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P#31 - P#40
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P#31
: Comings, D.E. (1994). Genetic factors in substance abuse based on studies of Tourette syndrome and ADHD probands and relatives. II. Alcohol abuse
ABSTRACT:Prior studies have suggested childhood ADHD as a risk factor for alcohol abuse in adults. Gilles de la Tourette syndrome, a hereditary tic and impulse disorder, is clinically and genetically similar to ADHD. To examine the hypothesis that individuals carrying the Gts gene are at increase risk to develop alcohol use problems, the same TS and ADHD probands, relatives and controls used in the prior study of drug abuse were studied using a structured questionnaire based on the Diagnostic Interview Schedule and the MAST test. The frequency of a positive response to any of 16 different questions concerning alcohol abuse showed a highly significant increase with increased genetic loading for Gts and ADHD genes. The percentage of more than one positive response in TS probands was markedly influenced by the presence of comorbid ADHD, discipline, obsessive-compulsive or drug abuse problems. Comorbid drug abuse problems were the best predictor of alcohol abuse problems. These results suggest that the genes responsible for TS and ADHD play an important role in alcohol abuse/dependence as well as drug abuse/dependence. One of the elements common to all of these disorders may be mutant genes affecting serotonin metabolism. Drug and Alcohol Dependence, 35, 17-24.
P#32
: Comings, D.E. (1994). The role of genetic factors in human sexual behavior based on studies of Tourette syndrome and ADHD probands and their relatives
ABSTRACT:Most significant variations in the expression of human sexuality are considered to be the result of learned behavior or psychological problems. Tourette syndrome (TS) is a common, hereditary tic and disinhibition disorder sometimes associated with compulsive use of obscene words (coprolalia) and previously reported to be occasionally associated with exhibitionism. To further explore the relationship between the Gts genes and sexual behavior, questions concerning a wide range of such behaviors were administered to 1,040 subjects, 14 years of age or older, consisting of 358 TS probands, 101 non-proband relatives with TS, 359 non-TS first degree relatives, 79 attention deficit hyperactivity disorder (ADHD) probands, 70 unaffected relatives of the ADHD probands, and 73 controls. The behaviors included magnitude of sex drive, sex orientation, exhibitionism, transvestitism, transsexualism, sadism, masochism, pedophilia, fetishism, aversion to being touched, and aversion to sex. While most of these behaviors occurred in a distinct minority of TS subjects, there was a significant positive correlation between each behavior examined and the degree of genetic loading for the Gts gene(s). The nature of these behaviors and their association with TS suggests many are variants of obsessive-compulsive disorder. Studies in animals indicate that changes in serotonin and dopamine play a significant role in the sexual behavior and many lines of evidence are consistent with the hypothesis that TS is due to genetic changes in serotonin and dopamine metabolism. These studies suggest that genetic factors play a much greater role in a wide range of forms of sexual expression than previously thought. Am.J.Med.Gen.(Neuropsych.Genet.), 54 , 227-241.
P#33
: 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
ABSTRACT: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. Drug and Alcohol Dependence, 34 , 175-180.
P#34
: Comings, D.E. (1995). The role of genetic factors in conduct disorder based on studies of Tourette syndrome and ADHD probands and their relatives
ABSTRACT:To examine the role of genetic factors in oppositional defiant disorder (ODD) and conduct disorder (CD), 38 variables relating to the relevant DSM-III-R criteria as well as other angry and aggressive behaviors, were examined in 1177 TS and ADHD probands, their first degree relatives and controls. Two techniques were used: 1) a genetic loading technique comparing the frequency of symptoms in groups with progressively less genetic loading for Gts and ADHD genes, and 2) comparison of the frequency of symptoms in relatives with, versus relatives without, TS or ADHD. When significant the latter rules out ascertainment bias and inappropriate controls. For TS the results were significant with most p values being < 10-8. The same trends were seen in the smaller number of ADHD families. A polygenic model is proposed in which TS and ADHD alone represent lesser degrees of genetic loading and expression and TS+CD'ADHD represent a higher degree of genetic loading and expression of genes common to all three disorders. These studies emphasize the important role of genetic factors in ODD and CD. The therapeutic implications are discussed. J.Dev.Behav.Pediatr., 16, 142-157.
P#35
: Comings, D.E. (1995). Genetic factors in depression based on studies of Tourette syndrome and Attention Deficit Hyperactivity Disorder probands and relatives
ABSTRACT:Tourette syndrome (TS) is a common, neuropsychiatric disorder which has many similarities to attention deficit hyperactivity disorder (ADHD). TS probands have a high frequency of a variety of behavioral disorders including depression. The depression may be due to a pleiotrophic effect of the Gts genes, proband ascertainment bias, or a result of coping with the chronic tics. To distinguish between these hypotheses we examined the responses to 17 Diagnostic Interview Schedule questions to evaluate the 9 DSM-III-R criteria for major depressive episode in 1080 adults consisting of TS and ADHD probands, their relatives and controls. Using a Bonferonni corrected p there was a significant progressive increase in 16 of 17 depressive symptoms and for a life time history of a major depressive episode in groups with increased genetic loading for Gts genes. Similar trends were seen in the small number of ADHD probands and their relatives. There was also a significant increase for these variables in non-proband TS relatives versus non-TS relatives, indicating the association of depression with Gts genes was not due to ascertainment bias or the inappropriate choice of controls. Multiple linear regression analysis indicated that obsessive-compulsive behaviors, sex, ADHD, drug abuse, and age all showed a more significant effect on depressive symptoms than the number of tics. The presence or absence of TS in the relatives had a much greater effect on risk for depression than the presence or absence of an episode of major depression in the proband. These results are consistent with the hypothesis that Gts and ADHD genes play a major role in depression. Am.J.Med.Gen.(Neuropsych.Genet.), 60 , 111-121.
P#36
: Comings, D.E. (1995). Tourette Syndrome: A Behavioral Spectrum Disorder
ABSTRACT:Tourette's syndrome is a fascinating, complex, hereditary, neuropsychiatric spectrum disorder in which the tics are only one of many symptoms. Data to date suggest the mechanism of inheritance is just as complex as the disorder itself and involves the coming together of a number of common genes that affect dopamine and serotonin metabolism. Because these neurotransmitters modulate the function of many areas of the brain, the result is a wide spectrum of behavioral disorders. As such TS provides a significant challenge to the physician. Because many of the newer medications are quite effective, taking on the treatment of this challenging and complex behavioral spectrum disorder can be extremely rewarding. In W. J. Weiner & A. E. Lang (Eds.), Behavioral Neurology of Movement Disorders. (pp. 293-303). New York: Raven Press.
P#37
: Comings, D.E. (1995). Tourette syndrome: A hereditary neuropsychiatric spectrum disorder
ABSTRACT:The objective was to determine if the high frequency of behavioral problems in Tourette syndrome (TS) probands is the result of the pleiotrophic expression of the Gts genes or due to ascertainment bias. It was possible to distinguish between these two hypotheses by comparing the frequency of these behaviors in nonproband relatives with TS to relatives without TS. Twenty behavioral problems were prospectively assessed in a consecutive series of 361 TS probands, 113 nonproband TS relatives, 380 relatives without TS, and 68 controls, by the administration of a questionnaire based on the Diagnostic Interview Schedule and the DSM-III-R. Significance was set at a very conservative level of p ¥= .001. Except for problems with smoking, reading and compulsive eating, all other behaviors were significantly more common in nonproband TS relatives than in relatives without TS. The relatives were also dichotomized on the basis of each of the behavioral problems. Regardless of the behavioral trait used, there was a higher frequency of all other behaviors in those who were positive versus those who were negative for that behavior. Ranking according to the number of behaviors that were significant indicated that mania, obsessive-compulsive behaviors and schizoid behaviors represented higher degrees of expression of the Gts genes than chronic tics. These results indicate that the Gts genes cause a spectrum of behavioral disorders in addition to chronic tics, indicate that TS is a behavioral spectrum disorder, and emphasize the role of genetic factors in a wide range of human behaviors. Ann.Clin.Psychiatry, 6, 235-247.
P#38
: 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
ABSTRACT: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. Biol.Psychiatry, 37, 798-805.
P#39
: Comings, D.E., Muhleman, D., Dietz, G., Sherman, M., & Forest, G. (1995). Sequence of human tryptophan 2,3-dioxygenase: Presence of a glucocorticoid response-like element composed of a GTT repeat and an intronic CCCCT repeat
ABSTRACT: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. Functional variants 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 show 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 variant was significantly associated with platelet serotonin levels. While only the association with TS was significant with a Bonferroni correction, we hope these preliminary results serve to stimulate further studies of the potential role of the TDO2 gene in a range of psychiatric disorders. Genomics, 29, 390-396.
P#40
: 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
ABSTRACT: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. Molecular Psychiatry, 1, 325-335.
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