DRD4 VNTR Research Articles

Dopamine D4 receptor gene variation impacts self-reported altruism

In this journal, Bachner-Melman et al.1 reported that the 48-bp variable number of tandem repeat in the third exon of the dopamine D4 receptor (DRD4 VNTR) is associated with self-reported altruism. Despite mounting evidence for a role of dopamine in prosocial behavior,2, 3, 4 this result has not been replicated yet, perhaps because of the rare usage of the applied Selflessness Scale. Here, we report a conceptual replication of the association between DRD4 VNTR and altruism measured with the well-established Revised NEO Personality Inventory (NEO-PI-R; see Strobel et al.2).

DRD4 polymorphism moderates the effect of alcohol consumption on social bonding.

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse.

<i>DRD4</i> VNTR polymorphism in Oceanic populations

<i>DRD4</i> VNTR polymorphism in Oceanic populations

Interaction between the DRD4 VNTR polymorphism and proximal and distal environments in alcohol dependence during emerging and young adulthood.

The manifestation of alcohol dependence at different developmental stages may be associated with different genetic and environmental factors. Taking a developmental approach, we characterized interaction between the dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism and developmentally specific environmental factors (childhood adversity, college/Greek organization involvement, and delayed adult role transition) on alcohol dependence during emerging and young adulthood. Prospective data were obtained from a cohort of 234 White individuals (56% women, 44% men) who were followed up at ages 18 through 34. A longitudinal hierarchical factor model was estimated to model a traitlike persistent alcohol dependence factor throughout emerging and young adulthood and 2 residual statelike alcohol dependence factors limited to emerging adulthood and young adulthood, respectively. We accounted for those alcohol dependence factors by modeling 3 two-way interaction effects between the DRD4 VNTR polymorphism and the 3 developmentally specific environment factors. Carriers of the DRD4 long allele showed greater susceptibility to environmental effects; they showed more persistent symptoms of alcohol dependence as childhood adversity increased and more alcohol dependence symptoms limited to emerging adulthood as college/Greek organization involvement increased. Alcohol dependence among noncarriers of the long allele, however, did not differ as a function of those environments. Although replication is necessary, these findings highlight the importance of repeated phenotypic assessments across development and modeling both distal and proximal environments and their interaction with genetic susceptibility at specific developmental stages.

Dopaminergic genes modulate response inhibition in alcohol abusing adults

Compulsion in alcohol use disorders (AUD) has been attributed to impairment in response inhibition. Because genes that regulate dopamine (DA) have been implicated not only for risk for AUD but also for impulsivity based on behavioral studies, we set out to examine the underlying neural mechanisms associated with these effects. We collected functional magnetic resonance imaging images on 53 heavy drinking but otherwise healthy adults while performing the Go/NoGo task. We predicted that genetic variants previously reported in the literature to be associated with substance abuse, specifically the DRD2 rs1799732 and DRD4 VNTR, will modulate neural processes underlying response inhibition. Our results showed differential neural response for the DRD4 VNTR during successful inhibition in the inferior frontal gyrus (IFG) (cluster-corrected P<0.05, z=1.9). Similarly, DRD2 rs1799732 groups were significantly different in the precuneus and cingulate gyrus during successful response inhibition (cluster-corrected P<0.05, z=1.9). These findings provide further evidence for the role of DAergic genes in modulating neural response in areas that underlie response inhibition and self-monitoring processes. Variants within these genes appear to influence processes related to impulsive behavior, which may increase one's risk for alcohol abuse and dependence.

Dopamine D4 receptor and serotonin transporter gene effects on the longitudinal development of infant temperament

Existing studies of the effect on infant temperament of the 48 base pair variable number of tandem repeats polymorphism in exon 3 of the dopamine D4 receptor gene, DRD4 VNTR, and the serotonin transporter-linked polymorphic region, 5-HTTLPR, have provided contradictory results, and age seems to be an important factor. The present study investigated the effect of these two polymorphisms on the stability of infant temperament between 4 and 9 months of age. Furthermore, the effect of a recently discovered single nucleotide polymorphism which modulates the 5-HTTLPR (rs25531) was investigated in relation to infant temperament. The study sample consisted of 90 infants, who were assessed by parental report at the two ages under consideration using the Revised Infant Behavior Questionnaire. It was found that infants carrying the 7-repeat allele of the DRD4 VNTR had higher levels of Negative Affect. Furthermore, there was an interaction between DRD4 VNTR and 5-HTTLPR genotype such that infants with the DRD4 VNTR 7-repeat allele and the highest expressing 5-HTTLPR genotype (L(A) L(A) ) had the highest level of Negative Affect. These effects were largely driven by scores on the Falling Reactivity scale. Genetic effects were stable across age. The results emphasize the need for developmental studies of genetic effects on temperament.

De invloed van het DRD4 VNTR polymorfisme op adaptatie aan andermans alcoholconsumptie Een onderzoek naar een genomgevinginteractie

The DRD4 VNTR polymorphism affects social adaptation of alcohol use: Investigation of a gene-environment interaction

Associations between dopamine and serotonin genes and job satisfaction: Preliminary evidence from the Add Health Study.

Previous behavioral genetic studies have found that job satisfaction is partially heritable. We went a step further to examine particular genetic markers that may be associated with job satisfaction. Using an oversample from the National Adolescent Longitudinal Study (Add Health Study), we found 2 genetic markers, dopamine receptor gene DRD4 VNTR and serotonin transporter gene 5-HTTLPR, to be weakly but significantly associated with job satisfaction. Furthermore, we found study participants' level of pay to mediate the DRD4 and job satisfaction relationship. However, we found no evidence that self-esteem mediated the relationships between these 2 genes and job satisfaction. The study represents an initial effort to introduce a molecular genetics approach to the fields of organizational psychology and organizational behavior.

Adult attachment and gene polymorphisms of the dopamine D4 receptor and serotonin transporter (5-HTT)

Recently, the Dopamine D4 Receptor Gene (DRD4) and the Serotonin Transporter Gene (5-HTT) have been found to be candidate genes for infant attachment disorganization. The present study aimed to explore the relationship of these genes to adult attachment representations. The Adult Attachment Interview was used to assess attachment representations in 167 German adults. DNA from buccal cells was genotyped for the DRD4 VNTR Exon III and 5-HTT LPR polymorphisms with respect to the presence of the 7repeat allele and the short allele, respectively. DRD4 7repeat allele carriers were significantly more likely to be securely attached than those without 7repeat but only for subjects with unloving caregiver recollections. No association between the 5-HTT LPR polymorphism and adult attachment was found. These findings encourage further investigations to explore endophenotypical and mediating psychological processes between the DRD4 Gene and secure attachment patterns.

The Dopamine D4 Receptor Gene (DRD4) is Associated with Attentional Bias in Heroin Abusers and Cigarette Smokers

The search for a genetic vulnerability gene for substance abuse has focused on dopaminergic genes, including the DRD4 receptor. In addition to clear biological mechanisms in substance abuse, many studies have found a psychologi- cal attentional bias to drug-related stimuli in substance users. This study aimed to determine whether a DRD4 gene poly- morphism is associated with such attentional biases to substance-related stimuli. Eighty heroin abusers in treatment, 80 cigarette smokers, 80 alcohol abusers in treatment and 80 non-smoking community controls undertook an emotional Stroop task to measure attentional bias to drug-related stimuli. DNA was obtained from cheek cell samples and the DRD4 VNTR polymorphism genotyped. Heroin abusers and cigarette smokers, but not controls, who carried the long variant at the DRD4 gene spent significantly longer responding to drug-related stimuli than they did to neutral stimuli when com- pared to those who did not carry the long variant at the DRD4 gene. A non-significant trend to delay was observed in al- coholics. These findings suggest that variants at the DRD4 gene influence attentional bias in substance abusers and offer further insight into the role of the DRD4 gene in drug dependence as well as individual differences in the susceptibility to attentional bias to drug-related environmental cues.

Association of dopamine, serotonin, and nicotinic gene polymorphisms with methylphenidate response in ADHD

Gene polymorphisms of the 3' untranslated region (3'-UTR) of the dopamine transporter (DAT1), Dopamine receptor exon 3 D4 variable number tandem repeat (DRD4VNTR), nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and serotonin transporter promoter (SLC6A4-5HTTLPR) are under consideration as potential risk factors for attention-deficit/hyperactivity disorder (ADHD). A post-hoc attempt was made to investigate the association between the allelic variations of these candidate genes and retrospective parental report of response to methylphenidate in an ADHD-enriched, population-based twin sample. Subjects (N = 243) were selected from the twin sample based on parent report that the child had been treated with methylphenidate for ADHD symptoms. The functional polymorphisms screened were the VNTR located in the 3'-UTR of the dopamine transporter, DRD4 VNTR, CHRNA4 (rs1044396 and rs6090384) and the long (L(A) and L(G)) and short (S) forms of the serotonin transporter promoter region. Logistic regression did not demonstrate a significant association between methylphenidate treatment response and the relevant polymorphisms. The sample size had high power to detect effect sizes similar to those reported in some prior methylphenidate pharmacogenetic studies; however, the categorical (yes/no) measure of parent-reported treatment response may not have been sensitive enough to pick up statistically significant differences in treatment response based on genotype. Further studies including quantitative measures of treatment response are warranted.

DRD4 VNTR polymorphism is associated with transient fMRI-BOLD responses to smoking cues

A dopamine receptor 4 variable number tandem repeat (DRD4 VNTR) polymorphism has been related to reactivity to smoking cues among smokers, but the effect of this genetic variation on brain responses to smoking cues has not been evaluated. The present study evaluated the relationship between carrying the DRD4 VNTR 7-repeat allele and transient functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent responses to smoking cues among adult dependent cigarette smokers. Smokers (n = 15) underwent fMRI scanning after 2-h abstinence. During scanning, they viewed visual smoking and control cues. A blood sample was assayed for the DRD4 VNTR polymorphism, and participants were categorized based on whether they carried one or two copies of the 7-repeat allele (DRD4 L, n = 7) or not (DRD4 S, n = 8). Contrasts in brain cue-reactivity (smoking minus control cues) between DRD4 groups were conducted using SPM2. Smoking cues as compared to control cues elicited transient brain responses in right superior frontal gyrus (BA 8/9/10/32), left anterior cingulate gyrus (BA 32), and right cuneus (BA 19). Exposure to smoking cues resulted in greater activation of right superior frontal gyrus (BA 10) and right insula in DRD4 L compared to DRD4 S individuals. By contrast, exposure to smoking cues among DRD4 S individuals resulted in no significant increases in activation compared to DRD4 L individuals. These brain imaging results suggest that DRD4 VNTR polymorphism is related to transient brain responses to smoking cues in regions subserving executive and somatosensory processes.

Genetic polymorphisms in dopamine-related genes and smoking cessation in women: a prospective cohort study

BackgroundGenes involved in dopaminergic neurotransmission have been suggested as candidates for involvement in smoking behavior. We hypothesized that alleles associated with reduced dopaminergic neurotransmission would be more common in continuing smokers than among women who quit smoking.MethodsThe study included 593 women aged 26–65 years who participated in a twelve month smoking cessation trial conducted in 1993–1994. Participants were contacted three years after the trial to obtain updated smoking history and biological specimens. Seven polymorphisms were assessed in genes involved in dopamine synthesis (tyrosine hydoxylase [TH]), receptor activation (dopamine receptors [DRD2, DRD3, DRD4]), reuptake (dopamine transporter [SLC6A3]), and metabolism (catechol-o-methyltransferase [COMT]). Smoking cessation was assessed as "short-term" quitting (abstinence for the seven days before the conclusion of the trial) and "long-term" quitting (abstinence for the six months before a subsequent interview conducted several years later).ResultsWe observed no association of any polymorphism with either short- or long-term quitting. Although some relative risk estimates were consistent with weak associations, either the direction of effect was opposite of that hypothesized, or results of the short- and long-term cessation endpoints differed. However, effect modification on smoking cessation was observed between DRD2 Taq1A and SLC6A3 VNTR polymorphisms, DRD3 Ser/Gly and d,1-fenfluramine, and DRD4 VNTR and d,1-fenfluramine.ConclusionAlthough these results fail to support prior findings of independent associations of these polymorphisms with smoking status, our exploratory findings suggestive of gene-gene and gene-treatment interactions warrants further investigation.

Effects of craving and DRD4 VNTR genotype on the relative value of alcohol: an initial human laboratory study

BackgroundCraving for alcohol is a highly controversial subjective construct and may be clarified by Loewenstein's visceral theory, which emphasizes craving's behavioral effects on the relative value of alcohol. Based on the visceral theory, this study examined the effects of a craving induction on the relative value of alcohol as measured by a behavioral choice task. In addition, based on previous evidence of its role in the expression of craving, the influence of DRD4 VNTR genotype (DRD4-L vs. DRD4-S) was also examined.MethodsThirty-five heavy drinkers (54% male; 31% DRD4-L) were randomly assigned to receive either a craving induction (exposure to personally relevant alcohol cues) or a control induction (exposure to neutral cues), which was followed by an alcohol-money choice task. Participants were assessed for craving and positive/negative affect throughout the procedure, and relative value of alcohol was derived from participant choices for alcohol versus money. DRD4 VNTR status was assessed retrospectively via buccal samples using previously established protocols.ResultsFactorial analysis of the craving induction revealed that it was associated with significant increase in craving (p < .001), but not greater relative value of alcohol. Factorial analyses including DRD4 VNTR genotype of did not suggest an influence on reactivity to the craving induction, although this analysis was substantially compromised by small cell sample sizes. Continuous analyses revealed that craving was significantly associated with the relative value of alcohol (p < .05) and possession of the DRD4-L allele further amplified this relationship (p < .001).ConclusionThese results are interpreted as generally supporting Loewenstein's visceral theory of craving and evidence of a functional role of DRD4 VNTR genotype in the expression of craving for alcohol. Methodological limitations, mechanisms underlying these findings, and future directions are discussed.

Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study

BackgroundResearch on the genetic basis for impulsivity has revealed an array of ambiguous findings. This may be a result of limitations to self-report assessments of impulsivity. Behavioral measures that assess more narrowly defined aspects of impulsivity may clarify genetic influences. This study examined the relationship between possession of the DRD2 TaqI A and DRD4 48 bp VNTR genetic polymorphisms and performance on a behavioral measure of impulsivity, the delay discounting task (DDT), and three traditional self-report measures.Methods195 individuals (42% male) were recruited from a university campus and were assessed in small group sessions using personal computers. Genotyping was conducted using previously established protocols. For the DRD2 TaqI A locus, individuals were designated as possessing at least one copy of the A1 allele (A1+) or not (A1-), and for the DRD4 48-bp VNTR locus, individuals were designated as having at least one long allele (7 repeats or longer, L+) or not (L-). Principal analyses used multiple univariate factorial 2 (A1+/A1-) × 2 (L+/L-) analyses of variance.ResultsA significant main effect of A1+ status on DDT performance was evident (p = .006) as well as a significant interaction effect (p = .006) between both genes. No other significant effects were evident on the self-report measures, with the exception of a trend toward an interaction effect on the Sensation Seeking Scale. Exploratory analyses suggested that the significant effects were not a function of population stratification or gender.DiscussionThese data suggest that the DRD2 TaqI A and DRD4 VNTR polymorphisms influence impulsivity as measured with a delay discounting task. Specifically, these findings suggest that an interaction between the functional effects of the two unlinked genotypes results in significant difference in the balance of mesolimbic dopaminergic activation relative to frontal-parietal activation. However, these findings are also the first in this area and must be replicated.ConclusionThese findings suggest a meaningful interaction between the DRD2 TaqI A and DRD4 VNTR polymorphisms in the expression of impulsivity and provide initial support for the utility of using behavioral measures for clarifying genetic influences on impulsivity.

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients

Background The VNTR polymorphism in the Dopamine D4 receptor gene ( DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. Method Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene ( L ≥ 7 [ n = 25], S = < 7 [ n = 52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge. Results The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. Discussion Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

A study of TH01 and IGF2-INS-TH haplotypes in relation to smoking initiation in three independent surveys

Recent studies suggest an association between a microsatellite locus (TH01) located in intron 1 of the tyrosine hydroxylase gene (TH) and nicotine dependence. We aimed here to study whether both TH01 and haplotypes of the wider IGF2-INS-TH region influence initiation of regular smoking in current smokers. A total of 3637 individuals from three independent studies (two of adults and one of adolescents) were analysed in relation to the age of first regular smoking (AFRS). Haplotypes and genotypes were obtained for the polymorphisms TH01, IGF2 ApaI, INS HphI and DRD4 VNTR (48 bp)n. Association between IGF2-INS-TH haplotypes and AFRS was tested by a regression model. A genotype-based genetic model assuming additivity was followed in order to estimate the effect of individual loci. Overall, no significant associations were found after correcting for multiple tests. However, an IGF2-INS-TH haplotype (*5) was found to be nominally associated with AFRS at younger ages in adult smokers. Analyses of individual loci points to TH01 as a possible candidate influencing initiation of regular smoking. An AFRS-lowering trend nominally associated with allele 9 in a dosage-dependent manner was identified in both adult cohorts. TH01 did not show association or trend with age of initiation (first puff) either in adolescents or in the adolescents smoking regularly at age 18. This study adds to the genetic evaluation of the associations of TH01 with smoking predisposition. Differences between historical and prospective surveys, different biological pathways and possible functional roles of this microsatellite in smoking initiation are discussed.

Family-based association study of DAT1 and DRD4 polymorphism in Korean children with ADHD

Although the etiology of Attention Deficit/Hyperactivity Disorder (ADHD) is not well understood, evidence from the family and twin studies suggest that ADHD is familial and highly heritable. The aim of the study was to test whether dopamine transporter gene ( DAT1) and dopamine receptor D4 gene ( DRD4) polymorphisms are in linkage disequilibrium with ADHD in Korean children, using a family-based association study. One hundred and twenty-six trios were studied and 87% of probands were boys (mean age = 8.2 years, mean IQ = 104). ADHD not otherwise specified (NOS) was the most common subtype and comorbidity rates were low. Descriptive analysis and the TDT test were the primary analyses. In exploratory analyses, logistic regression and QTDT were performed. The 10-repeat allele and 4-repeat allele were the most frequent for DAT1 and DRD4. TDT test for DAT1 and DRD4 did not show preferential transmission. Based on logistic regression and QTDT, the 5-repeat allele of DRD4 may confer protection for hyperactive-impulsivity symptom severity compared to the 4-repeat allele. The negative TDT finding between DAT1 and DRD4 VNTR polymorphisms and ADHD should be interpreted with caution; partly due to lack of power caused by low heterozygosity in the study population. Future studies are necessary to test the hypothesis generated in this study that the 5-repeat allele of DRD4 is protective for hyperactive-impulsivity symptom severity compared to the 4-repeat allele.

Cue-elicited craving for food: a fresh approach to the study of binge eating

Recent research has indicated that craving for food can be elicited by exposure to food cues, suggesting that exposure to food cues may represent a useful experimental paradigm to investigate mechanisms related to binge eating. The first objective of the present research was to replicate previous reports that exposure to food cues elicits craving for food. In addition, this investigation was designed to extend the extant literature by testing the effects of ‘priming’ portions of food, by examining the association between reactivity to food cues and indicators of binge eating, and to examine the role of a putative genetic factor previously found to be associated with cue-elicited craving for alcohol and tobacco. In Study 1, 48 individuals completed measures of craving and mood after exposure to control cues, after exposure to food cues, and after consuming each of three small portions of food. In Study 2, 31 individuals with subclinical symptoms of binge eating completed the same procedures. The results suggested that food cues reliably elicited craving, increased attention to the cues, and decreased positive affect in both samples, although reactivity was greater among the sample with greater eating pathology. Correlational analyses suggested that reactivity to food cues was correlated with binge eating and body mass index among women but not men. Results also suggest that the DRD4 VNTR polymorphism influences cue-elicited craving for food, although the influence of the DRD4 may depend on the population under study.

P.2.116 Association study of dopamine transporter gene 3′UTR VNTR polymorphism in bipolar affective disorder

The VNTR polymorphism in the Dopamine D4 receptor gene (DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship.Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene (L ≥ 7 [n = 25], S = < 7 [n = 52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge.The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes.Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.