Dopamine D2 Receptor Gene Research Articles

Low methylation rates of dopamine receptor D2 gene promoter sites in Japanese schizophrenia subjects

Objectives: According to the dopamine hypothesis, several studies on the gene for the dopamine receptor D2 (DRD2) have been conducted. However, no trait biomarkers on DRD2 are available. We examined whether the methylation rates in the upstream region of DRD2 in leukocytes are different in schizophrenia (SCZ) subjects compared to control subjects.Methods: We selected seven CpG sites in the upstream region of DRD2 that may theoretically bind major transcription factors. The methylation rates in these regions of 50 medicated and 18 drug-naïve SCZ subjects were compared with those of age-matched control subjects.Results: The methylation rates were significantly lower in medicated (CpG2, P < 0.0001; CpG4, P = 0.013; CpG7, P < 0.0001; and average: 12.9 ± 1.8 vs. 14.1 ± 2.2, P = 0.005) and drug-naïve SCZ subjects (CpG1, P = 0.006; CpG2, P = 0.001; CpG3, P = 0.001; CpG5, P = 0.02; CpG6, P = 0.015; CpG7, P = 0.027; and average: 9.86 ± 0.9 vs. 11.2 ± 1.3, P = 0.002).Conclusions: We confirmed low methylation rates in the upstream region of DRD2 in both medicated and drug-naïve SCZ subjects. Low methylation rates of DRD2 in leukocytes may be a trait biomarker for SCZ.

Sugar-Sweetened Beverage Consumption Is Adversely Associated with Childhood Attention Deficit/Hyperactivity Disorder.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral conditions. Evidence of the negative effects of sugar-sweetened beverages (SSBs) on mental health has not been convincing, although a few studies have found an association between high SSB levels and attention problems in children. This study aimed to test the hypothesis that SSB consumption is associated with ADHD among children. Doctor-diagnosed ADHD cases (n = 173) and non-ADHD controls (n = 159) between age 4 to 15 were recruited. SSB consumption, socio-demographic and lifestyle characteristics of the children, as well as of their mothers’ characteristics during pregnancy, were collected using a questionnaire. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. There was a dose-response relationship between SSB consumption and ADHD. After covariates were adjusted, children who consumed SSBs at moderate levels and high levels had 1.36 and 3.69 odds, respectively, of having ADHD, compared with those who did not consume SSBs (p for trend < 0.05). Similar results were obtained when females were excluded. Our findings highlighted the adverse correlation between SSB consumption and ADHD and indicated a dose-response effect even after covariates were adjusted.

Effects of l-Tyrosine on working memory and inhibitory control are determined by DRD2 genotypes: A randomized controlled trial

l-Tyrosine (TYR), the precursor of dopamine (DA), has been shown to enhance facets of cognitive control in situations with high cognitive demands. However some previous outcomes were mixed: some studies reported significant improvements, while other did not. Given that TYR increases DA level in the brain, we investigated, in a double-blind, randomized, placebo-controlled design, whether the C957T genotypes of a functional synonymous polymorphism in the human dopamine D2 receptor (DRD2) gene (rs6277) contribute to individual differences in the reactivity to TYR administration and whether this factor predicts the magnitude of TYR-induced performance differences on inhibiting behavioral responses in a stop-signal task and working memory (WM) updating in a N-back task. Our findings show that T/T homozygotes (i.e., individuals potentially associated with lower striatal DA level) showed larger beneficial effects of TYR supplementation than C/C homozygotes (i.e., individuals potentially associated with higher striatal DA level), suggesting that genetically determined differences in DA function may explain inter-individual differences in response to TYR supplementation. These findings reinforce the idea that genetic predisposition modulates the effect of TYR in its role as cognitive enhancer.

Externalizing Problem Behavior in Adolescence: Parenting Interacting With DAT1 and DRD4 Genes.

This study extends previous gene-by-environment (G×E) research through design and methodological advances and examines alternative hypotheses of diathesis stress, vantage sensitivity, and differential susceptibility. In a sample of 984 adolescents and their parents, we examined whether effects of parental support, proactive, punitive, harsh punitive, and psychological control on externalizing problem behavior are moderated by adolescents' genotype for the dopamine transporter (DAT1) or receptor D4 (DRD4) gene. Results provided evidence for main effects of parenting behavior and DRD4, and multiple interaction effects of which one survived Bonferroni correction. Adolescents carrying a long DRD4 variant were more susceptible to the effects of parental proactive control on aggression, for better and for worse. Critical considerations were made regarding the complexity of G×E research.

Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis

BackgroundAlthough dopamine D2 receptor antagonists lead to dose-dependent prolactin (PRL) elevations proportionate to their D2 affinity, considerable inter-individual differences exist. We conducted a meta-analytic review of associations between genetic variations in the dopamine D2 receptor gene (DRD2) and PRL levels in antipsychotic-treated subjects. MethodsSystematic literature search (5/8/2015) was performed to find published studies of pharmacogenetic associations between two DRD2 variants, Taq1A (rs1800497) and −141C Ins/Del (rs1799732), and PRL levels during antipsychotic treatment (excluding aripiprazole). Patients were included independent of age or diagnosis. Random effects models were used and Hedges’ g was calculated as the effect size measure. Subgroup analyses explored the effect of sex and diagnosis, (males vs females; schizophrenia vs non-schizophrenia). ResultsAltogether, 11 studies (n=1034, schizophrenia-spectrum=475) for Taq1A polymorphism, and 4 studies (n=451, schizophrenia-spectrum=274) for −141C Ins/Del polymorphism, each reporting on PRL levels but not on the proportion of patients with hyperprolactinemia, were meta-analyzed. Across all patients, there was no statistically significant association between PRL levels and either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype. However, in patients with schizophrenia, PRL levels were significantly higher in DRD2 Taq1A A1 carriers than A1 non-carriers (studies=5, n=475, Hedges’ g=0.250, 95% CI=0.068–0.433, p=0.007, I2=0%). DiscussionAlthough there was no significant association between either DRD2 Taq1A genotype or DRD2 −141C Ins/Del genotype and PRL levels in all included patients, our results suggest that DRD2 Taq1A genotype may affect antipsychotic-related PRL levels in patients with schizophrenia. Because of the small sample size, further studies are needed to confirm these results.

Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study.

The treatment of early Parkinson's disease with dopaminergic agents remains the mainstay of symptomatic therapy for this incurable neurodegenerative disorder. However, clinical responses to dopaminergic drugs vary substantially from person to person due to individual-, drug- and disease-related factors that may in part be genetically determined. Using clinical data and DNA samples ascertained through the largest placebo-controlled clinical trial of the monoamine oxidase B inhibitor, rasagiline (ClinicalTrials.gov number, NCT00256204), we examined how polymorphisms in candidate genes associate with the clinical response to rasagiline in early Parkinson's disease. Variants in genes that express proteins involved in the pharmacokinetics and pharmacodynamics of rasagiline, and genes previously associated with the risk to develop Parkinson's disease were genotyped. The LifeTechnologies OpenArray NT genotyping platform and polymerase chain reaction-based methods were used to analyse 204 single nucleotide polymorphisms and five variable number tandem repeats from 30 candidate genes in 692 available DNA samples from this clinical trial. The peak symptomatic response to rasagiline, the rate of symptom progression, and their relation to genetic variation were examined controlling for placebo effects using general linear and mixed effects models, respectively. Single nucleotide polymorphisms, rs2283265 and rs1076560, in the dopamine D2 receptor gene (DRD2) were found to be significantly associated with a favourable peak response to rasagiline at 12 weeks in early Parkinson's disease after controlling for multiple testing. From a linear regression, the betas were 2.5 and 2.38, respectively, with false discovery rate-corrected P-values of 0.032. These polymorphisms were in high linkage disequilibrium with each other (r(2) = 0.96) meaning that the same clinical response signal was identified by each of them. No polymorphisms were associated with slowing the rate of worsening in Parkinson symptoms from Weeks 12 to 36 after correction for multiple testing. This is the largest and most comprehensive pharmacogenetics study to date examining clinical response to an anti-parkinsonian drug and the first to be conducted in patients with early stage Parkinson's disease receiving monotherapy. The results indicate a clinically meaningful benefit to rasagiline in terms of the magnitude of improvement in parkinsonian symptoms for those with the favourable response genotypes. Future work is needed to elucidate the specific mechanisms through which these DRD2 variants operate in modulating the function of the nigrostriatal dopaminergic system.media-1vid110.1093/brain/aww109_video_abstractaww109_video_abstract.

Increased risk of attention-deficit/hyperactivity disorder associated with exposure to organophosphate pesticide in Taiwanese children.

Attention-deficit/hyperactivity disorder (ADHD) is male predominated, and the etiology of this disorder remains unclear. Past studies have assessed the association of low-level organophosphate pesticide exposure with childhood ADHD cross-sectionally and prospectively. However, the results have been inconsistent. A first case-control study was performed to investigate the relationship between organophosphate pesticide exposure and ADHD with adjusted covariates. We recruited 97 doctor-diagnosed ADHD cases and 110 non-ADHD controls who were 4-15years of age. Exposure was assessed using urinary levels of dialkylphosphate metabolites, which are biomarkers of OP pesticide exposure. Blood lead levels and polymorphisms of two commonly verified dopaminergic-related genes (the D4 dopamine receptor gene DRD4 and the dopamine transporter gene DAT1) were also analyzed. The sociodemographics and lifestyles of the children and of the mothers during pregnancy were collected using a questionnaire. The blood lead levels of both groups were similar (1.57±0.73 vs. 1.73±0.77μg/dL, p=0.15). Significant urinary concentration differences in one of the six dialkylphosphate metabolites, dimethylphosphate (DMP), were found between ADHD and control subjects (322.92±315.68 vs. 224.37±156.58nmol/g cr., p<0.01). A dose-response relationship was found between urinary concentrations of DMP and ADHD in both crude and adjusted analyses (p for trend<0.05). Children with higher urinary DMP concentrations may have a twofold to threefold increased risk of being diagnosed with ADHD. We report a dose-response relationship between child DMP levels and ADHD. Organophosphate pesticide exposure may have deleterious effects on children's neurodevelopment, particularly the development of ADHD.

Empirical tests of natural selection-based evolutionary accounts of ADHD: a systematic review.

ADHD is a prevalent and highly heritable mental disorder associated with significant impairment, morbidity and increased rates of mortality. This combination of high prevalence and high morbidity/mortality seen in ADHD and other mental disorders presents a challenge to natural selection-based models of human evolution. Several hypotheses have been proposed in an attempt to resolve this apparent paradox. The aim of this study was to review the evidence for these hypotheses. We conducted a systematic review of the literature on empirical investigations of natural selection-based evolutionary accounts for ADHD in adherence with the PRISMA guideline. The PubMed, Embase, and PsycINFO databases were screened for relevant publications, by combining search terms covering evolution/selection with search terms covering ADHD. The search identified 790 records. Of these, 15 full-text articles were assessed for eligibility, and three were included in the review. Two of these reported on the evolution of the seven-repeat allele of the ADHD-associated dopamine receptor D4 gene, and one reported on the results of a simulation study of the effect of suggested ADHD-traits on group survival. The authors of the three studies interpreted their findings as favouring the notion that ADHD-traits may have been associated with increased fitness during human evolution. However, we argue that none of the three studies really tap into the core symptoms of ADHD, and that their conclusions therefore lack validity for the disorder. This review indicates that the natural selection-based accounts of ADHD have not been subjected to empirical test and therefore remain hypothetical.

Neuropsychological performance measures as intermediate phenotypes for attention-deficit/hyperactivity disorder: A multiple mediation analysis.

Genetic influences on dopaminergic neurotransmission have been implicated in attention-deficit hyperactivity disorder (ADHD) and are theorized to impact cognitive functioning via alterations in frontal-striatal circuitry. Neuropsychological functioning has been proposed to account for the potential associations between dopamine candidate genes and ADHD. However, to date, this mediation hypothesis has not been directly tested. Participants were 498 youth ages 6-17 years (mean M = 10.8 years, SD = 2.4 years, 55.0% male). All youth completed a multistage, multiple-informant assessment procedure to identify ADHD and non-ADHD cases, as well as a comprehensive neuropsychological battery. Youth provided a saliva sample for DNA analyses; the 480 base pair variable number of tandem repeat polymorphism of the dopamine active transporter 1 gene (DAT1) and the 120 base pair promoter polymorphism of the dopamine receptor D4 gene (DRD4) were genotyped. Multiple mediation analysis revealed significant indirect associations between DAT1 genotype and inattention, hyperactivity-impulsivity, and oppositionality, with specific indirect effects through response inhibition. The results highlight the role of neurocognitive task performance, particularly response inhibition, as a potential intermediate phenotype for ADHD, further elucidating the relationship between genetic polymorphisms and externalizing psychopathology.

Data describing the effect of DRD4 promoter polymorphisms on promoter activity.

This data article tested whether polymorphisms within the dopamine D4 receptor (DRD4) gene promoter can lead to differences in the promoter activity. The variants, a 120-bp variable number tandem repeat (VNTR), −906 T/C, −809 G/A, −616G/C, and −521C/T, were introduced into the DRD4 promoter and the promoter activity was measured in a neural cell line using the luciferase assay. However, no differences were detected among the haplotypes investigated, and the in vitro data obtained from our protocol could not support the involvement of DRD4 promoter polymorphisms in heritable human traits.

Basic and Genetic Aspects of Food Intake Control and Obesity: Role of Dopamin Receptor D2 TaqIA Polymorphism

Regulation of food intake, energy expenditure and store are strikingly linked to obesity. Homeostatic control of food intake, hunger and satiety involves adipose and gastrointestinal hormones, such as leptin, insulin and ghrelin, which eventually affect neuronal signaling in the hypothalamus arcuate nucleus. On the other hand, hedonic control of food intake relates to substances such as opioids, endocannabinoids, gamma-aminobutyric acid, serotonin and dopamine, which act on the motivation and reward mechanisms. Dopamine is a precursor of noradrenaline and adrenaline and modulates a number of physiological functions, such as appetite, depending on the brain area and the type of receptor stimulated. It has been established as the main neurotransmitter of the hypothalamic reward system. Beyond the homeostatic and hedonic energy balance control, genetic aspects are also tightly involved in obesity pathophysiology. In this context, some Single Nucleotide Polymorphism (SNP) has been linked to common obesity. Here, we highlight the role of the dopamine receptor D2 gene TaqAI polymorphism, which affects the D2 receptor availability and has been associated to obesity. Therefore, the aim of this mini review is to cover basic aspects of food intake, energy balance, dopamine-related aspects, including genetic ones, and the relation with obesity.

Individual differences in flow proneness are linked to a dopamine D2 receptor gene variant.

Flow is a special mental state characterized by deep concentration that occurs during the performance of optimally challenging tasks. In prior studies, proneness to experience flow has been found to be moderately heritable. In the present study, we investigated whether individual differences in flow proneness are related to a polymorphism of the dopamine D2 receptor coding gene (DRD2 C957T rs6277). This polymorphism affects striatal D2 receptor availability, a factor that has been shown to be related to flow proneness. To our knowledge, this is the first study to investigate the association between this trait and a specific gene variant. In a sample of 236 healthy Hungarian adults, we found that CC homozygotes report higher flow proneness than do T allele carriers, but only during mandatory activities (i.e., studying and working), not during leisure time. We discuss implications of this result, e.g., the potential mediators of the relationship.

Evidence from pyrosequencing indicates that natural variation in animal personality is associated with DRD4 DNA methylation.

Personality traits are heritable and respond to natural selection, but are at the same time influenced by the ontogenetic environment. Epigenetic effects, such as DNA methylation, have been proposed as a key mechanism to control personality variation. However, to date little is known about the contribution of epigenetic effects to natural variation in behaviour. Here, we show that great tit (Parus major) lines artificially selected for divergent exploratory behaviour for four generations differ in their DNA methylation levels at the dopamine receptor D4 (DRD4) gene. This D4 receptor is statistically associated with personality traits in both humans and nonhuman animals, including the great tit. Previous work in this songbird failed to detect functional genetic polymorphisms within DRD4 that could account for the gene-trait association. However, our observation supports the idea that DRD4 is functionally involved in exploratory behaviour but that its effects are mediated by DNA methylation. While the exact mechanism underlying the transgenerational consistency of DRD4 methylation remains to be elucidated, this study shows that epigenetic mechanisms are involved in shaping natural variation in personality traits. We outline how this first finding provides a basis for investigating the epigenetic contribution to personality traits in natural systems and its subsequent role for understanding the ecology and evolution of behavioural consistency.

Dopamine receptor D2 and catechol-O-methyltransferase gene polymorphisms associated with anorexia nervosa in Chinese Han population: DRD2 and COMT gene polymorphisms were associated with AN

Dopamine receptor D2 (DRD2) and catechol-O-methyltransferase (COMT) are important in dopamine system which is proved to be associated with food-anticipatory behavior, food restriction, reward and motivation. This has made them good candidates for anorexia nervosa (AN). The aim of this work is to explore the roles of DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) gene polymorphisms in the susceptibility of AN within the Chinese Han population. We recruited 260AN patients with DSM-IV diagnosis criteria, and 247 unrelated, normal weight controls. DRD2 (rs1800497) and COMT (rs4680, rs4633, rs4818) were genotyped in all subjects. We found rs1800497 and rs4633 were associated with the susceptibility of AN within the Chinese Han sample, and allele C of rs1800497 was a protective factor. There was a gene–gene interaction between rs1800497 of DRD2 gene and rs4633 of COMT gene. We concluded that rs1800497 and rs4633 play important roles in the AN susceptibility with respect to the Chinese Han population. The gene–gene interaction between DRD2 and COMT contributes to the risk of AN.

An Analysis of Behavioral and Genetic Risk Factors for Chemotherapy-Induced Nausea and Vomiting in Japanese Subjects.

There are individual differences in the frequency of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. We investigated the individual variability in susceptibility to CINV with focus on both behavioral factors and genetic factors in Japanese cancer patients. We performed a prospective study to investigate the association between patient attributes (backgrounds and habits as well as gene polymorphisms) and anorexia, nausea, or vomiting in 55 Japanese cancer patients undergoing chemotherapy at Nagoya University Hospital. We found that gender (female), use of non-steroidal anti-inflammatory drugs, susceptibility to motion sickness, and anxiety were associated with the frequency of CINV. Gene polymorphisms of rs1076560 (dopamine D2 receptor gene), rs6766410 (serotonin 5-HT3C receptor gene) and rs4680 (catechol-O-methyltransferase gene) were also associated. Our data suggest that these attributes may thus be risk factors for CINV. Our results provide novel information that can be used to predict the incidence of CINV in Japanese patients undergoing chemotherapy; this can help provide a substantial improvement in supportive care for patients with different types of cancer.

The forecast of illicit drug use in adolescents with addictive behavior: personality traits and the level of genetic risk of substance dependence.

To clarify the psychological mechanism underlying the genetic risk of substance addiction at the first stage of drug use by adolescents. Genetic risk was evaluated by genotyping of 5 polymorphisms of the dopaminergic system genes (dopamine receptor D2 and D4 genes and tyrosine hydroxylase gene). Psychological testing was performed using the Russian version of Temperament and Character Inventory (TCI-125). Seventy-five adolescents, aged 14-17 years, (girls 32%), who misused alcohol, including 22 adolescents using drugs, were examined. The level of genetic risk was directly correlated with the probability of drug use by boys, for girls the correlation was not confirmed. The increase of the level of genetic risk for boys was correlated with the increase on the scale «Self-directedness» of TCI-125 that may reflect a probable tendency to replacement of negative information, feeling of illusory wellbeing. The findings clarify the direction of measures for the prevention of drug use.

Association between dopamine D2 receptor gene polymorphisms and the risk of heroin dependence.

Heroin dependence is a chronic relapsing brain disease. Researchers have reported that the dopamine D2 receptor (DRD2) is involved in the development of opiate dependence. To identify markers that contribute to the genetic susceptibility to heroin addiction, we examined the potential association between heroin dependence and six polymorphisms of the DRD2 gene using the MassARRAY system. Three hundred and thirty-four patients with heroin dependence and 299 healthy controls participated in the research. Compared with the healthy controls, heroin-dependent patients had a significantly lower frequency of the AA genotype of rs6275 (P = 0.038), and a significantly higher frequency of the C allele of rs1125394 (P = 0.030). Statistically significant differences were observed in the genotypic and allelic frequencies of rs17115583 (P = 0.005 and P = 0.001, respectively) and rs1079597 (P = 0.03 and P = 0.02, respectively). Haplotype analysis revealed that the T-G-A (block 1) haplotype of the DRD2 gene conferred a protective effect (P = 0.020). These findings point to a role for DRD2 polymorphism in heroin dependence in the Chinese Han population, and may be informative for future genetic or neurobiological studies on heroin dependence.

Dopamine D4 receptor VNTR polymorphism associated with greater risk for substance abuse among adolescents with disruptive behavior disorders: Preliminary results

The variable number tandem repeats (VNTR) polymorphism of the dopamine D4 receptor gene (DRD4) has received considerable attention as a potential genetic contributor to addiction. However, is unclear whether the polymorphism is involved in developing general traits that lead to risky behavior or an intermediate phenotype more specific to substance use disorders. Association studies have produced equivocal results. To control for potential confounds, the present study examined whether the long variant of the DRD4 VNTR polymorphism (DRD4L) is associated with greater substance misuse in a homogenous clinical sample of youth with a disruptive behavior disorder (DBD). Fifty-one psychiatrically hospitalized adolescents (mean age = 14.86 years) with a DBD diagnosis were recruited as part of a larger study. Participants provided saliva samples for genotyping procedures after completing a diagnostic interview and an assessment battery. The odds of a substance use disorder diagnosis were significantly greater among DRD4L than DRD4S carriers (OR = 5.20, 95%CI:1.42-19.04, p = .01). Relative to DRD4S homozygotes, DRD4L carriers also reported greater marijuana use (t = -2.68, p = .01) and hard drug use (t = -2.26, p = .03). Although adolescents with DBDs are already at heightened risk for substance misuse, the present findings suggest that DRD4L further increases those odds. As differences persisted even among a psychiatrically homogenous sample of impulsive and risk-prone adolescents, the present findings suggest that DRD4L may be involved in the development of an intermediate phenotype specific to substance abuse (eg, cue-elicited craving).

Brain-derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress.

BackgroundIn addition to experiencing traumatic events while deployed in a combat environment, there are other factors that contribute to the development of posttraumatic stress disorder (PTSD) in military service members. This study explored the contribution of genetics, childhood environment, prior trauma, psychological, cognitive, and deployment factors to the development of traumatic stress following deployment.MethodsBoth pre‐ and postdeployment data on 231 of 458 soldiers were analyzed. Postdeployment assessments occurred within 30 days from returning stateside and included a battery of psychological health, medical history, and demographic questionnaires; neurocognitive tests; and blood serum for the D2 dopamine receptor (DRD2), apolipoprotein E (APOE), and brain‐derived neurotropic factor (BDNF) genes.ResultsSoldiers who screened positive for traumatic stress at postdeployment had significantly higher scores in depression (d = 1.91), anxiety (d = 1.61), poor sleep quality (d = 0.92), postconcussion symptoms (d = 2.21), alcohol use (d = 0.63), traumatic life events (d = 0.42), and combat exposure (d = 0.91). BDNF Val66 Met genotype was significantly associated with risk for sustaining a mild traumatic brain injury (mTBI) and screening positive for traumatic stress. Predeployment traumatic stress, greater combat exposure and sustaining an mTBI while deployed, and the BDNF Met/Met genotype accounted for 22% of the variance of postdeployment PTSD scores (R 2 = 0.22, P < 0.001). However, predeployment traumatic stress, alone, accounted for 17% of the postdeployment PTSD scores.ConclusionThese findings suggest predeployment traumatic stress, genetic, and environmental factors have unique contributions to the development of combat‐related traumatic stress in military service members.

Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking

ABSTRACTIndividuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression’s hedonically rewarding qualities.