Association between novelty seeking and the type 4 dopamine receptor gene in a large Finnish cohort sample.

OBJECTIVE: An association between the type 4 dopamine receptor (DRD4) gene and the behavioral trait of novelty seeking has been reported, but several studies have failed to replicate this finding. In the present study, the authors tested for this association in a representative sample from the Finnish population. METHOD: The authors administered the Temperament and Character Inventory to 4,773 individuals from the 1966 birth cohort of northern Finland. They then genotyped 190 subjects with extreme scores for a 48 base-pair repeat polymorphism in the DRD4 gene. RESULTS: There was a significant difference in allele frequencies between the two groups. The 2- and 5-repeat alleles were significantly more common in the group of high scorers than in the group of low scorers. CONCLUSIONS: These results confirm the original findings of an association between the DRD4 gene and novelty seeking, while showing that novelty seeking is probably not influenced by the polymorphism itself but, rather, a different DNA variant in the DRD4 gene or another gene in linkage disequilibrium with it.     

Association study of catechol-O-methyltransferase gene and dopamine D4 receptor gene polymorphisms and personality traits in healthy young chinese females

Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect monoamine metabolism, is possibly associated with specific personality traits. In addition, a polymorphism in the dopamine D4 receptor (DRD4) gene exon 3 has been associated in some, but not all, studies with the novelty seeking personality trait, as evaluated by the Tridimensional Personality Questionnaire (TPQ). In this study, associations between these two polymorphisms and TPQ personality traits were investigated in a sample population of 120 healthy young Chinese females. The results of this analysis reveal that the COMT Val158Met polymorphism was significantly associated with novelty seeking (p = 0.017) and reward dependence scores (p = 0.015) in our sample. However, no significant differences were demonstrated comparing TPQ-specific scores for subjects bearing different DRD4 genotypes. The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence. Similar to the results of a recent meta-analytic review, however, no association was demonstrated between this DRD4 polymorphism and novelty seeking in our young Chinese female sample population.     

Minor genetic variants of the dopamine D4 receptor (DRD4) polymorphism are associated with novelty seeking in healthy Japanese subjects

Although an association between the dopamine receptor D4 (DRD4) gene and personality traits had been previously investigated, results from previous studies were not conclusive. This may be due to the method of grouping used, which categorized the gene population into two groups based on the length of the variable number of tandem repeats (VNTR) in exon 3. In the present study, we categorized 616 healthy Japanese subjects into more than two groups by further subdividing the DRD4 48-bp VNTR polymorphism, and compared Temperament and Character Inventory (TCI) scores among the groups. A significant difference was found between the DRD4 48-bp VNTR polymorphism and novelty seeking (p = 0.016). The novelty-seeking scores in the subjects carrying the 5/5 genotype were significantly higher than in those carrying the 2/2 genotype (p = 0.002) or the 4/4 genotype (p = 0.005). However, when the conventional method of grouping was used (i.e., short alleles vs. long alleles), there were no significant associations between the DRD4 VNTR polymorphism and any TCI scores. Our results suggest that minor 5-repeat allele is associated with high novelty-seeking scores in healthy Japanese subjects.     

Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders

We investigated whether polymorphisms of the dopamine D4 receptor (DRD4) and polymorphisms of the dopamine D3 receptor (DRD3) were associated with personality disorder symptomatology rather than with personality traits such as novelty seeking. DNA was obtained from 145 depressed patients in a clinical trial. These patients were assessed for the presence of personality disorder symptoms and disorders. The 2-repeat allele of the DRD4 exon III polymorphism was associated with increased rates of avoidant and obsessive personality disorder symptomatology. The T,T genotype of the DRD4 -521 C>T polymorphism was also associated with increased rates of avoidant and obsessive personality disorder symptomatology. The Gly9,Gly9 genotype of the DRD3 Ser9Gly polymorphism was associated with increased rates of obsessive personality disorder symptomatology. None of these three polymorphisms were associated with novelty seeking or other temperament traits on the Temperament and Character Inventory. Our results suggest that genetic polymorphisms of DRD4 and DRD3 may well be associated with personality traits, and that conflicting findings to date may arise from the problem of phenotype definition.     

Lack of association between polymorphisms of the dopamine D4 receptor gene and personality

Recent studies have suggested a role of two polymorphisms of the dopamine D(4) receptor gene (DRD4 exon III and -521C/T) in the modulation of personality traits such as "novelty seeking" or "extraversion", which are supposed to be modulated by individual differences in dopaminergic function. However, several replication studies have not provided positive findings. The present study was performed to further investigate whether DRD4 exon III and -521C/T are associated with individual differences in personality. One hundred and fifteen healthy German volunteers completed the NEO-Five-Factor Inventory (NEO-FFI) and were genotyped for the two DRD4 polymorphisms. We found no association between DRD4 exon III and -521C/T, respectively, and estimated novelty seeking, NEO-FFI extraversion or other personality factors. Our findings are in line with several earlier studies which have failed to replicate the initial association results. Hence, our data do not provide evidence for a role of DRD4 exon III and the -521C/T polymorphism in the modulation of novelty seeking and extraversion.     

DRD4 receptor gene exon III polymorphism in inpatient suicidal adolescents

Summary. Some studies have suggested possible association of the dopamine receptor subtype 4 (DRD4) gene exon III 48bp repeat polymorphism with novelty seeking behavior. As suicidal behavior in adolescents is linked to risk taking behavior, we evaluated the association of suicidality with DRD4 polymorphism in Israeli inpatient suicidal adolescents. Sixty-nine inpatient adolescents who recently attempted suicide were assessed by structured interview and rating scales for detailed clinical history, diagnoses, suicide intent and risk, impulsivity, violence, and depression. The frequency of DRD4 alleles was compared between the suicidal inpatients and 167 healthy control subjects. No significant association between the DRD4 polymorphism and suicidal behavior was found. Analysis of the suicide-related measures demonstrated a significant difference in depression severity between suicidal inpatients homozygote and heterozygote for the DRD4 alleles (p=0.003). The relevance of this finding to increased depression severity in suicidal adolescents, if replicated, is as yet unclear.     

Relationship between DRD4 polymorphism and lipid metabolism: what is the role of novelty seeking?

OBJECTIVE: This study examined the association of the dopamine receptor D4 (DRD4) gene polymorphism with the temperament dimension of novelty seeking (NS) on cardiovascular heart disease risk factors [the levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides]. METHOD: From the ongoing population-based study of 'Cardiovascular Risk in Young Finns', 125 participants were DRD4 genotyped in 1997 and responded to the NS scale of the Temperament and Character Inventory in 2001. Their cholesterol and triglyceride concentrations were assessed in 2001. RESULTS: Having a 2- or 5-allele DRD4 polymorphism was related to high HDL cholesterol levels in men, but to low HDL cholesterol levels in women. NS was related to triglycerides in men and to LDL in women, but this was mediated by behavioral, age, and weight factors, and NS was not the underlying factor for the association between the polymorphism and lipids. CONCLUSION: Our preliminary findings suggest that there is a link between the dopaminergic receptor gene DRD4 and lipid metabolism, but this link is dependent on gender.     

Lack of association between a polymorphism in the promoter region of the dopamine D2 receptor and personality traits.

Disturbances of the dopaminergic neurotransmitter system have been associated with a personality trait that involves novelty seeking. A functional polymorphism in the promoter region of the dopamine D2 receptor gene (DRD2) has been reported to be associated with schizophrenia. We examined the association between this polymorphism in the DRD2 promoter region and personality traits, as assessed with the Tridimensional Personality Questionnaire. No significant association emerged between the polymorphism in the DRD2 promoter region and personality traits. Entering sex and age as covariates in an analysis of covariance did not change the results. These data fail to confirm an association between a polymorphism in the promoter region of the DRD2 and personality traits.     

Sexually dimorphic link between dopamine D2 receptor gene and neuroticism-anxiety

Prior theory-driven research probing the association between dopaminergic candidate genes and human personality has focused on the trait of novelty seeking. Here, we examined the association between the dopamine D2 receptor (DRD2) TaqI A polymorphism and two other personality traits, neuroticism-anxiety and agentic extraversion. We found no significant associations for agentic extraversion. However, for men, but not for women, we observed a strong and specific association between low neuroticism-anxiety and the A1+ allele of the DRD2 TaqI A polymorphism across two independent samples and across two alternative personality scales. We conclude that new theoretical models are needed to account for these and other recent reports of associations between neuroticism-anxiety and brain dopamine, which cannot be interpreted within the traditional framework.     

Temperament and character profiles and the dopamine D4 receptor gene in ADHD

OBJECTIVE: This study was designed to investigate the link among attention deficit hyperactivity disorder (ADHD) in adults, novelty-seeking temperament, and the 48-base pair (bp) dopamine D4 receptor (DRD4) gene variant. METHOD: This study drew from a larger molecular genetic study of ADHD in which the ascertainment criterion was having an affected sibling pair with ADHD. Parents (N=171) from 96 families provided data. Of the 171 parents, 56 (33%) had a lifetime history of ADHD, with 28 (50%) continuing to meet DSM-IV criteria (i.e., "persistent" ADHD). Latent variable modeling was used to test whether the DRD4 gene variant or Temperament and Character Inventory factors could predict ADHD. RESULTS: Using latent variable modeling, the authors were able to confirm the first-order factor structure of the Temperament and Character Inventory. Furthermore, novelty seeking predicted ADHD lifetime diagnosis (R(2)=26%), while the DRD4 gene variant independently predicted ADHD (R(2)=5%) but not novelty seeking. CONCLUSIONS: In this unique sample of parents from multiply affected ADHD families, novelty seeking and the 48-bp DRD4 variant were associated with a lifetime history of ADHD. However, the association between novelty seeking and ADHD does not appear to be due to variation in the 48-bp DRD4 variant.     

Association between the dopamine D4 receptor (DRD4) exon III polymorphism and measures of Novelty Seeking in a German population.

Since the observation of an association between the dopamine D4 receptor (DRD4) exon III polymorphism and the temperament trait of Novelty Seeking,1 replication studies have yielded both positive2-5 and negative6-12 results. This raised the question whether the initial findings must be regarded as false positives.13 However, demographic or methodological differences between studies may have obscured the small effect of the DRD4 polymorphism on Novelty Seeking.14 Examination of clinical or older cohorts may have led to an underestimation of possible associations due to a restricted variation of Novelty Seeking in these cohorts. The use of different questionnaires provides another source of variation. In order to replicate the initial findings as precisely as possible, a cohort of 136 healthy, young volunteers was genotyped, and Novelty Seeking was ascertained using the TPQ.15,16 In addition, further aspects of novelty seeking behavior have been ascertained through additional trait measures. We could observe the reported association between long DRD4 alleles and significantly elevated scores (age- and sex-residualized) on the TPQ-Novelty Seeking total scale as well as on two of the subscales, Exploratory Excitability and Extravagance. The results provide further confirmation for the role of the DRD4 exon III polymorphism in modulation of Novelty Seeking. In addition, the pattern of associations between the polymorphism and other scales suggests that this polymorphism has its effect on exploratory, extravagant, and extraverted, rather than on impulsive and monotony-avoidant subtypes of Novelty Seeking.     

Dopamine D4 receptor exon III genotype influence on the auditory evoked novelty P3

The functional implications of the dopamine D4 receptor gene (DRD4) exon III polymorphism and its role in the modulation of temperament and in the pathophysiology of psychiatric disorders are still a matter of debate. Based on evidence from animal studies, we hypothesised that this polymorphism is involved in the modulation of the cortical response to novelty as reflected by the auditory evoked novelty P3 event-related potential. In a sample of 46 healthy volunteers, we observed an interactive effect of DRD4 exon III genotype and the eye-blink rate, a measure of central dopaminergic activity, on the novelty P3. These findings suggest that the DRD4 exon III polymorphism influences the processing of novelty and that this influence depends on tonic dopaminergic activity.     

Association of dopamine D4 receptor (<Emphasis Type="Italic">DRD4</Emphasis>) exon III repeat polymorphism with temperament in 3-year-old infants

The long forms of the dopamine D4 receptor (DRD4) exon III repeat polymorphism (L-DRD4) have been linked in some studies to the adult personality trait of novelty seeking (NS), as well as to infant personality traits related to interest and activity. The current investigation extends the results of our previous longitudinal study on 1- to 5-month-old neonates assessed by the Early and Revised Infancy Temperament Questionnaire (EITQ/RITQ), in which we found a significant correlation between the DRD4 polymorphism and the adaptability trait at 1 month of age. In this study, we examined the relationship between children′s behavior at 3 years of age, measured with the Toddler Temperament Scale (TTS), and DRD4 exon III repeat polymorphism. We found a significant association between the behavioral dimension of intensity of reaction and DRD4 genotypes. Current data failed to confirm the association with the adaptability trait. None of the extraversion and/or exploratory behavior measures was related to the L-DRD4 allele, as expected. In contrast, children with 4/7 genotypes showed worse response to new stimuli compared with 4/4 genotypes. This study corroborates only in part previous results on the link between the DRD4 gene and human temperament.     

The dopamine D4 receptor gene exon III polymorphism is associated with novelty seeking in 15-year-old males from a high-risk community sample

Summary. In recent years, studies focussing on a possible association between the dopamine D4 receptor (DRD4) gene exon III polymorphism and the personality trait of novelty seeking (NS) have yielded inconsistent results. The present study sought to examine the association of the DRD4-7r allele with NS in a sample of 303 15-year-old adolescents (144 males, 159 females) using data from a high-risk community sample. The Junior Temperament and Character Inventory – JTCI/12–18 was administered to assess dimensions of adolescent temperament. Males in the DRD4-7r allele group scored significantly higher on the NS (p=.002) and the harm avoidance (p=.045) scales than males without this allele. In females no association with temperament was observed. This association could not be explained by the presence of either an attention-deficit/hyperactivity disorder (ADHD) or a DRD4 by ADHD interaction.     

Nature and nurture in novelty seeking

A sample of children (n=92), derived from a representative population sample of healthy young Finns (n=2149), was studied from childhood to adulthood over 14 years to determine whether the childhood environment moderated the effect of dopamine receptor gene (DRD4) polymorphism on novelty seeking (NS). A significant interaction between the DRD4 alleles and environmental variables was observed. When the childhood-rearing environment was more hostile (emotionally distant, low tolerance of the child's normal activity, and strict discipline), the participants carrying any two- or five-repeat alleles of the DRD4 gene had a significantly greater risk of exhibiting NS scores that were above the 10th percentile on a population distribution of 2149 adult Finnish women and men. The genotype had no effects on NS when the childhood environment was more favorable. Although the results are preliminary, pending replication, they nevertheless provide important information on the long-term effects of nurture and nature on NS temperament.     

The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis.

BACKGROUND: We conducted a meta-analysis to re-evaluate the role of the dopamine D4 receptor gene 48-base-pair- repeat (DRD4) polymorphism in mood disorders. METHODS: DRD4 allele frequencies were compared between 917 patients with unipolar (UP) or bipolar affective disorder (BP) and 1164 control subjects from 12 samples, using the Cochrane Review Manager. RESULTS: An association was found between all mood disorder groups and DRD4.2. After correcting for multiple testing, the association between DRD4.2 and BP dropped to insignificance; however, the evidence of an association between the DRD4.2 allele and UP (p < .001) and the combined group (p < .001) remained. There was no evidence for heterogeneity or publication bias. CONCLUSIONS: These findings suggest that the DRD4.2 allele is a risk allele for depression symptomatology. Meta-analysis may be a valuable objective tool for a quantitative summary of evidence for association studies in psychiatric genetics.     

Association of the DRD4 exon III polymorphism with smoking in fifteen-year-olds: a mediating role for novelty seeking?

OBJECTIVE: This study was designed to examine the role of DNA variants of the dopamine D4 receptor gene (DRD4) in smoking experimentation in adolescents and to determine the extent to which novelty seeking (NS) could account for a possible effect of DRD4 on tobacco use. METHOD: Participants were from a longitudinal study of an original birth cohort (born 1986-1988) of 384 children from a high-risk community sample. At age 15 years, adolescents completed a self-report questionnaire measuring tobacco consumption and temperament (Junior Temperament and Character Inventory). DNA was taken from 303 participants (144 males, 159 females) and genotyped for the DRD4 exon III polymorphism. RESULTS: DRD4 was associated with smoking status and NS in males but not in females. Males with the seven repeat allele exhibited more smoking involvement (p < .002) and scored higher in NS (p < .002) than males without this allele. In addition, elevated tobacco use was related to a higher level of NS in both males and females (p < .001). Multiple regression analyses revealed that NS mediated the relationship between DRD4 and smoking in males. CONCLUSIONS: These findings highlight the importance of considering the mechanisms underlying the association between genetic factors and tobacco use separately by gender and, possibly, by developmental period.     

Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder.

OBJECTIVE: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. METHOD: Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. RESULTS: For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. CONCLUSIONS: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.     

“He who sees things grow from the beginning will have the finest view of them” A systematic review of genetic studies on psychological traits in infancy

This paper reviews the studies that have aimed to identify genes influencing psychological traits in infancy (from birth to age 12 months). The review also addresses why genetic research in infancy is worthwhile and what genetic approaches such as genome-wide association studies and next generation sequencing could offer infant genetics. The results revealed that: (a) all studies (N = 26) have employed a candidate gene association design; (b) existing studies have most commonly focused on the Dopamine receptor D4 (DRD4) and the Serotonin transporter promoter (5-HTTLPR) gene polymorphisms; (c) phenotypes that have been assessed are temperament, attachment, and attention. Two further studies included both temperament and electrophysiological markers; (d) among many unreplicated findings, the most promising result appeared to be an association between the long DRD4 polymorphism and several “positive” temperament characteristics from birth to 4-months of age and at 12-months of age. It is concluded that, to date, there are limited, and mixed, findings regarding the possible association of genes with psychological phenotypes in infancy.