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P#51 - P#60
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P#51
: Johnson, J.P., Muhleman, D., MacMurray, J., Gade, R., Verde, R., Ask, M., Kelley, J., & Comings, D.E. (1997). Association between the cannabinoid receptor gene (CNR1), and the P300 wave of event-related potentials, and drug dependence
ABSTRACT:In our prior study we observed a significant association between homozygosity for the "5 alleles of a microsatellite polymorphism of cannabinoid receptor gene (CNR1) and drug dependence. Decreased amplitude of the P300 wave of evoked related potentials (ERP) has long been shown to be associated with alcohol and drug dependence. The P300 wave reflects attentional resource allocation and active working memory. Since marijuana intoxication has a potent blocking effect on short term memory we examined the association between the CNR1 alleles and the P300 wave amplitude at three electrodes in 35 alcohol and drug addicts, by MANOVA. There was a significant decrease in amplitude of the P300 wave for all three electrodes (p = .028) that was most marked for the frontal lobes (p = .008) in subjects homozygous for the CNR1 "5 repeat alleles. Multivariate regression analysis indicated the CNR1 gene contributed to 20 percent of the variance of the frontal lobe P300 wave amplitude. Molecular Psychiatry, 2 , 169-171.
P#52
: Comings, D.E. (1997). Genetic aspects of childhood behavioral disorders
ABSTRACT:The evidence is reviewed to support the concept that many disruptive, childhood and adolescent behavioral disorders including ADHD, Tourette syndrome, learning disabilities, substance abuse, oppositional defiant disorder and conduct disorder, are part of a spectrum of inter-related behaviors that have a strong genetic component, are polygenically inherited, share a number of genes in common that affect dopamine, serotonin and other neurotransmitters, and are transmitted from both parents. Some of the implications of this hypothesis in relation to diagnosis and treatment are reviewed, including the possibility that the genes involved may be increasing in frequencyChild Psychiatry Human Devel., 27, 139-150.
P#53
: Comings, D.E., Gade, R., Wu, S., Chiu, C., Dietz, G., Muhleman, D., Saucier, G., Ferry, L., Burchete, R., Johnson, P., Verde, R., & MacMurray, J.P. (1997). Studies of the potential role of the dopamine D1 receptor gene in addictive behaviors
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 D1 and D2 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 = .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 percentage of controls, TS probands without the specific behavior, and TS probands with the specific behavior. There was a progressive, linear increase, significant at a *.005, for scores for problems with gambling, alcohol use and compulsive shopping. Problems with three additional behaviors, drug use, compulsive eating and smoking were significant at a *.05. All 6 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 = .0002). In a third independent group ofpathological gamblers, 55.8% carried the 11 or 22 genotype (p = .009 versus the combined controls). In the TS group and smokers there was an additive effect of the DRD1 and DRD2 genes. The results for both the DRD1 and DRD2 gene, 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. Molecular Psychiatry, 2, 44-56.
P#54
: 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)
ABSTRACT: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. Molecular Psychiatry, 2, 239-246.
P#56
: Comings, D.E., Muhleman, D., Gade, R., Johnson, P., Verde, R., Saucier, G., & MacMurray, J. (1997). Cannabinoid receptor gene (CNR1): Association with IV drug use
ABSTRACT:The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microstatellite 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 versus IV drug use showed a decrease in the frequency of the 4 allele, and the <4 alleles were rare, the alleles were divided into two groups, <5 and "5, and three genotypes <5/<5, heterozygotes, and "5/"5. 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 "5 repeat alleles showed the greatest effect. The number of drugs used IV was significantly greater for those carrying the "5/"5 genotype than other genotypes (p = .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. Molecular Psychiatry, 2, 161-168.
P#57
: Comings, D.E. (1998). Some genetic aspects of human sexual behavior
ABSTRACT:In addition to motor and vocal tics, Tourette syndrome (TS) can be associated with a wide range of behavioral problems including attention deficit hyperactivity disorder, obsessive-compulsive behaviors, learning disabilities, conduct disorder, and inappropriate sexual behaviors. The latter, which occur in a minority of patients, can include coprolalia, copropraxia, coprographia, exhibitionism, compulsive masturbation, touching themselves or others in the crotch or breast, and sexually self-abusive behaviors. Children who display these behaviors are often assumed to have been sexually abused. When teachers, social service agencies, or other professionals are not familiar with TS, injustice to families can occur. Professionals should be aware that TS can be an alternative to sexual abuse as an explanation of such behaviors. In L. Ellis (Ed.), Males, Females, and Behavior: Toward Biological Understanding. (pp. 1-12). New York: Praeger.
P#58
: Gade, R., Muhlemann, D., MacMurray, J., & Comings, D.E. (1998). Correlation of length of VNTR alleles at the X-linked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse
ABSTRACT:Abnormalities in monoamine oxidase (MAO) levels have been implicated in a wide range of psychiatric disorders. We have examined a VNTR polymorphism at the X-linked MAOA gene to test two hypotheses: 1. Do variants of the MAOA gene play a role in any of the behavioral disorders associated with Tourette syndrome or drug abuse? 2. If so, is there any correlation between the length of the alleles and the phenotypic effect? We examined two independent groups: 375 TS patients, relatives and controls, and 280 substance abusers and controls. The alleles were divided into four groups of increasing size. There was a significant association between the MAOA gene and behavioral phenotypes in both groups, and in both the longest alleles were associated with the greatest phenotypic effect. The strongest effect was for the diagnosis of drug dependence (p = .00003). The VNTR allele groups were in significant linkage disequilibrium with the Fnu4H1 polymorphism previously shown to be associated with MAO-A activity. While these results are consistent with the possibility that different sized alleles of the short-repeat polymorphisms themselves may play a role in gene regulation, further studies directly linking these alleles with enzyme levels need to be done. Molecular Psychiatry, 3, 50-60.
P#60
: Comings, D.E. (1998). Why Different Rules are Required for Polygenic Inheritance: Lessons from Studies of the DRD2 Gene
ABSTRACT: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. Alcohol, 16, 61-70.
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