Associations of the DRD2 TaqIA polymorphism with impulsivity and substance use: Preliminary results from a clinical sample of adolescents☆
Introduction
A number of large epidemiologic studies, e.g., the National Epidemiologic Survey on Alcohol and Related Conditions (Stinson et al., 2005), have demonstrated associations between substance use disorders (SUD) and externalizing psychiatric disorders such as Conduct Disorder (CD) and Attention Deficit Hyperactivity Disorder (ADHD). These associations, in turn, have led researchers to present evidence from both adolescent and adult twin studies that these disorders are related to an underlying shared genetic liability (Kendler, Prescott, Myers & Neale, 2003; Knopik et al., 2009-this issue, Krueger et al., 2002, Young et al., 2000).
Genes in several biological systems (e.g., dopamine, serotonin, GABA, glutamate) have been investigated in relation to both substance use disorders and externalizing psychiatric disorders, albeit with mixed results. Dopaminergic function in particular seems to underlie all drugs of abuse (Kalivas and Volkow, 2005), and variation in dopaminergic genes may impact dependence rates across multiple substances, including alcohol and marijuana use. A number of studies have found a relationship between the DRD4 gene and substance use. For example, Laucht, Becker, Blomeyer, and Schmidt (2007) found that male adolescents with the 7-repeat allele of DRD4 drank more alcohol per occasion and had higher rates of lifetime heavy drinking than males without this allele. Novelty seeking was found to moderate this relationship for males but not females. Several studies have also found a specific relationship between a DRD2 polymorphism and substance abuse. For example, one study found that the presence of the A1 allele of the TaqIA polymorphism close to the dopamine D2 receptor in the brains of adult alcoholics correctly classified 77% of alcoholics, relative to non-alcoholics (Blum et al., 1990). The authors concluded that this gene infers a genetic susceptibility to alcoholism, in this case a severe form of alcoholism, as most of the patients in this sample died due to the effects of alcohol.
Since the original paper by Blum et al. (1990), there have been a number of other studies implicating the role of this polymorphism (rs1800497) in alcohol abuse and dependence (see Noble, 2000). The findings, however, are not consistent. Variation in the findings across studies may reflect the fact that alcohol use disorders take many forms and have differing etiologies. The DRD2 gene may only be related to specific subtypes of alcoholism or specific characteristics of alcohol use disorders (Lu, Lee, Ko & Lin, 2001). Alternatively, the influence of genetic factors may differ depending on the stage of substance use, e.g., initiation to regular use/abuse to dependence (Kreek et al., 2005). For example, Poelen et al (2008) found that genetic factors were more important in explaining initiation of alcohol use in 12 to 15 year olds than environmental factors, while common environmental factors explained most of the variance in drinking frequency. Additional evidence has been found to suggest that historical DRD2 associations may have in fact been driven by variation in nearby genes. For example, Yang et al. (2008) report associations with alcohol and drug dependence and the “NTAD cluster” that includes NCAM1, TTC12, ANKK1 and DRD2. These results follow several other findings that suggest that the inconsistent literature on DRD2 TaqIA may in part be driven by variation in other genes (Dick et al., 2007, Gelernter et al., 2006, Yang et al., 2007).
Most studies in the literature use heterogeneous samples of individuals with SUD and do not examine stage of substance use. Limiting an investigation to adolescents helps to control some of this heterogeneity. Although adolescents may have a history of alcohol use, this history will be shorter than the histories of the participants in the studies described above. Positive associations of the DRD2 A1 allele and alcohol and drug use behaviors in an adolescent sample would suggest that either relatively shorter consumption histories still manifest the expected genetic differences or that the DRD2 polymorphism is related to some underlying vulnerability. Alternatively, the notion that the influence of genes may vary at different stages of development (Rende & Plomin, 1995) may be applicable here with gene penetrance being prominent even in adolescence.
There have been a number of studies of clinical and nonclinical populations that have found a significant percentage of adults with SUD also have a diagnosis of ADHD. Data from the National Comorbidity study indicated that adults with ADHD had significantly higher rates of SUDs than adults without ADHD (Kessler et al., 2006). About one-quarter of psychologically hospitalized adolescents also report a SUD (DeMilio, 1989). Similar to that found with substance use, recent studies also suggest a relationship between the dopamine transporter gene and ADHD (Faraone et al., 2005, Todd et al., 2005). For example, an association between ADHD and the A1 allele of the DRD2 gene has been found in a study of a Finnish birth cohort population sample (Nyman et al., 2007).
Epidemiologic studies have also documented a relationship between DRD2 and other externalizing disorders and behaviors (Kandel et al., 1997). In one such study, the DRD2 A1 allele was related to pathological gambling (Ratsma et al., 2001). Comings et al. (2000) examined the relationship of the dopamine, serotonin, and nonadrenaline genes to ADHD and CD and found that the DRD2 gene was partially related to CD. However, like the studies reviewed above with alcohol and other drugs, not all studies support this relationship between ADHD or externalizing disorders in general, and the DRD2 A1 status.
The heterogeneity of symptom presentation in individuals with the same diagnosis may also contribute to the variability in genetic findings. Consequently, in addition to examining psychiatric diagnoses, examination of intermediate phenotypes is critical to furthering our understanding of what behaviors underlie the relationship between diagnoses and genes. For example, the diagnostic criteria for alcohol dependence do not distinguish between persons who drink alcohol problematically for different reasons, e.g., as a means to self-medicate versus impulsively drinking to excess with peers. Variations in intermediate phenotypes may also contribute to differences across individuals in initiation and transitions across stages of substance use.
Impulsivity is a potential intermediate phenotype that is associated with alcohol and drug use in adolescents and adults (Colder and Chassin, 1997, Labouvie and McGee, 1986, Noble, 1998). Blum et al. (2000) postulated that the DRD2 gene may mediate the preference for immediate rewards in impulsive persons. Several studies have examined the role of impulsivity and the DRD2 gene in substance use with conflicting findings. On the one hand, Eisenberg et al. (2007) examined the DRD2 TaqI A locus classified as having one copy of the A1 allele (A1+) or not (A1−) in 195 college students. Each participant completed a delayed discounting task, a behavioral test of impulsivity. A main effect of A1+ status on delayed discounting was found, suggesting that those individuals with the A1+ allele exhibited greater impulsivity than those with the A1− allele. On the other hand, Limosin et al. (2003) administered the Barrett Impulsiveness Scale to 92 alcohol-dependent inpatients and found that the DRD2 TaqIA polymorphism was associated with lower impulsivity in this sample. Limosin et al. (2003) suggest that alcohol may be taken to stimulate dopamine activity in order to increase reward-related impulsivity.
Impulsivity is a cardinal symptom of both a CD and ADHD diagnosis (Sagvolden et al., 2005). Twin studies have also found that impulsivity has a significant heritable component (e.g., Seroczynski et al., 1999). In addition, genetic studies have also linked impulsivity evident in ADHD to the dopamine system (Li et al., 2006). Given that the symptom presentation in ADHD is variable, i.e. not all patients show the same degree of attentional problems or impulsivity, it is possible that impulsivity may be a specific link between SUD and ADHD. Similarly, diagnoses of CD may differ in the extent to which social norms do or do not affect problem behaviors. Thus, impulsivity may be a key factor in the subset of adolescents with CD who progress to SUDs (Nigg et al., 2006).
In this study we examine a subset of adolescents from a larger assessment study that characterizes alcohol and drug use in a sample of youth at high risk for the development of alcohol and drug dependence, adolescents with psychiatric disorders. We were interested in examining three major questions. First, is the DRD2 TaqIA polymorphism associated with more severe problem drinking and drug use in a sample of high risk adolescents? Second, does the DRD2 TaqIA polymorphism affect the well documented relationship between externalizing disorders, i.e. CD and ADHD, and alcohol or drug related problems? And third, does the DRD2 TaqIA polymorphism affect the nature of the relationship between the endophenotype of impulsivity, which is related to both CD and ADHD, and severity of problem drinking and drug use. We hypothesized that carriers of the A1+ allele of the DRD2 TaqIA polymorphism would report more severe problem drinking and drug use. Further, we hypothesized that those adolescents who met diagnostic criteria for ADHD, conduct disorder, or exhibited significant impulsivity, and were carriers of the A1+ allele of the DRD2 TaqIA polymorphism, would report more severe alcohol and drug use problems than those who exhibited these externalizing diagnoses/behavior but were non-carriers of the A1+ allele of the DRD2 TaqIA polymorphism.
Section snippets
Participants
One hundred and forty-nine adolescents hospitalized on an acute adolescent psychiatric inpatient unit and their parents/guardians were asked to participate on a voluntary basis. The large majority of adolescents were hospitalized due to suicidal thoughts or behavior. Adolescents were recruited from a child psychiatric hospital located in the Northeast which accepts both uninsured and privately insured youth. Of those approached for participation, 118 (79%) were successfully recruited. However,
Participant characteristics
Approximately 32% of participants met criteria for conduct disorder and 39% for Attention-Deficit/Hyperactivity Disorder (35% inattentive subtype, 5% hyperactive subtype, 60% combined inattentive/hyperactive subtype). Approximately 32% of participants endorsed the impulsivity item from the ADHD screen. Further, 38.5% of the sample was found to be carriers of the A1 allele of the DRD2 TaqIA polymorphism (A1+) and 61.5% were non-carriers (A1−). The mean SASSI face valid alcohol total raw score
Discussion
The first aim of this study was to investigate whether the DRD2 TaqI polymorphism was associated with problem drinking and drug use in a group of adolescents with psychiatric disorders. There was no direct relationship found between the DRD2 TaqIA polymorphism and problem drinking or drug use behavior. These results suggest that the DRD2 TaqIA polymorphism may not be directly associated with problem drinking or drug use among adolescents.
With regard to externalizing diagnoses, a direct
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Research supported by a grant from the National Institute of Mental Health (NIMH) 5R01MH065885-03 (CES) and a Research Career Development Award from the Medical Research Service of the Department of Veterans Affairs (JEM).