Genetic factors in substance abuse based on studies of Tourette Syndrome and ADHD probands and relatives. I. Drug abuse
There have been relatively few studies of genetic factors in drug abuse. Childhood Attention Deficit Hyperactivity Disorder (ADHD) has been implicated as a risk factor, and pedigree studies of Tourette Syndrome (TS), a hereditary impulse disorder closely related to ADHD, show an increased prevalence of substance abuse in relatives. These observations suggest the genes for TS and ADHD may play an important role in the development of drug abuse. To examine this hypothesis 217 TS probands and 328 of their relatives, 58 ADHD probands and 35 of their relatives, and 50 controls were prospectively studied using a structured questionnaire based on the Diagnostic Interview Schedule. All subjects were Caucasians 16 to 49 years of age. The responses concerning the use of 8 different drugs and 8 different symptoms of drug abuse were compared. The results showed a highly significant increase in positive responses with increased loading for the TS and ADHD genes for 6 of the 8 drugs and all of the drug abuse symptoms. The percentage of positive responses in TS probands was markedly influenced by the presence of comorbid ADHD, as well as discipline, obsessive-compulsive, or alcohol problems. These results suggest that the genes responsible for TS and ADHD play an important role in drug abuse/dependence. The dopamine D-2 receptor gene (DRD2) appears to be one of these genes since variants at this locus are significantly increased in frequency in TS, ADHD, conduct disorder and drug abuse.
[Show abstract] [Hide abstract] ABSTRACT: The comorbidity of tic disorders (TD) and obsessive-compulsive disorder (OCD) has long been recognized in the clinical literature and appears to be bidirectional, affecting 20-60% of individuals with each disorder. Coffey et al. (1998) found that adults with TD+OCD had a more severe comorbidity profile than adults with OCD or TD alone. This exploratory study in children attempts to evaluate whether heightened diagnostic severity, increased comorbidity load, and lower functioning is more commonplace in youth with TD+OCD in comparison to either syndrome alone. Participants were 306 children (seeking clinical evaluation) with TD, OCD, or TD+OCD. Assessment consisted of a diagnostic battery (including structured diagnostic interviews and standardized parent-report inventories) to evaluate diagnostic severity, comorbid psychopathology, behavioral and emotional correlates, and general psychosocial functioning. Data from this study sample were not supportive of the premise that youth with both a tic disorder and OCD present with elevated diagnostic severity, higher risk-for or intensity-of comorbidity, increased likelihood of externalizing/internalizing symptomatology, or lower broad-based adaptive functioning. The OCD group had elevated rates of comorbid anxiety disorders and attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were more prevalent among youth in the TD group. The three groups also differed on key demographic variables. Our findings suggest that, in contrast to adults, TD+OCD in children and adolescents does not represent a more severe condition than either disorder alone on the basis of diagnostic comorbidity, symptom severity, or functional impairment.0Comments 37Citations
- "Some adult studies have supported a clinical distinction among the three diagnostic groups, OCD, TD, and TD+OCD. Obsessive-Compulsive Disorder, when accompanied by a tic disorder, has been associated with higher rates of comorbid mood, anxiety, disruptive behavior, and substance use disorders than OCD or TD in the absence of the other (Comings 1994; Coffey et al. 1998; King et al.1999; Cath et al. 2001). Such studies have suggested that TD+OCD is a more severe phenotype than TD or OCD alone, and is often accompanied by multiple comorbidities (Coffey et al., 1998). "
[Show abstract] [Hide abstract] ABSTRACT: Prior studies have reported an association between the presence of the 7 repeat allele of the 48 bp repeat polymorphism of the third cytoplasmic loop of the dopamine D4 receptor gene (DRD4) and novelty seeking behaviors, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), pathological gambling, and substance abuse. However, other studies have failed to replicate some of these observations. To determine whether we could replicate these associations we genotyped 737 individuals from four different groups of control subjects, and 707 index subjects from four different groups of impulsive, compulsive addictive behaviors including substance abuse, pathological gambling, TS, and ADHD. Chi-square analysis of those carrying the 7 allele versus non-7 allele carriers was not significant for any of the groups using a Bonferroni corrected alpha of.0125. However, chi-square analysis of those carrying any 5 to 8 allele versus noncarriers was significant for pathological gambling (p <.0001), ADHD (p </=.01) and the total index group (p </=.0004). When the comparison included all 7 alleles the results were significant for gamblers (p <.0001), TS (p </=.003), ADHD (p </=.003), and the total group (p </=.0002). There was a significant increase in the frequency of heterozygosity versus homozygosity for all alleles for pathological gamblers (p </=.0031) and the total index group (p </=.0015), suggesting that heterosis played a role. In the substance abuse subjects a quantitative summary variable for the severity of drug dependence, based on the Addiction Severity Index, showed that the scores varied by increasing severity across the following genotypes: 44 </= heterozygotes </= 77 </= 22. Studies of other quantitative traits indicated an important role for the 2 allele and the 22, 24, and 27 genotypes. All studies indicated that the role of the DRD4 gene in impulsive, compulsive, addictive behaviors is more complex than a sole focus on the 7 versus non-7 alleles.0Comments 162Citations
- "To avoid the loss of power involved with multiple tests, we examined only four of these variables: ADHD, oppositional defiant (ODD) and conduct disorder (CD), and tics [Comings, 1995a]. The details of how these scores are compiled have been provided elsewhere [Comings, 1995a; Comings et al., 1996c]. "
[Show abstract] [Hide abstract] ABSTRACT: Background: Considering that platelets have been established to be good peripheral markers for the study of catecholaminergic neurons, we have applied an assay to measure the uptake of (3H)-dopamine (DA) into platelet storage granules (PSG). Recently, we reported that Tourette's syndrome (TS) patients (pts) show decreased DA uptake into PSG. Methods: In the present study, 28 first-degree relatives (3 with chronic motor tics, 3 with transient tics, 6 with obsessive-compulsive behavior, and 16 without symptomatology) belonging to the families of 13 patients, and 14 unrelated healthy controls were studied. Results: Double reciprocal plots were constructed for each subject, and the apparent maximum velocity (Vmax) and Michaelis constant (K(m)) were determined by linear regression analysis (Lineaweaver-Burke plots). The uptake of DA (0.5-5 mumol/L) (mean +/- SEM) by PSG from relatives with symptomatology was similar to the TS patients (symptomatic relatives Vmax 181 +/- 22.2 fmol/mg protein, K(m) (mumol/L) 6.42 +/- 0.29; TS pts Vmax 108 +/- 6.9, K(m) 7.79 +/- 0.64). Relatives without symptomatology on the contrary showed DA affinity characteristics similar to the controls (t test, paired t test, multivariate analysis of variance, and log transformation). Conclusions: The data presented suggest that TS is hereditary, but they do not distinguish between an autosomal dominant inheritance and a mixed or polygenic model.0Comments 1Citation
- "The results obtained suggested that TS and other associated behavior disorders (like attention-deficit hyperactivity disorder, stuttering, conduct and oppositional defiant disorder, etc.) are inherited in a polygenic way. Moreover previous studies of Comings (1984 Comings ( , 1995), have suggested the polygenic inheritance of TS, with each gene contributing only 1–10% of the variance. The purpose of the present study was to examine the DA uptake by PSG in families from TS patients to find out if there is some relation between the clinical features of From the Department of Neurology (JMR, IA, TT, ADK) and Department of Chemical Pathology (ZO), Tel Aviv Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. "