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.     

Gene flow by selective emigration as a possible cause for personality differences between small islands and mainland populations

Whether personality differences exist between populations is a controversial question. Even though such differences can be measured, it is still not clear whether they are due to individual phenotypic responses to the environment or whether they have a genetic influence. In a population survey we compared the personality traits of inhabitants of an Italian archipelago (the three Egadi islands; N = 622) with those of the closest mainland population (Trapani area; N = 106) and we found that personality differences between small populations can be detected. Islanders scored significantly lower on the personality traits of openness to experience and extraversion and higher on conscientiousness. We suggest that these personality trait differences could be an adaptive response to a confined socio‐environmental niche, genetically produced by a strong, non‐random gene flow in the last 20–25 generations, rather than the flexible response of islanders to environmental variables. To test this hypothesis, we compared subsets of the islander population classified by ancestry, birthplace, immigration and emigration and found that differences in extraversion can be accounted for by gene flow, while openness to experience and conscientiousness can also be accounted for by some gene–environment interactions. We propose a Personality Gene Flow hypothesis suggesting that, in small isolated communities, whenever there is strong, non‐random emigration, paired with weak and random immigration, we can expect rapid genetic personality change within the population. Copyright © 2010 John Wiley & Sons, Ltd.     

Dopamine receptor D4 gene variation predicts preschoolers' developing theory of mind

Individual differences in preschoolers' understanding that human action is caused by internal mental states, or representational theory of mind (RTM), are heritable, as are developmental disorders such as autism in which RTM is particularly impaired. We investigated whether polymorphisms of genes affecting dopamine (DA) utilization and metabolism constitute part of the molecular basis of this heritability. Seventy-three 42- to 54-month-olds were given a battery of RTM tasks along with other task batteries that measured executive functioning and representational understanding more generally. Polymorphisms of the dopamine D4 receptor gene (DRD4) were associated with RTM performance such that preschoolers with shorter alleles outperformed those with one or more longer alleles. However, polymorphisms of the catechol-O-methyl transferase gene (COMT) and the dopamine transporter gene (DAT1) genes were not associated with children's RTM performance. Further tests showed that the association between DRD4 allele length and RTM performance was not attributable to a common association with executive functioning or representational understanding more generally. We conclude that DRD4 receptors, likely via their effects on frontal lobe development and functioning, may represent a neuromaturational constraint governing the stereotypical and universal trajectory of RTM development.     

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.     

The DRD4 VNTR polymorphism moderates craving after alcohol consumption.

Recent research has suggested that alterations in mesolimbic dopamine neurotransmission are central to the development and expression of craving for alcohol. Because the D4 dopamine receptor gene, variable numbers of tandem repeats (DRD4 VNTR) polymorphism putatively expresses functional differences in dopamine receptors, the present study tested whether this polymorphism influences the effects of a priming dose of alcohol on craving. Participants consumed 3 alcoholic drinks or 3 control drinks and completed measures of craving after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele were classified as DRD4 L, whereas the other participants were classified as DRD4 S. Results suggested that DRD4 L participants demonstrated significantly higher craving after consumption of alcohol as compared with the control beverage.     

Experimental evidence for differential susceptibility: dopamine D4 receptor polymorphism (DRD4 VNTR) moderates intervention effects on toddlers' externalizing behavior in a randomized controlled trial

In a randomized controlled trial we tested the role of genetic differences in explaining variability in intervention effects on child externalizing behavior. One hundred fifty-seven families with 1- to 3-year-old children screened for their relatively high levels of externalizing behavior participated in a study implementing Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD), with six 1.5-hr intervention sessions focusing on maternal sensitivity and discipline. A moderating role of the dopamine D4 receptor (DRD4) variable-number tandem repeat (VNTR) exon III polymorphism was found: VIPP-SD proved to be effective in decreasing externalizing behavior in children with the DRD4 7-repeat allele, a polymorphism that is associated with motivational and reward mechanisms and Attention Deficit Hyperactivity Disorder (ADHD) in children. VIPP-SD effects were largest in children with the DRD4 7-repeat allele whose parents showed the largest increase in the use of positive discipline. The findings of this first experimental test of (measured) gene by (observed) environment interaction in human development indicate that children may be differentially susceptible to intervention effects depending on genetic differences.     

The role of parenting and dopamine D4 receptor gene polymorphisms in children's inhibitory control

Temperamental effortful control has important implications for children's development. Although genetic factors and parenting may influence effortful control, few studies have examined interplay between the two in predicting its development. The current study investigated associations between parenting and a facet of children's effortful control, inhibitory control (IC), and whether these associations were moderated by whether children had a 7‐repeat variant of the DRD4 exon III VNTR. A community sample of 409 3‐year‐olds completed behavioural tasks to assess IC, and observational measures of parenting were also collected. Negative parenting was associated with lower child IC. The association between children's IC and positive parenting was moderated by children's DRD4 7‐repeat status, such that children with at least one 7‐repeat allele displayed lower IC than children without this allele when positive parenting was lower. These effects appeared to be primarily influenced by parent support and engagement. Results extend recent findings suggesting that some genetic polymorphisms may increase vulnerability to contextual influences.     

The adaptive value of personality differences revealed by small island population dynamics

Whether differences in personality among populations really exist and, if so, whether they are only due to cultural and linguistic differences or have a genetically selected adaptive value, is a controversial issue. In this research, we compared three Italian populations living on three small archipelagos in the Tyrrhenian Sea (n = 993), with their corresponding neighbouring mainlanders (n = 598), i.e. sharing the same geographical origin, culture and language. We used an adjective‐based Big Five questionnaire in order to measure personality traits in four categories of individuals for each archipelago/mainland population: (1) original islanders; (2) non‐original islanders; (3) mainlanders and (4) immigrants to the islands. We further analysed original and non‐original islanders who had or had not emigrated from the islands. We found that islanders had different personality traits from mainlanders, the former being more conscientious and emotionally stable and less extraverted and open to experience. We also found that the subgroup of islanders whose ancestors had inhabited their island for about 20 generations in isolation (original islanders, n = 624) were less extraverted and open to experience than immigrants (n = 193). In contrast, immigrants retained the typical personality profile of the mainland populations. Lastly, emigrants from the islands (n = 209) were significantly more extraverted and open to experience than original and non‐original islanders who had never left their island (n = 741). We hypothesise that population differences in extraversion and openness to experience are more probably related to genetic differences which evolved rapidly, presumably through an active gene flow produced by selective emigration from the islands. Copyright © 2006 John Wiley & Sons, Ltd.     

Effects of dopamine transporter and receptor polymorphisms on smoking cessation in a bupropion clinical trial.

This study examined the role of dopaminergic genes in prospective smoking cessation and response to bupropion treatment in a placebo-controlled clinical trial. Smokers of European ancestry (N=418) provided blood samples for genetic analysis and received either bupropion or placebo (10 weeks) plus counseling. Assessments included the dopamine D2 receptor (DRD2) genotype, dopamine transporter (SLC6A3) genotype, demographic factors, and nicotine dependence. Smoking status was verified at the end of treatment (EOT) and at 6-month follow-up. The results provided evidence for a significant DRD2 * SLC6A3 interaction effect on prolonged smoking abstinence and time to relapse at EOT, independent of treatment condition. Such effects were no longer significant at 6-month follow-up, however. These results provide the first evidence from a prospective clinical trial that genes that alter dopamine function may influence smoking cessation and relapse during the treatment phase.     

Linking Gene, Brain, and Behavior: DRD4, Frontal Asymmetry, and Temperament

ABSTRACT— Gene-environment interactions involving exogenous environmental factors are known to shape behavior and personality development. Although gene-environment interactions involving endogenous environmental factors are hypothesized to play an equally important role, this conceptual approach has not been empirically applied in the study of early-developing temperament in humans. Here we report evidence for a gene- endo environment (i.e., resting frontal brain electroencephalogram, EEG, asymmetry) interaction in predicting child temperament. The dopamine D4 receptor (DRD4) gene (long allele vs. short allele) moderated the relation between resting frontal EEG asymmetry (left vs. right) at 9 months and temperament at 48 months. Children who exhibited left frontal EEG asymmetry at 9 months and who possessed the DRD4 long allele were significantly more soothable at 48 months than other children. Among children with right frontal EEG asymmetry at 9 months, those with the DRD4 long allele had significantly more difficulties focusing and sustaining attention at 48 months than those with the DRD4 short allele. Resting frontal EEG asymmetry did not influence temperament in the absence of the DRD4 long allele. We discuss how the interaction of genetic and endoenvironmental factors may confer risk and protection for different behavioral styles in children.     

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。     

The Dopamine Receptor D4 Gene (<Emphasis Type="Italic">DRD4</Emphasis>) Moderates Family Environmental Effects on ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the DRD4 promoter 120-bp tandem repeat polymorphism, previously associated with ADHD, moderated the effects of inconsistent parenting and marital conflict on ADHD or Oppositional-Defiant Disorder (ODD). Participants were 548 children with ADHD and non-ADHD comparison children and their parents. Homozygosity for the DRD4 promoter 120-bp tandem repeat insertion allele increased vulnerability for ADHD and ODD only in the presence of inconsistent parenting and appeared to increase susceptibility to the influence of increased child self-blame for marital conflict on ADHD inattention. DRD4 genotypes may interact with these proximal family environmental risk factors by increasing the individual’s responsivity to environmental contingencies.     

The DRD4 VNTR polymorphism influences reactivity to smoking cues

Recent research has indicated that craving for tobacco can be reliably elicited by exposure to smoking cues, suggesting that cue-elicited craving for tobacco may be a useful phenotype for research on genetic factors related to nicotine dependence. Given the potential role of dopamine in cue-elicited craving, the authors examined whether the DRD4 VNTR polymorphism is associated with cue-elicited craving for tobacco. Participants who were homozygous or heterozygous for the 7 repeat (or longer) allele were classified as DRD4 L, and all other participants were classified as DRD4 S. Participants were exposed to smoking cues before smoking either high-nicotine cigarettes or control cigarettes. Analyses suggested that participants in the L group demonstrated significantly greater craving, more arousal, less positive affect, and more attention to the smoking cues than did the participants in the S group.     

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.     

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.     

Genetic moderation of contextual effects on negative arousal and parenting in African-American parents

A three-stage context amplification model was tested with a sample of 345 African-American parent-child dyads. The model combined the conceptual structure of stress generation with recent findings regarding genetic susceptibility. Because the 7R + allele of the dopamine transporter (DRD4) has the potential to enhance contextual priming and arousal, this allele was examined as a potential moderator of each stage of the amplification process. Particular attention was given to the hypothesized influence of parental negative arousal on valence of parent-child interactions. The literature on genetic susceptibility led to the hypothesis that DRD4 would moderate each stage of the model in a "for better or for worse" manner. The model was partially supported. DRD4 moderated effects at all three stages of the model and, as hypothesized, DRD4 moderated contextual effects on negative arousal in a "for better or for worse" manner. Effects on parent-child interaction, however, were moderated in a "for worse" manner only. These results indicate that parenting interactions may amplify the effects of positive and negative contexts in a stress-generating manner, and that a susceptibility framework captures the way in which DRD4 moderates the impact of context on negative arousal.     

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

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

A Genetic Component to National Differences in Happiness

National differences in subjective well-being (SWB) have been attributed to socioeconomic, climatic, and genetic factors. We focus on one particular facet of SWB—happiness or positive affect—measured by the nationally representative World Values Survey (WVS). We find that national percentages of very happy people across the three latest WVS waves (2000–2004, 2005–2009, 2010–2014) are consistently and highly correlated with national prevalence of the rs324420 A allele in the FAAH gene, involved in the hydrolysis of anandamide, a substance that reportedly enhances sensory pleasure and helps reduce pain. Climatic differences are also significantly associated with national differences in happiness, whereas economic wealth, recent economic growth, rule of law, pathogen prevalence, and the distribution of short versus long alleles in the serotonin transporter gene SLC6A4 are not significant predictors of national happiness.     

Genetic associations with personality and mental toughness profiles of English academy football players: An exploratory study

Psychological characteristics influence the performance of youth football players and are significant predictors of development and success at adulthood. Although genetic factors may explain a considerable portion of inter-individual differences in psychological traits, psychogenetic research in football is scarce. As such, the purpose of this study was to examine the association of ten single nucleotide polymorphisms (SNPs) with personality and mental toughness profiles of academy football players. Seventy-three male under-12 to under-18 football players from a Category 3 English academy were genotyped for ten SNPs. Personality and mental toughness were assessed using a 50-item IPIP Big Five personality traits questionnaire and the Mental Toughness Index, respectively. Simple linear regression was used to analyse individual SNP associations with personality dimensions and mental toughness, whereas both unweighted and weighted total genotype scores (TGSs; TWGSs) were computed to measure the combined influence of all SNPs. There was a significant association between DRD3 (rs167771) and agreeableness (p = .043), where A/A homozygotes scored higher than G allele carriers. TGSs and/or TWGSs were significantly correlated with mental toughness and each personality dimension except openness, explaining between 3 and 17% of the variance. The results of this study suggest psychological characteristics of youth football players are partly determined by genetic factors.     

Exploring the association between the 2-repeat allele of the MAOA gene promoter polymorphism and psychopathic personality traits,arrests, incarceration,and lifetime antisocial behavior

A line of research has revealed that a polymorphism in the promoter region of the MAOA gene is related to antisocial phenotypes. Most of these studies examine the effects of low MAOA activity alleles (2-repeat and 3-repeat alleles) against the effects of high MAOA activity alleles (3.5-repeat, 4-repeat, and sometimes 5-repeat alleles), with research indicating that the low MAOA activity alleles confer an increased risk to antisocial phenotypes. The current study examined whether the 2-repeat allele, which has been shown to be functionally different from the 3-repeat allele, was associated with a range of antisocial phenotypes in a sample of males drawn from the National Longitudinal Study of Adolescent Health. Analyses revealed that African-American males who carried the 2-repeat allele were, in comparison with other African-American male genotypes, significantly more likely to be arrested and incarcerated. Additional analyses revealed that African-American male carriers of the 2-repeat allele scored significantly higher on an antisocial phenotype index and on measures assessing involvement in violent behaviors over the life course. There was not any association between the 2-repeat allele and a continuously measured psychopathic personality traits scale. The effects of the 2-repeat allele could not be examined in Caucasian males because only 0.1% carried it.