DAT1 Genotype Research Articles

Theorizing the Role of Dopaminergic Polymorphic Risk Alleles with Intermittent Explosive Disorder (IED), Violent/Aggressive Behavior and Addiction: Justification of Genetic Addiction Risk Severity (GARS) Testing.

Scientific studies have provided evidence that there is a relationship between violent and aggressive behaviors and addictions. Genes involved with the reward system, specifically the brain reward cascade (BRC), appear to be associated with various addictions and impulsive, aggressive, and violent behaviors. In our previous research, we examined the Taq A1 allele (variant D2 dopamine receptor gene) and the DAT-40 base repeat (a variant of the dopamine transporter gene) in 11 Caucasian boys at the Brown School in San Marcus, Texas, diagnosed with intermittent explosive disorder. Thirty supernormal controls were screened to exclude several reward-deficit behaviors, including pathological violence, and genotyped for the DRD2 gene. Additionally, 91 controls were screened to exclude ADHD, pathological violence, alcoholism, drug dependence, and tobacco abuse, and their results were compared with DAT1 genotype results. In the schoolboys vs. supercontrols, there was a significant association with the D2 variant and a trend with the dopamine transporter variant. Results support our hypothesis and the involvement of at least two gene risk alleles with adolescent violent/aggressive behaviors. This study and the research presented in this paper suggest that violent/aggressive behaviors are associated with a greater risk of addiction, mediated via various genes linked to the BRC. This review provides a contributory analysis of how gene polymorphisms, especially those related to the brain reward circuitry, are associated with violent behaviors.

Association between dopamine transporter gene (DAT1/SLC6A3) variants and infertility in the Turkish females

Objective Worldwide, approximately 10–15% of couples is affected by infertility and infertility is associated with disturbances in female and/or male reproductive systems. The aim of the current study is to investigate the relationship between DAT1 (SLC6A3) VNTR polymorphism with female infertility. Methods Genomic DNA extractions were performed in 98 fertile and 90 infertile females, 3' untranslated region (3’ UTR) variable number tandem repeat (VNTR) polymorphism of DAT1/SLC6A3 was determined by the use of Polymerase Chain Reaction (PCR) method. Results It has been demonstrated that there was no statistically significant difference between female infertile and fertile groups in the terms of DAT1 genotypes (p > .05). Moreover, there was no significant difference regarding the frequencies of 9R and 10R alleles in infertile and fertile groups (p > .05). Conclusion This is the first study for investigating the relationship between DAT1/SLC6A3 gene polymorphism and infertility in females. Our study contributes to the growing awareness of the relationship between dopaminergic system and female infertility despite no significant differences were reported between infertile females and corresponding fertile subjects in DAT1/SLC6A3 gene.

Children’s ADHD and Dysregulation Problems, DAT1 Genotype and Methylation, and their Interplay with Family Environment

BackgroundInternational literature has underlined the complex interplay between genetic and environmental variables in shaping children’s emotional-behavioral functioning.ObjectiveThis study aimed to explore the dynamic relationship between children’s Dopamine Transporter (DAT1) genotype and methylation, and maternal and paternal affective environment, on children’s Attention Deficit Hyperactivity Disorder (ADHD) problems and dysregulation problems.MethodIn a community sample of 76 families with school-aged children, we assessed children’s DAT1 genotype and methylation, their own ADHD problems and dysregulation profile (CBCL 6–18 DP), and maternal and paternal psychopathological risk, parenting stress, and marital adjustment. Hierarchical regressions were carried out to verify the possible moderation of children’s genotype on the relationship between children’s methylation and psychopathological risk, parental environment and children’s methylation, and parental environment and children’s psychopathological risk.ResultsThe levels of methylation at M1 CpG significantly predicted ADHD problems among children with 10/10 genotype, whereas high levels of methylation at M6 CpG predicted low ADHD problems for children with 9/x genotype. High levels of methylation at M3 CpG were associated with high scores of CBCL DP. DAT1 genotype moderated the relationship between maternal and paternal variables with children’s methylation and psychopathological risk. The scores of maternal and paternal Dyadic Adjustment Scale showed indirect effects on children’s methylation and psychopathological risk in relation to those exerted by risk factors.ConclusionOur study has supported the emerging evidence on the complex nature of children’s emotional-behavioral functioning and the associated risk and protective factors, with important implications for the planning of preventive programs.

DAT1 polymorphism associated with poor decision-making in males with antisocial personality disorder and high psychopathic traits.

Studies suggest that abnormalities of the dopaminergic system underlie decision-making deficits, a hallmark of antisocial personality disorder (ASPD) and psychopathy. The dopamine transporter gene (DAT1) is of particular interest due to a polymorphism that controls dopamine transporter (DAT) activity. However, the association between DAT1 genotypes and decision-making in ASPD has never been studied. The current study investigated the effect of DAT1 genotype on decision-making, as measured by the Iowa Gambling Task (IGT), in ASPD and healthy controls. A total of 17 participants with ASPD and 16 healthy control participants without ASPD were sampled. The Hare Psychopathy Checklist-Revised and the IGT were administered to all participants. All participants provided blood samples for genotyping. Data revealed a novel interaction effect between DAT1 genotype and diagnosis, whereby ASPD participants with low DAT activity genotypes performed significantly worse on the IGT and selected from disadvantageous decks more often, whereas the low DAT activity genotype in the healthy control group was associated with better performance on the IGT, and they selected from disadvantageous decks less often. We demonstrate, for the first time, that low DAT activity genotypes in ASPD with high psychopathic traits contribute to poor decision-making.

The Interplay Between Prenatal Adversity, Offspring Dopaminergic Genes, and Early Parenting on Toddler Attentional Function.

Background: Few studies have explored the complex gene-by-prenatal environment-by-early postnatal environment interactions that underlie the development of attentional competence. Here, we examined if variation in dopamine-related genes interacts with prenatal adversity to influence toddler attentional competence and whether this influence is buffered by early positive maternal behavior.Methods: From the Maternal Adversity, Vulnerability and Neurodevelopment cohort, 134 participants (197 when imputing missing data) had information on prenatal adversity (prenatal stressful life events, prenatal maternal depressive symptoms, and birth weight), five dopamine-related genes (DAT1, DRD4, DRD2, COMT, BDNF), observed maternal parenting behavior at 6 months and parent-rated toddler attentional competence at 18 and 24 months. The Latent Environmental and Genetic Interaction (LEGIT) approach was used to examine genes-by-prenatal environment-by-postnatal environment interactions while controlling for sociodemographic factors and postnatal depression.Results: Our hypothesis of a three-way interaction between prenatal adversity, dopamine-related genes, and early maternal parenting behavior was not confirmed. However, consistent two-way interactions emerged between prenatal adversity and dopamine-related genes; prenatal adversity and maternal parenting behavior, and dopamine-related genes and maternal parenting behavior in relation to toddler attentional competence. Significant interaction effects were driven by the DAT1, COMT, and BDNF genotypes; prenatal stressful life events; maternal sensitivity, tactile stimulation, vocalization, and infant-related activities.Conclusions: Multiple dopamine-related genes affected toddler attentional competence and they did so in interaction with prenatal adversity and the early rearing environment, separately. Effects were already visible in young children. Several aspects of early maternal parenting have been identified as potential targets for intervention.

Dopamine transporter (DAT1) gene in combat veterans with PTSD: A case-control study

The dopamine transporter (DAT1) gene has been postulated to be involved in PTSD; however, existing studies have shown inconsistencies when examining genotypic and allelic associations. The primary objective of this study was to examine whether DAT1–40bp-VNTR (DAT1) 9R polymorphism might increase the risk of PTSD development in combat veterans, utilizing a case-control gene association study with both control and PTSD cases having previous exposure to combat traumas. Participants with PTSD (N = 365) and combat-exposed controls without PTSD (N = 298) were included in analysis. After controlling for race, sex and age, when dichotomized, absence of DAT1 10R/10R genotypes was associated with PTSD diagnosis compared to no PTSD diagnosis; these results were not statistically significant when trichotomized 10R/10R, 10R/X, 9R/9R. Similarly, odds ratio for absence of 10R/10R genotype showed a statistically significant increase in the risk of developing PTSD. DAT1 genotype was also associated with statistically significant mean total CAPS scores, both when dichotomized and trichotomized. In conclusion, our results indicate that the absence of 10R/10R is associated with an increased risk of PTSD and higher CAPS total scores.

DAT1 and Its Psychological Correlates in Children with Avoidant/Restrictive Food Intake Disorder: A Cross-Sectional Pilot Study

International research has underlined the role played by children’s and maternal psychopathological symptoms on the onset of avoidant/restrictive food intake disorder (ARFID) in early childhood. No study has considered the possible interplay between children’s dopamine transporter (DAT1) genotype and methylation, dysregulation problems and maternal psychopathological risk. This study aimed to investigate the complex relationship between these variables, considering the possible mediation role played by children’s DAT1 methylation on the relationship between mothers’ psychopathological risk and children’s dysregulation problems, moderated by children’s DAT1 genotype. Our sample consisted of 94 early children and their mothers, divided into four subgroups, based on children’s ARFID subtypes (irritable/impulsive (I/I), sensory food aversions (SFA), post-traumatic feeding disorders subtypes (PTFD), and a non-clinical group (NC)). We addressed children’s dysregulation problems and maternal psychopathological risk, and collected children’s DNA through buccal swabs. Results showed that children’s 9/x genotype was associated with PTFD and NC groups, whereas the 10/10 genotype was associated with the SFA group, with large effect size. There were significant large differences in the study groups on children’s DAT1 total methylation, children’s dysregulation problems, and maternal psychopathological risk. Children’s DAT1 methylation did not mediate the relationship between mother’s psychopathological risk and children’s dysregulation problems, but there was a significant large direct effect. Children’s 9/x genotype moderated the relationship between maternal psychopathological risk and children’s DAT1 methylation but, respectively, with a large and small effect. Our pilot study suggested that the relationship between children’s DAT1 genotype and methylation, dysregulation problems, and maternal psychopathological risk has a crucial contribution to ARFID.

Emotional-Behavioral Regulation, Temperament and Parent-Child Interactions Are Associated with Dopamine Transporter Allelic Polymorphism in Early Childhood: A Pilot Study.

International research has highlighted the role played by individual genetic polymorphism, children’s emotional-behavioral functioning, and quality of parent–child feeding interaction in shaping children’s development. Few studies have focused on the dopamine transporter (DAT1) gene in these processes. In a community sample of 81 families with young children aged between 19 and 28 months (37 males and 44 females), this pilot study aimed to explore possible relationships between children’s DAT1 genotype (9/x: 9/9, 9/19 contrasted to 10/10), their own psychological profiles, parental psychopathological risk, and the quality of mother–child and father–child feeding interactions. Children’s DAT1 genotype was assessed collecting DNA through buccal; children’s temperament and emotional-behavioral regulation, and parental psychopathological risk were assessed, respectively, through report-form and self-report instruments; then, dyadic exchanges were videotaped during a mealtime, and coded based on the Scala di Valutazione dell′Interazione Alimentare (SVIA). Results showed significant differences in the variables under study based on children’s DAT1 genotype, with a higher risk associated with the 10/10. Our findings have provided preliminary new evidence on the relationship between a different child’s polymorphisms, their own emotional-behavioral functioning, and the quality of the family environment, with important implications for the planning of more targeted prevention programs.

Involvement of DAT1 Gene on Internet Addiction: Cross-Correlations of Methylation Levels in 5'-UTR and 3'-UTR Genotypes, Interact with Impulsivity and Attachment-Driven Quality of Relationships.

Internet influences our communication, social and work interactions, entertainment, and many other aspects of life. Even if the original purpose was to simplify our lives, an excessive and/or maladaptive use of it may have negative consequences. The dopamine transporter (DAT1) gene was studied in relation to addictions, including excessive use of the Internet. The crucial role of DAT1 was previously underlined in modulating emotional aspects, such as affiliative behaviors. The present research follows a new approach based on cross-correlation between (de)methylation levels in couples of CpG loci, as previously shown. We investigated the possible relationships between Internet addiction, impulsivity, quality of attachment, DAT1 genotypes (from the 3′-untranslated region (UTR) variable number of tandem repeats (VNTR) poly-morphism), and the dynamics of methylation within the 5’-UTR of the DAT1 gene. From a normative sample of 79 youths, we extrapolated three subgroups a posteriori, i.e., one “vulnerable” with high Internet Addiction Test (IAT) scores (and high Barrat Impulsivity Scale (BIS) scores; n = 9) and two “controls’’ with low BIS scores and 10/10 vs. 9/x genotype (n = 12 each). Controls also had a “secure” attachment pattern, while genotypes and attachment styles were undistinguished in the vulnerable subgroup (none showed overt Internet addiction). We found a strongly positive correlation in all groups between CpG2 and CpG3. An unsuspected relationship between the 3’-UTR genotype and a 5’-UTR intra-motif link was revealed by CpG5–CpG6 comparison. The negative correlation between the CpG3–CpG5 positions was quite significant in the control groups (both with genotype 10/10 and with genotype 9/x), whereas a tendency toward positive correlation emerged within the high IAT group. In conclusion, future attention shall be focused on the intra- and inter-motif interactions of methylation on the CpG island at the 5′-UTR of DAT1.

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20–30 years) and 37 older (age 60–75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

3207 Relation between Dopamine Transporter (DAT1) polymorphism and subjective effects of alcohol among non-dependent drinkers

OBJECTIVES/SPECIFIC AIMS: Dopamine transporter (DAT1) gene variation is associated with reward-related phenotypes including alcohol response. There is also evidence for a potential moderating role for mu-opioid receptor (OPRM1) gene variation on the relationship between DAT1 variation and alcohol response measures. We aimed at studying the interaction between the DAT1 VNTR and OPRM1 A118G polymorphisms on alcohol consumption and subjective responses among non-dependent drinkers. METHODS/STUDY POPULATION: We employed a progressive ratio (PR) paradigm of intravenous alcohol self-administration (IV-ASA) using the Computer-Assisted Infusion System (CAIS) to assess the motivation for alcohol seeking and consumption in a sample of nondependent drinkers. We used the Drug Effects Questionnaire (DEQ) and Biphasic Alcohol Effects Questionnaire (BAES) to assess subjective response. IV-ASA measures included average breath alcohol concentration (BrAC) and total ethanol infused. Peripheral blood samples were collected for genotyping. Ethics approval was obtained from the NIH Addictions Institutional Review Board. RESULTS/ANTICIPATED RESULTS: Fifty participants completed the PR IV-ASA session after informed consent. There were significant interactions between the DAT1 and OPRM1 genotypes in subjective effects of alcohol. Simple main effects analysis showed that DAT1 10a allele carriers that were also OPRM1 G allele carriers had significantly higher scores for several measures: “feel the drug effects” (F (1,46)=6.573, P = 0.014), “feel intoxicated”(F(1,46)=8.613, P = 0.005) and “feeling high” (F(1,46)=10.889, P = 0.002) in DEQ and higher sedation (F(1,46)=4.575, P = 0.038) in BAES. The genotypes statistically significantly predicted average breath alcohol (F (1,61) =3.295, p=0.044) and total ethanol infused(F(1,61)=3.632, p=0.032. DAT1 VNTR and OPRM1 A118G polymorphisms taken together accounted for 6.9 and 7.8% of variations in average breath alcohol and total ethanol infused respectively. DISCUSSION/SIGNIFICANCE OF IMPACT: Polymorphic variations in DAT1 and OPRM1 interact with each other in determining subjective effects of alcohol in intravenous alcohol infusion assessing motivation for alcohol seeking and consumption in nondependent drinkers. These epistatic interactions in subjective effects of alcohol are salient in the context of predicting and understanding neurobiological effects of alcohol and thereby the therapeutic responses in treating alcohol use disorders.

Homozygosity for the 10-repeat dopamine transporter (DAT1) allele is associated with reduced EEG response in males with ASD

BackgroundIndividuals with autism spectrum disorder (ASD) have reduced interest in human faces and atypical event-related brain potentials (ERPs) in response to face stimuli, suggesting that face processing may be a functional marker of ASD susceptibility. MethodThis report explored the visual processing of individuals with ASD (n = 50) compared with their first-degree relatives (n = 117) using electroencephalogram (EEG), and associated EEG response with specific polymorphisms in the COMT, OXTR, SLC6A4 and DAT1 genes. ResultsPolymorphisms in the COMT and OXTR genes were not associated with any specific EEG response; on the other hand, the 5-HTTLPR polymorphism located upstream of SLC6A4 was associated with increased latency of the P1 component of the EEG response, and DAT1 genotype correlated with reduced amplitude of the N170 component in male participants with ASD. ConclusionThese results suggest an interaction between DAT1 genotype and male participants with ASD characterized by reduced cognitive performance when processing faces as measured by EEG. Identifying ASD functional markers and grouping individuals with shared genetic biomarkers or endophenotypes may facilitate greater understanding of the heterogeneity underlying ASD leading to improved diagnosis and treatment of ASD.

The dopamine transporter VNTR polymorphism moderates the relationship between acute response to alcohol and future alcohol use disorder symptoms.

Alcohol use disorder (AUD) is a genetically influenced disease with peak onset in young adulthood. Identification of factors that predict whether AUD symptoms will diminish or persist after young adulthood is a critical public health need. King and colleagues previously reported that acute response to alcohol predicted future AUD symptom trajectory. Genes associated with brain dopamine signaling, which underlies alcohol's rewarding effects, might influence this finding. This study analyzed whether variation at a variable number tandem repeat polymorphism in DAT1/SLC6A3, the gene encoding the dopamine transporter, moderated the predictive relationships between acute response to alcohol and future AUD symptoms among participants enrolled in the Chicago Social Drinking Project (first two cohorts). Heavy-drinking young adults (N=197) completed an alcohol challenge, in which acute response (liking, wanting, stimulation, and sedation) was measured. Alcohol use disorder symptoms were assessed over the following 6years. DAT1 genotype significantly moderated the interactions between follow-up time and alcohol liking (P=0.006) and wanting (P=0.006) in predicting future AUD symptoms. These predictive effects were strongest among participants who carried the DAT1 9-repeat allele, previously associated with enhanced striatal dopamine tone relative to the 10-repeat allele. Exploratory analyses indicated that DAT1 effects on the relationship between alcohol liking and AUD symptoms appeared stronger for females (n=79) than males (n=118) (P=0.0496). These data suggest that heavy-drinking DAT1 9-repeat allele carriers who display high alcohol-induced reward in young adulthood may be predisposed to persistent AUD symptoms and support combining genotypic and phenotypic information to predict future AUD risk.

Interaction Effects between the Cumulative Genetic Score and Psychosocial Stressor on Self-Reported Drinking Urge and Implicit Attentional Bias for Alcohol: A Human Laboratory Study.

The current candidate gene and environment interaction (cGxE) study examined whether the effects of an experimentally manipulated psychosocial stressor on self-reported drinking urge and implicit attentional bias for alcohol cues differ as a function of a cumulative genetic score of 5-HTTLPR, MAO-A, DRD4, DAT1 and DRD2 genotypes. The current study also examined whether salivary alpha-amylase level or self-reported anxiety state mediate these cGxE effects. Individuals with high cumulative genetic risk score of the five monoamergic genotypes showed greater attentional bias toward alcohol cues when exposed to a psychosocial stressor than when not exposed. Frequent binge-drinking Caucasian young adults (N = 105; mean age = 19; 61% male) completed both the control condition and stress condition (using the Trier Social Stress Test) in order. Regarding attentional bias, individuals with high and medium cumulative genetic risk scores showed greater attentional bias toward alcohol stimuli in the stress condition than in the control condition, whereas, those with low genetic risk scores showed greater attentional bias toward alcohol stimuli in the control condition than in the stress condition. No mediating roles of salivary alpha-amylase and anxiety state in the cGxE effect were found. Regarding self-reported drinking urge, individuals with high cumulative genetic score reported greater drinking urge than those with low genetic score regardless of experimental conditions. Although replication is necessary, the findings suggest that the association of a psychosocial stressor on implicit (but not explicit, self-reported) alcohol outcomes may differ as a function of the collective effects of five monoamine genes.

Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested. In addition, interactions between APZ and a genetic composite comprising the DAT1 VNTR and functional polymorphisms in catechol-O-methyltransferase (COMT), DRD2, and DRD4 were evaluated. Ninety-four non-treatment-seeking individuals with AUD were genotyped for these polymorphisms, randomized to APZ (titrated to 15 mg) or placebo for 8 days, and underwent an fMRI alcohol cue-reactivity task (day 7; n=81) and a bar lab paradigm (day 8). Primary outcomes were alcohol cue-elicited ventral striatal (VS) activation and the number of drinks consumed in the bar lab. DAT1 genotype significantly moderated medication effects, such that APZ, relative to placebo, reduced VS activation and bar-lab drinking only among carriers of the DAT1 9-repeat allele, previously associated with lower DAT expression and greater reward-related brain activation. The genetic composite further moderated medication effects, such that APZ reduced the primary outcomes more among individuals who carried a larger number of DAT1, COMT, DRD2, and DRD4 alleles associated with higher DA tone. Taken together, these data suggest that APZ may be a promising AUD treatment for individuals with a genetic predisposition to higher synaptic DA tone.

Individual differences in the processing of smoking-cessation video messages: An imaging genetics study

Studies testing the benefits of enriching smoking-cessation video ads with attention-grabbing sensory features have yielded variable results. Dopamine transporter gene (DAT1) has been implicated in attention deficits. We hypothesized that DAT1 polymorphism is partially responsible for this variability. Using functional magnetic resonance imaging, we examined brain responses to videos high or low in attention-grabbing features, indexed by “message sensation value” (MSV), in 53 smokers genotyped for DAT1. Compared to other smokers, 10/10 homozygotes showed greater neural response to High- vs. Low-MSV smoking-cessation videos in two a priori regions of interest: the right temporoparietal junction and the right ventrolateral prefrontal cortex. These regions are known to underlie stimulus-driven attentional processing. Exploratory analysis showed that the right temporoparietal response positively predicted follow-up smoking behavior indexed by urine cotinine. Our findings suggest that responses to attention-grabbing features in smoking-cessation messages is affected by the DAT1 genotype.

Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers.

The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers. There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele. These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems.

Is prepulse modification altered by continuous theta burst stimulation? DAT1 genotype and motor threshold interact on prepulse modification following brain stimulation.

Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.

Relations between three dopaminergic system genes, school attachment, and adolescent delinquency.

Both environmental factors and genetic variation, particularly in genes responsible for the dopaminergic system such as DRD4, DRD2, and DAT1 (SLC6A3), affect adolescent delinquency. The school context, despite its developmental importance, has been overlooked in gene-environment research. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (NICHD ECCYD), this study examined key interactions between school attachment and (a) each of the DRD4, DRD2, and DAT1 (SLC6A3) genotypes; and (b) a polygenic score. Results indicate that there is a main effect of school attachment, unlike genetic variation, on delinquency. Interestingly, there are important interactive effects of school attachment and dopaminergic genotypes on delinquency. Carriers of the DRD2-A1 allele were differentially affected by both positive and negative school environments, whereas DAT1-10R carriers fared the same as 9R homozygotes in poorer and moderate school environments, but fared disproportionately better in more positive environments. Contrary to expectations, youth without the DRD4-7R allele were particularly affected by the school environment. These findings contribute to the literature considering the roles of both context and genes in delinquency research, and inform our understanding of the individual-level traits that influence sensitivity to particular contexts. (PsycINFO Database Record

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.