DRD4 Genotype Research Articles

Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use.

Although peer pressure can influence adolescents' alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents' susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7% female; 92.8% White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence.

Addendum to the Special Issue Entitled Genetic Influences on Peer and Family Relationships Across Development.

This August issue begins with a follow-up on July’s special issue. The July special issue, entitled ‘‘Genetic Influences on Peer and Family Relationships across Development,’’ was co-edited by Lisabeth F. DiLalla and Paula Y. Mullineaux. Both focus on the role of genetic influences on adolescent and child development. Their expertise is what led them to develop the outstanding special issue published in July. Regrettably, the lead co-editor’s own contribution to the special issue was inadvertently excluded. There are no good remedies for addressing publishing errors, even in the age of online publishing. The best that we could do was to publish her piece in the following issue. As a result, this issue begins with my sincere apologies for the error and with her article: ‘‘Peer Victimization and DRD4 Genotype Influence Problem Behaviors in Young Children’’ by Lisabeth Fisher DiLalla, Kyle Bersted and Sufna Gheyara John. While we were thinking through how to remedy the failure to include a manuscript in the hard copy version of the special issue, we realized another omission. Although it is not customary to do so, we found it incumbent on us to publically extend our appreciation to the reviewers who helped develop the special issue. As a look at the special issue reveals, the special issue editors and reviewers upheld the journal’s standards and furthered its mission of supporting cutting-edge multidisciplinary work. For that, we are very grateful to the following researchers: Kevin Beaver Sara Biebl Marieke Buil Alex Burt Kit Elam Sufna Gheyara John Tina Kretschmer Kelly Klump Alison Pike Michael Pogue-Geile Soo Rhee Erica Spotts Pol Van Lier Frank Vitaro

DRD4 Genotype and the Developmental Link of Peer Social Preference with Conduct Problems and Prosocial Behavior Across Ages 9-12Years.

The peer environment is among the most important factors for children’s behavioral development. However, not all children are equally influenced by their peers, which is potentially due to their genetic make-up. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence children’s susceptibility to the peer environment. In the present study, we explored whether variations in the DRD4 gene moderated the association between children’s social standing in the peer group (i.e., social preference among classmates) with subsequent conduct problems and prosocial behavior among 405 (51 % females) elementary school children followed annually throughout early adolescence (ages 9–12 years). The behavioral development of children with and without the DRD4 7-repeat allele was compared. The results indicated that children who had higher positive social preference scores (i.e., who were more liked relative to disliked by their peers) showed less conduct problem development in subsequent years relative to children who had lower positive social preference scores. In contrast, children who had more negative preference scores (i.e., who were more disliked relative to liked among peers) showed more conduct problem development in subsequent years, relative to children who had less negative preference scores. However, these effects only occurred when children had a 7-repeat allele. For children who did not have a 7-repeat allele, the level of social preference was not associated with subsequent conduct problems. No evidence for gene–environment interaction effects for prosocial behavior was found. The implications for our understanding of conduct problem development and its prevention are discussed.

Preschool Children Without 7-repeat DRD4 Gene More Likely to Develop Disorganized Attachment Style


 
 
 
 Background: A disorganized attachment style is characterized by fearful and disoriented behaviours when a child is separated from their caregiver. Its presence is an early predictor of the later development of psychopathology, including depression. This study seeks to determine the effects of one environmental factor - the incidence of low birth weight - and one genetic factor - the presence of the long (7-repeat) polymorphism of the dopamine D4 receptor (DRD4) gene - on the development of disorganized attachment between the child and the mother.
 Methods: We sampled 251 mother-child dyads from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. We measured birth weight and DRD4 genotype, and assessed attachment style using modified separation-reunion procedure.
 Results: Birth weight did not have a significant effect on disorganized attachment (b=-0.001, t(230)=0.006, p=0.910). Presence of DRD4 7-repeat polymorphism had a significant negative effect on presence of disorganized attachment style (b=-1.196, t(230)=0.411, p=0.004).
 Conclusion: Children without the DRD4 7-repeat allele were more likely to display a disorganized attachment style compared to children with the DRD4 7-repeat allele. This indicates that the 7-repeat allele of the DRD4 gene may serve as a protective factor against disorganized attachment.
 
 
 

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis.

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use.

DRD4 gene polymorphism in great tits: gender-specific association with behavioural variation in the wild

Recent studies indicate that polymorphisms of the DRD4 gene may be related to behavioural variation in mammals and birds. The purpose of this study was to ascertain a connection between DRD4 genotypes and behavioural patterns in a wild passerine bird during breeding time. We evaluated changes in birds’ parental provisioning behaviour in the presence of a novel object. As a behavioural trait, we measured the duration of feeding interruption from the first time that each bird noticed the novel object until they entered the nest box. We found a gender-specific association between DRD4 gene polymorphism and parental behaviour. Males with a CC genotype delayed feeding for a longer period than those with CT and TT genotypes. No significant effect of genotype on provisioning behaviour was observed among females. We conclude that (i) DRD4 gene polymorphism in wild birds can be associated with behaviour related to fearfulness, and (ii) this effect is supposedly gender-specific during the breeding time, potentially explained by sex differences in parental care or hormonal levels.

Childhood sexual abuse and impulsive personality traits: Mixed evidence for moderation by DRD4 genotype

This project examines associations between childhood sexual abuse (CSA) and two dimensions of impulsivity (sensation seeking and premeditation), and tests whether CSA-personality associations are moderated by the DRD4 exon III VNTR polymorphism. Sample 1 is from a longitudinal study of university students measured at 10 waves over ages 18–24years (n=500). Sample 2 is from a national sample of young adult sibling pairs, ages 18–24, from the National Longitudinal Study of Adolescent Health (n=2559). In both samples, CSA was associated with elevated sensation seeking. In Sample 1, the association between CSA and sensation seeking was moderated by DRD4 genotype; this gene×environment interaction effect, however, was not replicated in Sample 2. Results suggest new avenues for research on CSA in the area of normal-range personality variation.

DRD4 and susceptibility to peer influence on alcohol use from adolescence to adulthood

BackgroundThe long allele of DRD4 is associated with greater susceptibility to peer influences on alcohol use in young adulthood, but it is unclear whether this increased susceptibility extends to other developmental periods. This study examined the interactive effects of DRD4 polymorphism and friends’ alcohol use from adolescence to adulthood. MethodsParticipants (N=340; 59% female; 98% White) reported on their own and their friends’ alcohol use at four time points between mean ages 17 and 33. Autoregressive cross-lagged models evaluated reciprocal relationships between friends’ alcohol use and participants’ own alcohol use and frequency of heavy drinking over time. Multigroup modeling tested differences in model paths and covariances across high vs. low risk DRD4 polymorphisms. ResultsAlcohol use at age 33 was predicted by previous friends’ alcohol use and correlated with current friends’ alcohol use only for carriers of the DRD4 long allele. Regardless of DRD4 genotype, friends’ alcohol use at age 17 predicted greater alcohol use and more frequent heavy drinking at age 23. Alcohol use and/or heavy drinking predicted greater friends’ alcohol use at later time points for both genotype groups across adolescence and adulthood. ConclusionsThe long allele of DRD4 is associated with increased susceptibility to peer influences on alcohol use in young adulthood, but not earlier in development. Adults with the long allele of DRD4 may benefit from interventions educating them about this risk and equipping them with strategies to reduce affiliations with and influence of drinking friends.

Differential susceptibility in a developmental perspective: DRD4 and maternal sensitivity predicting externalizing behavior.

This study is the first to investigate the longitudinal effects of gene-environment interplay between DRD4 genotype and maternal sensitivity on child externalizing behavior. Multiple measures of maternal sensitivity (14, 36, and 48 months) and externalizing behavior (18 months, 36 months, and 5 years) were assessed in a large cohort study (N = 548). Early maternal insensitivity (14 months) was associated with early externalizing behavior (18 months) in a for better and for worse manner, but only in children with at least one DRD4 7-repeat, consistent with a differential susceptibility model. Later insensitivity (48 months) predicted externalizing behavior at age 5 independent of DRD4 genotype. A structural equation model including all measures across time supported the differential susceptibility model: The overall effect of early maternal sensitivity on later externalizing behavior was significant only for children with a DRD4 7-repeat allele. The results highlight the importance of studying gene-environment interactions across development.

Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence

Insensitive and unresponsive caregiving during infancy has been linked to externalizing behavior problems during childhood and adolescence. The 7-repeat (7r) allele of the dopamine D4 receptor (DRD4) gene has meta-analytically been associated with a heightened susceptibility to adverse as well as supportive environments. In the present study, we examined long-term effects of early maternal care, DRD4 genotype and the interaction thereof on externalizing and internalizing psychopathology during adolescence. As part of an ongoing epidemiological cohort study, early maternal care was assessed at child's age 3 months during a nursing and playing situation. In a sample of 296 offspring, externalizing and internalizing symptoms were assessed using a psychiatric interview conducted at age 15 years. Parents additionally filled out a questionnaire on their children's psychopathic behaviors. Results indicated that adolescents with the DRD4 7r allele who experienced less responsive and stimulating early maternal care exhibited more symptoms of ADHD and CD/ODD as well as higher levels of psychopathic behavior. In accordance with the hypothesis of differential susceptibility, 7r allele carriers showed fewer ADHD symptoms and lower levels of psychopathic behavior when exposed to especially beneficial early caregiving. In contrast, individuals without the DRD4 7r allele proved to be insensitive to the effects of early maternal care. This study replicates earlier findings with regard to an interaction between DRD4 genotype and early caregiving on externalizing behavior problems in preschoolers. It is the first one to imply continuity of this effect until adolescence.

Neural correlates of inhibitory control and functional genetic variation in the dopamine D4 receptor gene

BackgroundThe dopamine D4 receptor gene (DRD4) has been implicated in psychiatric disorders in which deficits of self-regulation are a prominent feature (e.g., attention-deficit hyperactivity disorder and substance use disorders) and in dopamine D4 receptor insensitivity within prefrontal regions of the brain. Our hypothesis was that carriers of 7-repeats in the Variable Number of Tandem Repeats (VNTR) of DRD4 (7R+) would recruit prefrontal brain regions involved in successful inhibitory control to a lesser degree than non-carriers (7R−) and demonstrate less inhibitory control as confirmed by observation of locally reduced blood oxygenation level dependent (BOLD) % signal change and lower accuracy while performing “No-Go” trials of a Go/No-Go task. MethodsParticipants (age=18, n=62, 33 females) were recruited from the general population of the St. Louis, Missouri region. Participants provided a blood or saliva sample for genotyping, completed drug and alcohol-related questionnaires and IQ testing, and performed a Go/No-Go task inside of a 3T fMRI scanner. ResultsGo/No-Go task performance did not significantly differ between 7R+ and 7R− groups. Contrast of brain activity during correct “No-Go” trials with a non-target letter baseline revealed significant BOLD activation in a network of brain regions previously implicated in inhibitory control including bilateral dorsolateral prefrontal, inferior frontal, middle frontal, medial prefrontal, subcortical, parietal/temporal, and occipital/cerebellar brain regions. Mean BOLD % signal change during “No-Go” trials was significantly modulated by DRD4 genotype, with 7R+ showing a lower hemodynamic response than 7R− in right anterior prefrontal cortex/inferior frontal gyrus, left premotor cortex, and right occipital/cerebellar areas. Follow-up analyses suggested that 7-repeat status accounted for approximately 5–6% of the variance in the BOLD response during “No-Go” trials. DiscussionThe DRD4 7-repeat allele may alter dopaminergic function in brain regions involved in inhibitory control. When individuals must inhibit a prepotent motor response, presence of this allele may account for 5–6% of the variance in BOLD signal in brain regions critically associated with inhibitory control, but its influence may be associated with a greater effect on brain than on behavior in 18-year-olds from the general population.

Interactive association of dopamine receptor (DRD4) genotype and ADHD on alcohol expectancies in children.

Positive and negative alcohol expectancies (AEs) are beliefs about the consequences of alcohol use (e.g., happy, sad, lazy) and they predict patterns of adolescent and adult alcohol engagement in clinical and nonclinical samples. However, significantly less is known about predictors of AE in children, despite significant variability in AE early in and across development. To identify temporally ordered risk factors that precede AE, we evaluated the independent and interactive association of the functional 7-repeat polymorphism of the dopamine D4 receptor (DRD4) genotype and attention-deficit/hyperactivity disorder (ADHD) with respect to individual differences in positive-social, negative-arousal, sedated/impaired, and wild/crazy AE in school-age children (N = 149) prospectively followed from 6-9 to 8-13 years of age. Controlling for age, sex, and wave, DRD4 7+ carriers reported more wild/crazy AE, but DRD4 was unrelated to the remaining AE domains. ADHD symptoms independently predicted higher negative-arousal, sedated/impaired, and wild/crazy AE, but not positive-social. We also observed a significant interaction in which ADHD symptoms positively predicted wild/crazy AE only in youth with the 7-repeat DRD4 genotype; the same interaction marginally predicted sedated/impaired AE. No interactive effects were observed for the remaining AE domains. These preliminary results suggest that, among DRD4 youth, early ADHD symptoms predict that children will expect alcohol to have wild/crazy effects. We consider these results within a developmental framework to better understand pathways to and from youth alcohol problems.

The relationship between DRD4 polymorphisms and phenotypic correlations of behaviors in the collared flycatcher.

There is increasing evidence that the genetic architecture of exploration behavior includes the dopamine receptor D4 gene (DRD4). Such a link implies that the within-individual consistency in the same behavior has a genetic basis. Behavioral consistency is also prevalent in the form of between-individual correlation of functionally different behaviors; thus, the relationship between DRD4 polymorphism and exploration may also be manifested for other behaviors. Here, in a Hungarian population of the collared flycatcher, Ficedula albicollis, we investigate how males with distinct DRD4 genotypes differ in the consistent elements of their behavioral displays during the courtship period. In completely natural conditions, we assayed novelty avoidance, aggression and risk-taking, traits that were previously shown repeatable over time and correlate with each other, suggesting that they could have a common mechanistic basis. We identified two single-nucleotide polymorphisms (SNP554 and SNP764) in the exon 3 of the DRD4 gene by sequencing a subsample, then we screened 202 individuals of both sexes for these SNPs. Focusing on the genotypic variation in courting males, we found that “AC” heterozygote individuals at the SNP764 take lower risk than the most common “AA” homozygotes (the “CC” homozygotes were not represented in our subsample of males). We also found a considerable effect size for the relationship between SNP554 polymorphism and novelty avoidance. Therefore, in addition to exploration, DRD4 polymorphisms may also be associated with the regulation of behaviors that may incur fear or stress. Moreover, polymorphisms at the two SNPs were not independent indicating a potential role for genetic constraints or another functional link, which may partially explain behavioral correlations.

Effects of Nicotine Deprivation and Replacement on BOLD-fMRI Response to Smoking Cues as a Function of DRD4 VNTR Genotype

Reactivity to smoking cues is an important factor in the motivation to smoke and has been associated with the dopamine receptor 4 variable number tandem repeat (DRD4 exon III VNTR) polymorphism. However, little is known about the associated neural mechanisms. Non-treatment-seeking Caucasian smokers completed overnight abstinence and viewed smoking and neutral cues during 2 separate functional magnetic resonance imaging scans while wearing either a nicotine or placebo patch (order randomized) and were genotyped for the DRD4 VNTR. We conducted mixed-effects repeated-measures analyses of variance (within-subject factor: nicotine or placebo patch; between-subject factor: DRD4 long [L: ≥ 1 copy of ≥ 7 repeats] or short [S: 2 copies ≤ 6 repeats] genotype) of 6 a priori regions of interest. Relative to neutral cues, smoking cues elicited greater activity in bilateral ventral striatum and left amygdala during nicotine replacement and deactivation in these regions during nicotine deprivation. A patch × DRD4 interaction was observed in the left amygdala, an area associated with appetitive reinforcement and relapse risk, such that S allele carriers demonstrated greater activation on active patch than on placebo patch. Brain systems associated with reward salience may become primed and overreactive at nicotine replacement doses intended for the first step of smoking cessation and may become inhibited during nicotine withdrawal in DRD4 S but not in DRD4 L carriers. These findings are consistent with the role of these regions in drug reinforcement and suggest a differential influence of nicotine replacement on amygdala activation in the association of incentive salience with smoking stimuli across DRD4 genotypes.

Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2).

Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most frequently studied candidate variant for addiction in DRD2 for association with brain structure. We tested whether this variant showed associations with regional brain volumes across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). We hypothesized that this addiction-related polymorphism would be associated with structural brain differences in regions previously implicated in familial vulnerability for drug dependence. Then, we assessed the generalizability of our findings by testing this polymorphism in a non-overlapping replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. In both cohorts, the minor allele-previously linked with increased risk for addiction-was associated with larger volumes in various brain regions implicated in reward processing. These findings suggest that neuroanatomical phenotypes associated with familial vulnerability for drug dependence may be partially mediated by DRD2 genotype.

Interaction between prenatal stress and dopamine D4 receptor genotype in predicting aggression and cortisol levels in young adults

Considerable evidence suggests that genetic factors combine with environmental influences to impact on the development of aggressive behavior. A genetic variant that has repeatedly been reported to render individuals more sensitive to the presence of adverse experiences, including stress exposure during fetal life, is the seven-repeat allele of the dopamine D4 receptor (DRD4) gene. The present investigation concentrated on the interplay of prenatal maternal stress and DRD4 genotype in predicting self-reported aggression in young adults. As disruption of the hypothalamic-pituitary-adrenal system has been discussed as a pathophysiological pathway to aggression, cortisol stress reactivity was additionally examined. As part of an epidemiological cohort study, prenatal maternal stress was assessed by maternal interview 3 months after childbirth. Between the ages of 19 and 23 years, 298 offspring (140 males, 158 females) completed the Young Adult Self-Report to measure aggressive behavior and were genotyped for the DRD4 gene. At 19 years, 219 participants additionally underwent the Trier Social Stress Test to determine cortisol reactivity. Extending earlier findings with respect to childhood antisocial behavior, the results revealed that, under conditions of higher prenatal maternal stress, carriers of the DRD4 seven-repeat allele displayed more aggression in adulthood (p = 0.032). Moreover, the same conditions which seemed to promote aggression were found to predict attenuated cortisol secretion (p = 0.028). This is the first study to indicate a long-term impact of prenatal stress exposure on the cortisol stress response depending on DRD4 genotype.

Environmental smoking and smoking onset in adolescence: the role of dopamine-related genes. Findings from two longitudinal studies.

Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents' and friends' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system.

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks. We used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back). Fifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used. On bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back. These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.

Association analyses for dopamine receptor gene polymorphisms and weight status in a longitudinal analysis in obese children before and after lifestyle intervention

BackgroundDopamine receptors are involved in midbrain reward circuit activation. Polymorphisms in two dopamine receptor genes, DRD2 and DRD4, have been associated with altered perception of food reward and weight gain. The objective of this study was to determine whether the same risk alleles were associated with overweight/obesity and with lower reduction of overweight after a 1-year lifestyle intervention.MethodsIn a longitudinal study the association of polymorphisms in DRD2 (rs18000497, risk allele: T, formerly A1 allele at the TaqI A1 polymorphism) and DRD4 (variable number of tandem repeats (VNTR); 48 bp repeat in exon III; risk alleles: 7 repeats or longer: 7R+) was tested on weight loss success following a 1-year lifestyle childhood obesity intervention (OBELDICKS). An additional exploratory cross-sectional case-control study was performed to compare the same DRD polymorphisms in these overweight/obese children and adolescents versus lean adult controls. Subjects were 423 obese and 28 overweight children participating in lifestyle intervention (203 males), age median 12.0 (interquartile range 10.0–13.7) years, body mass index - standard deviation score (BMI-SDS) 2.4 ± 0.5; 583 lean adults (232 males); age median 25.3 (interquartile range 22.5–26.8) years, BMI 19.1 ± 1.9 kg/m2. BMI, BMI-SDS and skinfold thickness measures were assessed at baseline and after 1 year; genotyping was performed for DRD2 risk variant rs1800497 and DRD4 exon III VNTR.ResultsThe DRD2 genotype had a nominal effect on success in the weight loss intervention. The weakest BMI-SDS reduction was in children homozygous for two rs1800497 T-alleles (n = 11) compared to the combined group with zero (n = 308) or one (n = 132) rs1800497 T-allele (-0.08 ± 0.36 vs. -0.28 ± 0.34; p < 0.05). There was no association between the DRD4 VNTR alleles and genotypes and success in the weight loss intervention. No associations of the risk alleles of the DRD2 and DRD4 polymorphisms and obesity were observed in the cross-sectional part of the study.ConclusionsWe did not find association between polymorphisms in DRD2 and DRD4 genes and weight status. However, obese carriers of two DRD2 rs1800497 T-alleles may be at risk for weak responses to lifestyle interventions aimed at weight reduction.Trial registrationObesity intervention program “Obeldicks” is registered at clinicaltrials.gov (NCT00435734).

Functional Connectivity in Healthy Subjects Is Nonlinearly Modulated by the COMT and DRD2 Polymorphisms in a Functional System-Dependent Manner

The dopamine system is known to modulate brain function in an inverted U-shaped manner. Recently, the functional networks of the brain were categorized into two systems, a "control system" and a "processing system." However, it remains unclear whether the inverted U-shaped model of dopaminergic modulation could be applied to both of these functional systems. The catechol-O-methyltransferase (COMT) and dopamine D2 receptor (DRD2) were genotyped in 258 healthy young human subjects. The local and long-range functional connectivity densities (FCDs) of each voxel were calculated and compared in a voxel-wise manner using a two-way (COMT and DRD2 genotypes) analysis of covariance. The resting-state functional connectivity analysis was performed to determine the functional networks to which brain regions with significant FCD differences belonged. Significant COMT × DRD2 interaction effects were found in the local FCDs of the superior portion of the right temporal pole (sTP) and left lingual gyrus (LG) and in the long-range FCDs of the right putamen and left medial prefrontal cortex (MPFC). Post hoc tests showed nonlinear relationships between the genotypic subgroups and FCD. In the control system, the sTP and putamen, components of the salience network, showed a U-shaped modulation by dopamine signaling. In the processing system, however, the MPFC of the default-mode network and the LG of the visual network showed an inverted U-shaped modulation by the dopamine system. Our findings suggest an interaction between COMT and DRD2 genotypes and show a functional system-dependent modulation of dopamine signaling.