P#42

: 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

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 Pharmacogenetics, 6, 223-234.

Back to The Paper's Index Page

P#43

: Comings, D.E., Muhleman, D., & Gysin, R. (1996). The dopamine D2 receptor (DRD2) gene in posttraumatic stress disorder: A study and replication

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. Biol.Psychiatry, 40, 368-372.

Back to The Paper's Index Page

P#46

: Comings, D.E. (1996). Polygenetic inheritance of psychiatric disorders

While family, twin and adoption studies have clearly demonstrated a role of genes in many human behavioral disorders, there has been little success in the identification of which genes are involved. It is proposed that the reason for this is that the wrong genetic models and thus the wrong techniques are being used. The most popular model is that of a rare, disease specific, autosomal dominant gene with reduced penetrance and the assumption that the mutations are in exons. The most popular technique, based on this model, is linkage analysis using large families. I propose that the correct model, capable of giving identical appearing pedigrees, is that of polygenic inheritance. The best technique of identifying the genes involved in such model is the use of association studies with large numbers of severely affected probands compared to unrelated controls. It is also suggested that the polygenes (mutant genes involved in polygenic inheritance) are not disease specific but are involved in a spectrum of disorders and are fundamentally different from those involved in single gene disorders in that they have a much milder effect on gene function and tend to involve non-exon sequences. As such the carrier rate in the population can be high. Their deleterious effect comes when individuals inherit a greater than threshold number of polygenes. By binding transcription factors, dinucleotide, trinucleotide and other repeat polymorphisms may affect gene function and thus may be one cause of polygenes. One of the distinctive characteristics of polygenic inheritance is that the genes are contributed by both parents, and in psychiatric disorders the relatives on both the maternal and paternal sides often demonstrate an increased frequency of a spectrum of behavioral disorders. In K. Blum, E. P. Noble, R. S. Sparks, & P. J. Sheridan (Eds.), Handbook of Psychiatric Genetics. (pp. 235-260). Boca Raton,FL: CRC Press.

Back to The Paper's Index Page

P#47

: Comings, D.E., Wu, J., Chiu, C., Muhleman, D., & Sverd, J. (1996). Studies of c-Harvey-Ras gene in psychiatric disorders

Herault et al. (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey-Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the prevalence of the > 2.1 kb alleles in 164 probands with Tourette's syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive- compulsive and phobic symptoms in > 2.1 kb homozygotes. While this locus requires further study, in conjunction with the results of Herault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders.Psychiatry Res., 63, 25-32.

P#48

: 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

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. Pharmacogenetics, 6, 73-79.

Back to The Paper's Index Page

P#49

: 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

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.Am.J.Med.Gen.(Neuropsych.Genet.), 67, 264-288.

Back to The Paper's Index Page

P#50

: Comings, D.E., Muhleman, D., Gade, R., Chiu, C., Wu, H., Dietz, G., Winn-Dean, E., Ferry, L., Rosenthal, R.J., Lesieur, H.R., Rugle, L., Sverd, J., Johnson, P., & MacMurray, J.P. (1996). Exon and intron mutations in the human tryptophan 2,3-dioxygenase gene and their potential association with Tourette syndrome, substance abuse and other psychiatric disorders

Defects in serotonin metabolism, and abnormalities in both blood serotonin and tryptophan levels, have been reported in many psychiatric disorders. Tryptophan 2,3-dioxygenase (TDO2) is the rate limiting enzyme for the breakdown of tryptophan to N-formyl kenurenine. Mutations of this gene could account for the observed simultaneous increases or decreases of both serotonin and tryptophan in various disorders. We have identified four different polymorphisms of the human TDO2 gene. Association studies with over 900 subjects have shown a significant association of one or more of these poylmorphisms with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) and drug dependence. The intron 6G->T mutation was associated with a significant change in platelet serotonin level. These associations are consistent with the hypothesis that these disorders are inherited in a polygenic fashion, that the TDO2 gene is contributing to a portion of the phenotype, and that these and related disorders are due, in part, to mutations that disturb serotonin metabolism. Pharmacogenetics, 6, 307-318.

Back to The Paper's Index Page