risk factor in late-onset non-insulin-dependent diabetes mellitus (NIDDM).
Comings, D.E., Muhleman, D., Ahn, C., Gysin, R., & Flanagan, S.D. (1994). The dopamine D2 receptor gene: A genetic risk factor in substance abuse. .Drug and Alcohol Dependence, 34: 175-180.
Drug abuse has grown to epidemic proportions. Dopaminergic reward pathways have frequently been implicated in the etiology of drug addiction. To examine the possible role of genetic variants of the dopamine D2 (DRD2) gene in susceptibility to drug abuse we determined the prevalence of the TaqI A1 variant of the DRD2 gene in 200 White patients hospitalized in the Addiction Treatment Unit of a VA Hospital. While the prevalence of the D2A1 allele was not significantly increased over controls, it did increase from 21% in subjects with alcohol abuse only to 32% in subjects with alcohol dependence only, consistent with other studies showing an association with the severity of alcoholism. By contrast, of 104 subjects with a discharge diagnosis of drug and alcohol abuse/dependence, 42.3% carried the D2A1 allele versus 29.0% of the 763 White controls (representing all White controls published to date) (p = 0.006). Of those who spent more than $25/week on two or more substances, 56.9% carried the D2A1 allele versus 28.2% of those abusing a single substance (p <0.0005). Multiple logistic regression analysis showed a highly significant association between multiple substance abuse based on money spent and the presence of the D2A1 allele (p = 0.0003) and age of onset of abuse (p < 0.0001). D2A1 carriers exceeded D2A2A2 subjects for a history of being expelled from school for fighting (p = 0.001), and of those ever jailed for violent crimes, 53.1% carried the D2A1 allele versus 28.8% of those jailed for non-violent crimes (p=.011). This increased to 69.2% for those who were both jailed for violent crime and expelled from school. We conclude that possession of the D2A1 allele is significantly associated with drug abuse/dependence and some aggressive behaviors.
Comings, D.E., MacMurray, J., Johnson, P., Dietz, G., & Muhleman, D. (1995). Dopamine D2 Receptor Gene (DRD2) Haplotypes and the Defense Style Questionnaire in Substance Abuse, Tourette Syndrome and Controls. . Biol.Psychiatry, 37: 798-805.
The defence style questionnaire (DSQ) was administered to Caucasian males consisting of 123 subjects from a V.A. addiction treatment unit (ATU), 42 Tourette syndrome (TS) subjects, and 49 controls. For the ATU and TS subjects, there was a significant decrease in the mean score for mature defenses and a significant increase in mean score for immature defenses compared to controls. Many of the individual subscores showed the same significant differences. Dopamine D2 receptor (DRD2) gene haplotypes, identified by allelespecific polymerase chain reaction of two mutations (G/T and C/T) 241 base pairs apart, were determined in 57 of the ATU subjects and 42 of the controls. Subjects with the 1 haplotype tended to show a decrease in mature and an increase in neurotic and immature defense styles compared to those without the 1 haplotype. Of the eight times that the subscale scores were significant for haplotype 1 versus non-1, they were always in this direction. There results suggest that the DRD2 locus is one factors controlling defense styles. The difference in the mean scores between controls and substance abuse subjects indicates that other genes and environmental factors also play a role.
Comings, D.E., MacMurray, J.P., Gade, R., Muhleman, D., & Peters, W.R. (1996). Genetic variants of the human obesity gene: Association with psychiatric symptoms and body mass index in young women, and interaction with the dopamine D2 receptor gene. Molecular Psychiatry, 1: 325-335.
To examine the possible role of genetic variants the OB gene in obesity we examined alleles of a dinucleotide repeat polymorphism, D7S1875, close to the gene, in a group of adult, non-Hispanic Caucasians. There was a significant correlation with body mass index (BMI) at age 26-30 years for males and females combined (p = .04) and females only (.028). Because of the frequent association between obesity and psychiatric symptoms all subjects were screened with the Symptom List 90 (SCL-90). There was a significant increase in scores for anxiety (p = .0005), depression (p = .003), and other behaviors for subjects homozygous for the OB1875 <208 bp alleles. Analysis of covariance indicated this was directly related to the OB alleles and not secondary to the presence of obesity. There was a significant association between the BMI at ages 16 to 40 and homozygosity for the OB1875 <208 bp alleles and/or the presence of the DRD2 Taq A1 allele for males and females combined (p = .002 to .005), and for females alone (p = .0017 to .0005). For females alone these two genes accounted for up to 22.8% of the variance of the BMI. These results are consistent with the polygenic inheritance of obesity and suggest that variants of the OB gene are causally involved not only in human obesity but its associated behavioral disorders.
Comings, D.E., Rosenthal, R.J., Lesieur, H.R., Rugle, L., Muhleman, D., Chiu, C., Dietz, G., & Gade, R. (1996). A study of the dopamine D2 receptor gene in pathological gambling. Pharmacogenetics, 6: 223-234.
Pathological gambling has been termed both the 'pure' and the 'hidden' addiction. 'Pure' because it is not associated with the intake of any addicting substance, and 'hidden' because it is an extension of a common, socially accepted behaviour. The Taq A1 variant of the human DRD2 gene has been associated with drug addiction, some forms of severe alcoholism, and other impulsive, addictive behaviours. We have sought to determine if there is a similar association with pathological gambling. A total of 222 non-Hispanic Caucasian pathological gamblers from multiple sites across the US participated in the study. Of these 171 donated a sample of blood, 127 filled out several questionnaires, and 102 did both. Of the 171 pathological gamblers 50.9% carried the D2A1 allele versus 25.9% of the 714 known non-Hispanic Caucasian controls screened to exclude drug and alcohol abuse, p < 0.00000001, odds ratio (OR) = 2.96. For the 102 gamblers who filled out the questionnaires, 63.8% of those in the upper half of the Pathological Gambling Score (more severe) carried the D2A1 allele (OR versus controls = 5.03), compared to 40.9% in the lower half (less severe). Of those who had no comorbid substance abuse, 44.1% carried the D2A1 allele, compared to 60.5% of those who had comorbid substance abuse. Forty-eight controls and 102 gamblers completed a shorter version of the Pathological Gambling Score. Of the 45 controls with a score of zero, 17.8% carried the D2A1 allele. Of the 99 gamblers with a score of 5 or more, 52.5% carried the D2A1 allele (chi 2 = 15.36, p = 0.00009). These results suggest that genetic variants at the DRD2 gene play a role in pathological gambling, and support the concept that variants of this gene are a risk factor for impulsive and addictive behaviours.
Comings, D.E., Muhleman, D., & Gysin, R. (1996). The dopamine D2 receptor (DRD2) gene in posttraumatic stress disorder: A study and replication. Biol.Psychiatry, 40: 368-372.
Subjects on an addiction treatment unit who had been exposed to severe combat conditions in Vietnam were screened for posttraumatic stress disorder (PTSD). Of 24 with PTSD, 58.3% carried the D2A1 allele. Of the remaining eight who did not meet PTSD criteria, 12.5% carried the D2A1 allele (p = 0.04). In a replication study of 13 with PTSD, 61.5% carried the D2A1 allele. Of the remaining 11 who did not meet criteria for PTSD, 0% carried the D2A1 allele (p = 0.002). For the combined group 59.5% of those with PTSD carried the D2A1 allele versus 5.3% of those who did not have PTSD (p = 0.0001). These results suggest that a DRD2 variant in linkage disequilibrium with the D2A1 allele confers an increased risk to PTSD, and the absence of the variant confers a relative resistance to PTSD.
Comings, D.E., Ferry, L., Bradshaw-Robinson, S., Burchette, R., Chiu, C., & Muhleman, D. (1996). The Dopamine D2 Receptor (DRD2) Gene: A Genetic Risk Factor in Smoking. Pharmacogenetics, 6: 73-79.
Of a group of 312 non-Hispanic Caucasians who smoked at least one pack per day, had unsuccessfully attempted to stop smoking, and were free of alcohol or other drug dependence, 48.7% carried the A1 allele of the DRD2 gene. This was significantly greater than the 25.9% prevalence in the 714 known non-Hispanic Caucasian controls without alcohol or drug abuse, p < 10(-8), and significantly greater than in a smaller set of our study controls. There was a significant, inverse relationship between the prevalence of the D2A1 allele and the age of onset of smoking, p = 0.02, and the maximum duration of time the smokers had been able to quit smoking on their own, p = 0.02. These results suggest the DRD2 gene is one of a multifactorial set of risk factors associated with smoking.
Comings, D.E., Wu, H., Chiu, C., Ring, R.H., Dietz, G., & Muhleman, D. (1996). Polygenic inheritance of Tourette syndrome, stuttering, ADHD, conduct and oppositional defiant disorder: The Additive and Subtractive Effect of the three dopaminergic genes - DRD2, DBH and DAT1. Am.J.Med.Gen.(Neuropsych.Genet.), 67: 264-288.
Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine b-hydroxylase (DbH), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse, and general anxiety — behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.
Blum, K., Braverman, E.R., Wu, S., Cull, J.G., Chen, T.J.H., GIll, J., Wood, R., Eisenberg, A., Sherman, M., Davis, K.R., Matthews, D., Fischer, L., Schnautz, N., Walsh, W., Pontius, A.A., Zedar, M., Kaats, G., & Comings, D.E. (1997). Association polymorphisms of dopamine D2 receptor (DRD2), Dopamine transporter (DAT1) with schizoid/avoidant behavors (SAB). Molecular Psychiatry, 2: 239-246.
The dopaminergic system, and in particular the dopamine D2 receptor, has been implicated in reward mechanisms in the brain. Dysfunction of the D2 dopamine receptors leads to aberrant substance-seeking behaviors (ethanol, drugs, tobacco, and food) and other related behaviors (pathological gambling, Tourette's disorder, attention-deficit/hyperactivity disorder). This is the first study supporting a strong association between the dopamine D2 receptor Taq A1 allele with schizoid/avoidant behavior (SAB). Additionally, an albeit weaker association between the 480-bp VNTR 10/10 allele of the dopamine transporter (DAT1) gene with SAB was similarly found.
Comings, D.E. (1998). Why Different Rules are Required for Polygenic Inheritance: Lessons from Studies of the DRD2 Gene. Alcohol, 16: 61-70.
In 1990 Blum, Noble and coworkers reported a significant association between the 1 allele of the Tarq1A polymorphism of the D2 dopamine receptor gene (DRD2) and severe alcoholism. Subsequently, some reports using both linkage and association techniques supported this finding whereas others either did not, or seemed not to support this association. Although some of the controversy is due to true variability in the frequency of the D2A1 allele in different groups of alcoholics and controls, some is also due to the frequent attempt to apply the rules of single-gene disorders to what is in all likelihood a multifactorial, polygenic disorder. When the rules that are appropriate to polygenic inheritance are used a significant portion of the controversy is resolved. Those rules, and their application to the role of the DRD2 gene in addictive, impulsive behaviors, are reviewed.
Comings, D.E. (1998). The molecular genetics of pathological gambling. CNS Spectrums, 3: 20-37.
As gambling becomes available to more and more individuals in this country, the problem of compulsive or pathological gambling will also increase. As with other forms of addiction both environmental and genetic factors are involved. The identification of the genes involved in increasing a persons risk for pathological gambling will lead to a better understanding of the disorder and to more rational and effective treatment. While studies of the molecular genetics of pathological gambling are just beginning, a number of interesting observations made to date are reviewed. As with other addictive behaviors, abnormalities in dopaminergic reward pathways are likely to be involved. Consistent with this, we have observed a significant association between pathological gambling and the dopamine D1 (DRD1), dopamine D2 (DRD2), dopamine D3 (DRD3) and dopamine D4 (DRD4) genes. The additive effect of these is consistent with the polygenic inheritance of a susceptibility to pathological gambling. The involvement of multiple dopamine genes is consistent with the 'reward deficiency syndrome' which suggests that addictive, impulsive disorders are due, at least in part, to genetic abnormalities of the dopamine reward pathways. One the basis of this hypothesis, other genes likely to also play a role in a person's susceptibility to pathological gambling, are described.
Miller WB, Pasta DJ, MacMurray J, Chiu C, Wu H, Comings DE (1999) Dopamine receptor genes are associated with age at first sexual intercourse. J Biosoc Sci 31:43-54
The dopaminergic system in the brain seems to play an important role in the regulation of sexual behaviour. The relationship between genes for the D1, D2 and D4 dopamine receptors and age at first sexual intercourse (AFSI) was examined in a sample of 414 non-Hispanic, European-American men and women. A significant association was observed between a DRD2 allele and AFSI and an even stronger association when the DRD2 allele was interacted with a DRD1 allele. A constrained regression model was constructed predicting AFSI using sex and a group of nine psychosocial variables as predictors. Adding the DRD2 and the DRD2-by-DRD1 predictors to this model increased the explained variance by 23 and 55%, respectively. Although these findings suggest a stronger association among males than among females, further research will be necessary to clarify this question, as well as to establish whether the observed association holds in other racial/ethnic groups.
Comings, DE. (1999). Molecular heterosis as the explanation for the controversy about the effect of the DRD2 gene on dopamine D2 receptor density. Molecular Psychiatry 4:213-215.
Points out that heterosis explains the apparent controversy abut whether the A1 allele of the dopamine DRD2 gene is associated with a lower density of receptor in the brain than the A2 allele. When analyzed on the basis of genotype, those with the 12 genotype have a significantly lower D2 density than whose with the 22 genotype.
Madrid GA, MacMurray J, Lee JW, Anderson BA, Comings DE. (2001) Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism. Alcohol 23:117-22
Results of earlier studies have shown that rating of prior stress exposure in preadolescent boys influenced the association between DRD2 genotypes and alcoholism risk factors, suggesting that variability in stress exposure, either in patient or control samples, could readily account for at least part of the confusion in DRD2 study outcomes. In order to test the hypothesis that the DRD2 A1 allele is only associated with alcoholism in subjects with elevated stress exposure, we examined the gene-stress interactional model in a sample of males of Mayan descent in the Olancho district of Honduras. Ascertainment was based on an epidemiologic, observational cross-sectional design, and the study was approved by the Institutional Review Board. A total of 309 adult males (age range 18-87 years) were interviewed by a physician or a public health nurse, blood samples were obtained for genetic studies, and participants were administered the short version of the Michigan Alcoholism Screening Test (S-MAST) and the Hispanic Stress Inventory (HSI). Three explanatory models were evaluated. The first model tested the effect of the demographic variables alone as predictors of MAST scores, the second tested the effects of stress and DRD2 genotypes separately, and the third tested the effect of the interaction between stress and the DRD2 genotypes. Neither model 1 nor model 2 yielded significant results; neither MAST scores nor HSI scores were found to be associated with DRD2 genotypes. However, Model 3 was confirmed reflecting a significant (P<.05) interaction between DRD2 genotype and stress score as a predictor of MAST score. Additionally, this difference was found to be largely accounted by the HSI occupational/economic stress score, which had a highly significant (P=.003) interaction with DRD2 genotype as a predictor of MAST score. This stress score was the only one of four that showed levels of stress as high as HSI scores in a US population. The MAST scores of A2A2 genotype participants were found to be nearly identical in low stress and high stress participants, whereas the MAST scores of A1A2 participants increased modestly with stress (P=.01) and that of A1A1 participants increased markedly with stress (P=.001). These findings support the hypothesis that DRD2 genotype-phenotype associations depend on the magnitude of stress exposure, and they lend support to the view that variability in DRD2 study outcomes may in part be explained by this gene-environment interaction.