Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine β‐hydroxylase (DβH), 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. © 1996 Wiley‐Liss, Inc.

No abstract

No abstract

--These results suggest the A1 allele of the DRD2 gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.

The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT) n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs IV drug use showed a decrease in the frequency of the 4 allele, and the Ͻ4 alleles were rare, the alleles were divided into two groups, Ͻ5 and Ն5, and three genotypes Ͻ5/Ͻ5, heterozygotes, and Ն5/Ն5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the Ն5 repeat alleles showed the greatest effect. The number of IV drugs used was significantly greater for those carrying the Ն5/Ն5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.

Based on an evolutionary theory of socialization, Belsky and colleagues proposed that girls exposed to a stressful environment, especially when due to father absence in the first 7 years of life, showed an early onset of puberty, precocious sexuality, and unstable relationships as adults. The authors of this article examined an alternative explanation that a variant X-linked androgen receptor (AR) gene, predisposing the father to behaviors that include family abandonment, may be passed to their daughters causing early puberty, precocious sexuality, and behavior problems. The results of a study of 121 White males and 164 White females showed a significant association of the short alleles of the GGC repeat polymorphism of the AR gene with a range of measures of aggression and impulsivity, increased number of sexual partners, sexual compulsivity, and lifetime number of sex partners in males; and paternal divorce, father absence, and early age of menarche in females. These findings support a genetic explanation of the Belsky psychosocial evolutionary hypothesis regarding the association of fathers' absence and parental stress with early age of onset of menarche and early sexual activity in their daughters. A genetic explanation of the father absence effect is proposed in which fathers carrying the AR alleles are more likely to abandon a marriage (father absence) and pass those alleles to their daughters in whom they produce an earlier age of menarche and behavioral problems.

No abstract

Abnormalities in the dopaminergic reward pathways have frequently been implicated in substance abuse and addictive behaviors. Recent studies by Self and coworkers have suggested an important interaction between the dopamine D 1 and D 2 receptors in cocaine abuse. To test the hypothesis that the DRD1 gene might play a role in addictive behaviors we examined the alleles of the Dde I polymorphism in three independent groups of subjects with varying types of compulsive, addictive behaviors -Tourette syndrome probands, smokers and pathological gamblers. In all three groups there was a significant increase in the frequency of homozygosity for the DRD1 Dde I 1 or 2 alleles in subjects with addictive behaviors. The DRD1 11 or 22 genotype was present in 41.3% of 63 controls and 57.3% of 227 TS probands (P = 0.024). When 23 quantitative traits were examined by ANOVA those carrying the 11 genotype consistently had the highest scores. Based on these results, we examined the prevalence of the 11 genotype in controls, TS probands without a specific behavior, and TS probands with a specific behavior. There was a progressive, linear increase, significant at ␣ Յ 0.005 for scores for gambling, alcohol use and compulsive shopping. Problems with three additional behaviors, drug use, compulsive eating and smoking were significant at ␣ Յ 0.05. All six variables were related to addictive behaviors. In a totally separate group of controls and individuals attending a smoking cessation clinic, and smoking at least one pack per day, 39.3% of the controls versus 66.1% of the smokers carried the 11 or 22 genotype (P = 0.0002). In a third independent group of pathological gamblers, 55.8% carried the 11 or 22 genotype (P = 0.009 vs the combined controls). In the TS group and smokers there was a significant additive effect of the DRD1 and DRD2 genes. The results for both the DRD1 and DRD2 genes, which have opposing effects on cyclic AMP, were consistent with negative and positive heterosis, respectively. These results support a role for genetic variants of the DRD1 gene in some addictive behaviors, and an interaction of genetic variants at the DRD1 and DRD2 genes.