The Dopamine D4 Receptor (DRD4) Exon 3 VNTR Contributes to Adaptive Personality Differences in an Italian Small Island Population

The search for evolutionary forces shaping the diversity of human personality traits encouraged studies that have found that islanders are relatively closed and introverted, with little interest in the external world. The ‘personality gene flow’ hypothesis was proposed to explain the mechanism underlying this difference, suggesting that the frequency of alleles that influence islander personality traits might progressively increase in the gene pools on islands because of selective emigration of individuals not displaying these alleles. We genotyped 96 individuals from the Italian mainland and 117 from Giglio Island, whose residents were previously assessed regarding their personality traits. We genotyped three polymorphisms: the dopamine D4 receptor (DRD4) exon 3 repeat region, the serotonin‐transporter SLC6A4 5‐HTTLPR indel and the dopamine transporter SLC6A3 DAT1 3′UTR repeat region. Only the DRD4 exon 3 repeat was hypothesised to show varying allele frequencies because this polymorphism could be associated with human migration and personality traits such as extraversion, openness and novelty seeking. As predicted, no differences in allele frequencies were found for the SLC6A4 and SLC6A3 polymorphisms, whereas significant differences were observed in the frequency of the DRD4 exon 3 alleles. The DRD4.2 repeat was more common in mainlanders, as expected, whereas the DRD4.7 allele was over‐represented among islanders who never emigrated. This last result contradicts the suggested association of this allele with long‐distance migrations. We suggest that emigration might have caused gene flow out the island that resulted in somewhat unpredictable changes in the frequencies of specific alleles, thus influencing islander personality traits. Copyright © 2013 European Association of Personality Psychology     

DRD4基因与亲社会行为的关联及其潜在脑机制

DRD4基因是亲社会行为的重要候选基因,且与环境交互影响亲社会行为的发生发展。通过梳理既有研究,本文从性别差异、亲社会行为的不同类型及发展动态性等角度探讨了亲社会行为遗传研究存在分歧的原因,并在此基础上探索了DRD4基因作用于亲社会行为的潜在脑机制。未来研究应采用纵向设计探究DRD4基因影响亲社会行为的发展动态性问题,并深入探索其性别差异;采用多质多法分析考察不同类型亲社会行为遗传机制的差异性;采用影像遗传学设计揭示“DRD4基因—脑—亲社会行为”作用机制。     

Dopaminergic polymorphisms and educational achievement: results from a longitudinal sample of Americans

Although educational attainment has been found to be moderately heritable, research has yet to explore candidate genes for it. Drawing on data from the National Longitudinal Study of Adolescent Health, in the current study, we examined the association between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4), a dopamine index, and educational attainment. Statistically significant effects were found for DAT1, DRD2, DRD4, and the dopamine index for highest level of education. This study is the first to our knowledge that links measured genes to educational attainment.     

COMT gene polymorphisms,cognitive performance,and physical fitness in older adults

ObjectiveIt is well known that genetic predispositions might influence cognitive performance, particularly in older adults. One gene related to executive functioning is the COMT gene with met/met carriers outperforming val/val carriers in cognitive tasks. Further, it has been shown that fitness is positively related to cognitive functioning in older adults. As both, the COMT genotype and physical exercise have been shown to influence dopamine availability and as changes in dopamine metabolism seem to play a key role in cognitive aging, the aim of this study was to analyze the association of the COMT gene polymorphisms with the relationship between fitness and cognition.DesignWe used a cross-sectional design.MethodSixty-eight healthy older adults between 62 and 79 years of age were analyzed in this study. DNA was extracted from capillary blood samples. Participants performed a modified version of the Flanker Task as an indicator of executive control and a battery of motor and physical tests as indicators of fitness.ResultsHierarchical regression analyses revealed a positive influence of overall fitness and an interactive effect of fitness and COMT polymorphisms on Flanker accuracy performance. Val/val carriers revealed the highest positive correlation between fitness and cognition.ConclusionsOur data suggest that particularly val/val allele carriers benefit from exercise by improved cognitive functioning whereas met/met carriers already perform closer at their optimum level.     

Association of Dopamine D2 Receptor Gene with Creative Ideation

Although several studies suggest that dopamine D2 receptor (DRD2) gene may contribute to creativity, the relationship between DRD2 and creativity still needs to be further validated. To further test the relevance of DRD2 and creativity, this study explored the association between DRD2 and creative ideation in 483 unrelated healthy Chinese undergraduate students. A total of 15 single nucleotide polymorphisms (SNPs) covering the DRD2 were genotyped, and creative ideation was assessed by the Runco Ideational Behavior Scale (RIBS). Single SNP analysis showed that 2 SNPs (rs4648317 and rs4938019) were nominally associated with fluency, 4 SNPs (rs4648317, rs4938019, rs4648319, and rs1800497) were nominally associated with flexibility, and 1 SNP (rs4648317) was nominally associated with originality. Haplotype analysis showed several haplotypes were nominally associated with various creative ideation indexes. However, none of these nominal associations survived correction for multiple testing. Overall, this study provides suggestive evidence for the genetic impact of DRD2 on creative ideation and supports the assumption that the genotype variations in DRD2 contribute to creativity.     

多巴胺相关基因甲基化、家庭环境与创造力的关系

“遗传与环境”的争论一直是创造力研究的核心问题, 但目前对于环境以及遗传与环境交互作用对创造力影响的分子生物机制还未有研究涉及。近年来, 随着表观遗传学的兴起, 揭示影响心理行为的表观遗传机制现已成为心理学研究的热点。作为环境与基因组之间的纽带, 表观遗传学研究为揭示环境以及遗传与环境交互作用对创造力影响的分子生物机制提供了机遇。本研究以多巴胺相关基因、家庭环境以及两者对于创造力的交互作用为切入点, 对影响创造力的表观遗传机制进行考察, 并在此基础之上, 对环境以及遗传与环境交互作用对创造力影响的分子生物机制进行探索。具体研究内容包括：(1)通过对多巴胺相关基因甲基化模式与创造力关系的系统考察, 筛选出甲基化模式与创造力有关的基因; (2)对筛选出的基因, 进一步考察其甲基化模式在家庭环境及其遗传多态性与家庭环境交互作用对创造力影响中的中介作用。本研究有助于揭示创造力的表观遗传机制, 深化关于遗传与环境对创造力影响的作用机制的理解。     

Depressive rumination and the C957T polymorphism of the DRD2 gene

Depressed individuals who ruminate have difficulties learning from punishment and suppressing task-irrelevant information. The C957T polymorphism of the DRD2 gene, which affects functioning of D2 dopamine receptors (DRD2) that are expressed predominantly in the indirect pathway of the basal ganglia, has been found to influence suppression and punishment learning. Given these associations, we examined in the present study whether depressive rumination is related to the C957T polymorphism in 317 clinically depressed individuals and 317 never-depressed control individuals. A 2 × 2 (diagnostic group ×C957T polymorphism) analysis of variance conducted on depressive rumination scores yielded a significant interaction of group and C957T: Individuals with two 957C alleles reported higher levels of depressive rumination than did individuals with one or two 957T alleles if they were depressed, but not if they were healthy. The present findings suggest that the dopaminergic system and DRD2 are related to the frequency of maladaptive rumination in depressed individuals. Thus, DRD2 may be an important target for the pharmacological treatment of depressive rumination.     

On the molecular genetics of flexibility: The case of task-switching,inhibitory control and genetic variants

The adjustment of behavior to changing goals and environmental constraints requires the flexible switching between different task sets. Cognitive flexibility is an endophenotype of executive functioning and is highly heritable, as indicated by twin studies. Individual differences in global flexibility as assessed by reaction-time measurement in a task-switching paradigm were recently related to a single nucleotide polymorphism in the vicinity of the dopamine d2 receptor gene DRD2. In the present study, we assessed whether the DRD2 gene is related to backward inhibition, a control mechanism that contributes to cognitive flexibility by reducing proactive interference by no longer relevant task sets. We found that carriers of the DRD2 A1+ variant who have a lower striatal dopamine d2 receptor density than A1– carriers show a larger backward inhibition effect. This is in line with previous results demonstrating increased behavioral flexibility in carriers of this genetic variant. The discussion relates the present finding to those of previous studies assessing the neurogenetic foundations of inhibitory control.     

The association between dopamine D4 receptor exon III polymorphism and intensity of PTSD symptoms among flood survivors

Abstract

Thanks to the development of molecular genetics methods it is now possible to look for the genes which may contribute to posttraumatic stress disorder (PTSD). Polymorphism located in exon III of dopamine receptor type 4 (DRD4) gene was related to maladaptive stress responses as well as temperament traits related to PTSD. This study analyzed the association between the variable number tandem repeat (VNTR) DRD4 exon III polymorphism and intensity of PTSD symptoms in 107 (57 women and 50 men) survivors of a flood aged 14–62. Intensity of PTSD symptoms was measured using PTSD-F and PTSD-C questionnaires. Multivariate analysis of covariance (MANCOVA) was conducted to test the main and interactive effects of genotype and level of trauma exposure. Participants with at least one copy of the DRD4 long allele (seven or eight repetitions) had more intense PTSD symptoms on the Avoidance/Numbing scale (Cohen's f = .22) and the Total Scale (Cohen's f = .2) of the PTSD-F than participants who did not have these alleles in genotype. The results must be treated with caution, however, due to methodological restrictions and they need to be replicated on a larger sample.     

<Emphasis Type="Italic">DRD4</Emphasis> Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design

Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD. Use of a multiplex family design (i.e., samples of families that included multiple affected members) may facilitate identification of additional gene variants of interest and advance understanding of gene-environment interplay in regard to parenting. Thirty multiplex families consisting of 114 individuals (66 youth, 48 parents) completed a multi-stage, multi-informant diagnostic and neurocognitive assessment, measures of parenting, and provided saliva samples for DNA analyses. Sanger sequencing of the DRD4 gene yielded 16 rare variants; a polygenic risk score was computed for both parents and youth. Generalized estimating equations (GEE) examined the predictive effects of parental ADHD symptoms, parental neurocognitive functioning, and poor parenting dimensions on youth ADHD as well as moderation of these effects by parental and youth DRD4 variants. Findings indicated that parental DRD4 variants moderated the impact of parental ADHD and neurocognitive functioning on youth ADHD symptoms. Youth DRD4 variants moderated the impact of parental inconsistent discipline on child ADHD. In all cases, stronger associations were observed for those individuals with more risk variants. These exploratory findings highlight the potential utility of a multiplex family design for examining the interplay between parent and child characteristics in predicting youth outcomes.     

Warriors versus worriers: the role of COMT gene variants

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.     

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis

Multiple theories of Attention-Deficit/Hyper- activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.     

Joint effect of dopaminergic genes on likelihood of smoking following treatment with bupropion SR.

OBJECTIVE: To determine the relationship between joint variation in 2 dopaminergic genes and the likelihood of nonsmoking following treatment with bupropion sustained release (SR). DESIGN: Three hundred twenty-three participants in a bupropion SR smoking cessation effectiveness trial with 12-month follow-up were genotyped for variants of dopamine receptor gene DRD2 and dopamine transporter SLC6A3. MAIN OUTCOME MEASURES: Self-reported 7-day point prevalence of nonsmoking. RESULTS: Neither genotype alone was associated with 7-day point-prevalent nonsmoking at the 12-month follow-up. However, in the presence of the DRD2 A1 allele, SLC6A3 status was significantly associated with the likelihood of nonsmoking at the 12-month follow-up (individuals with DRD2 A1+ and SLC6A3 9- were more likely to be smoking). In the absence of the DRD2 A1 allele, the association between SLC6A3 status and nonsmoking was nonsignificant. CONCLUSION: Although these results are suggestive, a more compelling test is needed of the hypothesis that dopaminergic gene interaction underlies, in part, the likelihood of smoking following treatment with bupropion SR. Most likely this will come from larger studies involving prospective randomization to treatment based on genotype.     

An association between the DAT1 polymorphism and smoking behavior in young adults from the National Longitudinal Study of Adolescent Health.

Associations between smoking behavior and polymorphisms in the dopaminergic genes (DAT1 and DRD2) were tested by using within- and between-family measures of allelic transmission in 2,448 young adults from the National Longitudinal Study of Adolescent Health. The 9-repeat allele of the dopamine transporter gene polymorphism (DAT1) was inversely associated with smoking in samples that included all subjects and only those who had initiated smoking, accounting for approximately 1% of the variance. Never smokers and current nonsmokers had an excess transmission of the 9-repeat allele compared with regular smokers, suggesting a protective effect of the 9-repeat allele, which is hypothesized to alter synaptic dopamine levels.     

Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single nucleotide polymorphisms (SNPs) within the genes. This study investigates the association between memory and SNPs in genes involved in the dopaminergic pathway, as well as in the BDNF and MTHFR genes, in a sample of healthy individuals. The sample includes 134 Taiwanese undergraduate volunteers of similar cognitive ability. The Chinese versions of the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III) were employed. Our findings indicate that the BDNF Met66Val polymorphism and dopamine receptor D3 (DRD3) Ser9Gly polymorphism are associated significantly with long-term auditory memory. Further analysis detects no significant associations in the other polymorphisms and indices. Future replicated studies with larger sample sizes, and studies that consider different ethnic groups, are encouraged.     

Teacher–student relationships and adolescent behavioral engagement and rule-breaking behavior: The moderating role of dopaminergic genes

This study examined whether the dopamine transporter DAT1 and the dopamine receptor DRD4 genes moderate the effect of student-reported teacher–student relationship affiliation or dissatisfaction on parent-reported adolescent rule-breaking behavior and behavioral engagement. The sample included 1053 adolescents (51% boys, M_age = 13.79) from grades 7 to 9. Regression analyses were conducted using Mplus while controlling for multiple testing and nested data. Adolescents who experienced stronger affiliation with their teachers were more engaged in school, whereas greater dissatisfaction predicted more rule-breaking behavior. In addition, a significant gene–environment interaction was found for both genes examined. The link between low teacher–student affiliation and low engagement was more pronounced for DAT1-10R homozygotes. The link between high teacher–student dissatisfaction and more rule-breaking was stronger for DRD4 non-long carriers. Implications for understanding the role of teacher–student relationships in adolescence and suggestions for future research are outlined.     

The impact of stress on the life history strategies of African American adolescents: cognitions, genetic moderation, and the role of discrimination

The impact of 3 different sources of stress--environmental, familial (e.g., low parental investment), and interpersonal (i.e., racial discrimination)--on the life history strategies (LHS) and associated cognitions of African American adolescents were examined over an 11-year period (5 waves, from age 10.5 to 21.5). Analyses indicated that each one of the sources of stress was associated with faster LHS cognitions (e.g., tolerance of deviance, willingness to engage in risky sex), which, in turn, predicted faster LHS behaviors (e.g., frequent sexual behavior). LHS, then, negatively predicted outcome (resilience) at age 21.5 (i.e., faster LHS → less resilience). In addition, presence of the risk ("sensitivity") alleles of 2 monoamine-regulating genes, the serotonin transporter gene (5HTTLPR) and the dopamine D4 receptor gene (DRD4), moderated the impact of perceived racial discrimination on LHS cognitions: Participants with more risk alleles (higher "sensitivity") reported faster LHS cognitions at age 18 and less resilience at age 21 if they had experienced higher amounts of discrimination and slower LHS and more resilience if they had experienced smaller amounts of discrimination. Implications for LHS theories are discussed.     

反社会行为的遗传基础:基因多态性和DNA甲基化

反社会行为是受遗传与环境共同影响的不良行为。分子遗传学和神经生物学的研究发现,基因以基因多态性和DNA甲基化的方式影响脑结构、功能及脑内神经递质的产生和释放,进而影响反社会行为的发生发展。本文从基因多态性和DNA甲基化两方面整理了5-HTT、MAOA、OXTR等8个候选基因与反社会行为的关联。并提出未来研究需进一步探讨基因、脑和神经递质对反社会行为的联合作用。同时,扩展多基因位点、基因多态性与DNA甲基化、积极环境与基因交互作用对反社会行为影响的研究,以全面探索反社会行为发生的遗传基础,进而更加有效的预防反社会行为。     

反社会行为的遗传基础:基因多态性和DNA甲基化

反社会行为是受遗传与环境共同影响的不良行为。分子遗传学和神经生物学的研究发现,基因以基因多态性和DNA甲基化的方式影响脑结构、功能及脑内神经递质的产生和释放,进而影响反社会行为的发生发展。本文从基因多态性和DNA甲基化两方面整理了5-HTT、MAOA、OXTR等8个候选基因与反社会行为的关联。并提出未来研究需进一步探讨基因、脑和神经递质对反社会行为的联合作用。同时,扩展多基因位点、基因多态性与DNA甲基化、积极环境与基因交互作用对反社会行为影响的研究,以全面探索反社会行为发生的遗传基础,进而更加有效的预防反社会行为。     

Beyond heritability: neurotransmitter genes differentially modulate visuospatial attention and working memory

A cued, visuospatial attention task and a working memory task were administered to 89 healthy adults genotyped for a T-to-C polymorphism in CHRNA4, a nicotinic receptor subunit gene. Increasing gene dose of the C allele of the CHRNA4 gene (i.e., no C alleles, one C allele, two C alleles) was associated with increased reaction time (RT) benefits of valid attentional cuing and reduced RT costs of invalid cues, but was not associated with working memory performance. In a second experiment, 103 healthy persons were genotyped for a G-to-A polymorphism of the dopamine beta-hydroxylase (DBH) gene. Increasing gene dose of the G allele of the DBH gene was associated with increased working memory accuracy at a high memory load. However, there was no consistent association between the DBH gene and visuospatial attention. Thus, a double dissociation was observed, with visuospatial attention associated with CHRNA4 but not the DBH gene and, conversely, working memory associated with the DBH gene but not CHRNA4. The results show that normal allelic variations in single neurotransmitter genes modulate individual differences in processing components of cognitive functions in healthy individuals.