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Candidate genes for novelty-seeking: a meta-analysis of association studies of DRD4 exon III and COMT Val158Met
Abstract
Objective:
Two widely studied genetic polymorphisms in the dopaminergic system [DRD4 exon III variable number of tandem repeat (VNTR) and COMT Val158Met] have been reported to be associated with novelty-seeking, but the results have been highly inconsistent. Therefore, a meta-analysis of the associations between these two polymorphisms and novelty-seeking was conducted.
Participants and methods:
For DRD4, 24 studies comprising 27 samples and including 4933 participants were selected. Genotype grouping, sex, mean age, ethnicity, and sample characteristics were examined as moderators. For COMT, nine studies comprising 13 samples and including 2633 participants were selected. Sex, mean age, ethnicity, and sample characteristics were included as moderators. We also tested for possible publication bias.
Results:
The significant association between the DRD4 polymorphism and novelty-seeking was supported, but no association was found between the COMT polymorphism and novelty-seeking. In addition, our findings revealed that sex and age both directly moderate the relationship between DRD4 and novelty-seeking. Meanwhile, ethnicity can interact with age, sex, and genotype grouping, and age and sex can interact with each other, to moderate the association between the DRD4 exon III VNTR polymorphism and novelty-seeking.
Conclusion:
Our results provide evidence of association between the DRD4 exon III VNTR polymorphism and novelty-seeking, which is inconsistent with the results of previous meta-analysis. Furthermore, several direct and indirect moderators are also identified to explain contradictory results in the existing literature. However, our results regarding COMT are consistent with those of previous meta-analysis.
... which subsequently has a positive effect on romantic relationships. The 7R allele is thought to be associated with a reduced ability of DRD4 to bind dopamine and a greater need for risk-taking behaviors, more diverse sexual behaviors, a greater desire for children early in love relationships, and novelty-seeking (He et al., 2018;Acevedo et al., 2020). It seems possible that individuals with a higher number of 7R alleles of the DRD4 gene tend to be more romantically intense in short-term relationships but less able to maintain relationships in the longer term (Minkov and Bond, 2015). ...
... There is sufficient empirical support for the critical role of the dopaminergic system in the formation and maintenance of romantic relationships. For example, the receptor variant DRD4-7R is associated with features of sexual behavior, the desire for more diverse sexual experiences, higher levels of promiscuity, and a higher intensity of romantic relationships in the short term, such as the initial period of relationship formation (Halley et al., 2016;He et al., 2018;Acevedo et al., 2020). Regarding the dopamine-and catecholamine-related signaling pathway, the studies analyzed in this review focused on three dopamine receptor genes (DRD1, DRD2, and DRD4) and the catechol-O-methyltransferase (COMT) gene. ...
Introduction: Couples’ relationships defined by a complex interaction between the two partners and their intrapersonal traits. Romantic; relationships and love are associated with marital satisfaction and stability, as well as couples’ happiness and health. Personality traits influence romantic relationships and, personality influenced by genetical and non-genetically factors. The roles of non-genetically factors such as socioeconomic position and external appearance have revealed in determining the quality of romantic relationships.
Methods: We; performed a scoping systematic review to assess the association between genetics and epigenetic factors and romantic relationship. Relevant articles were identified by PubMed, EMBASE, Web of Science, Scopus, and the APA PsycInfo searching between inception and 4 June 2022.
Results: Different studies evaluated the associated polymorphisms in 15 different genes or chromosomal regions. In the first step; we classified them into four groups: (1) Oxytocin-related signaling pathway ( OXTR , CD38 , and AVPR1A ); (2) Serotonin-related signaling pathway ( SLC6A4 , HTR1A , and HTR2A ); (3) Dopamine and catecholamine-related signaling pathway ( DRD1 , DRD2 , DRD4 , ANKK1 , and COMT ); and (4) other genes ( HLA , GABRA2 , OPRM1 , and Y-DNA haplogroup D-M55). Then, we evaluated and extracted significant polymorphisms that affect couple adjustment and romantic relationships.
Discussion: Overall, the findings suggest that genetic and epigenetics variants play a key role in marital adjustment and romantic relationships over time.
... VA Author Manuscript VA Author Manuscript [11]. Furthermore, these researchers exhibited a correlation of the DRD4 gene with Self-Transcendence, the association with NS was not found in their sample of SUD [12]. ...
It is with a saddened heart that we are dedicating this article to the loving memory of our dear departed friend and associate B. William Downs. Bill was well known in the nutritional space worldwide for his major contributions to the health and welfare of millions around the globe. The founder of Victory Nutrition International (VNI) in conjunction with Kim Downs, as well as so many contributions to scientific literature, to those that knew him personally will forever be touched. Bill was a highly spirited human with a never ending love for caring and helping so many individuals. To know Bill is to walk in the face of a music lover playing drums, trained as a martial artist, and riding through the winds of a Beamer driven by an iconic man driven to victory. Our hearts may be saddened but Bills spirit to those that know him will be forever. In this article we discuss and review some potential futuristic concepts and technological advancements in terms of geneospirituality engineering to help prevent relapse and or even protect against an unwanted predisposition to RDS behaviors. Futuristic development may contribute to an attenuation of both DNA antecedents as well as epigenetic reward system insults leading to unwanted substance and non-substance addictive behaviors.
... (Ausmees et al., 2021) and other adventure sports, but also to consume exotic meals and be involved in illegal activities (Aluja, Garcia, & Garcia, 2003;Zuckerman, 1994). Several meta-analyses have also confirmed significant associations between novelty-or excitementseeking and DRD4 (He, Martin, Zhu, & Liu, 2018;Munafò, Yalcin, Willis-Owen, & Flint, 2008), the so-called Wanderlust gene, which is believed to be responsible for the urge to travel and migrate (Chen, Burton, Greenberger, & Dmitrieva, 1999;Eisenberg, Campbell, Gray, & Sorenson, 2008). However, when interpreting these findings one should be constantly mindful of the fact that age outperformed-and mostly by a large margin-the effect of personality traits on travelling abroad for all examined traits. ...
... Heritability estimates for the TCI scales range from 30-60% [21,22]. During the past decades, the theory driven conceptualisation of the TCI-temperament and -character dimensions has been discussed and evaluated by a variety of phenotypic and genetic studies [21][22][23][24][25][26][27]. The proposed temperament traits have been found to be associated with several psychiatric disorders. ...
Background
Up to now several subtypes of social anxiety disorder (SAD) have been proposed.
Methods
In the present study, we used a cluster analytic approach to identify qualitatively different subgroups of SAD based on temperament characteristics, that is, harm avoidance (HA) and novelty seeking (NS) dimensions of Cloninger’s Temperament and Character Inventory.
Results
Based on a large, diverse clinical sample ( n = 575), we found evidence for two distinct subgroups of SAD: a larger (59%) prototypic, inhibited cluster characterized by high HA and low NS, and a smaller atypic, and comparatively more impulsive cluster characterized by medium to high HA and increased NS. The subgroups differed regarding a variety of sociodemographic and clinical variables. While the prototypic SAD subtype suffered from more severe SAD and depressive symptoms, suicidal ideation, and reduced social functioning, the atypic NS subtype showcased higher reproductive behaviour, self-directedness and -transcendence, comparatively. Additional hierarchical logistic regression highlights the contribution of age and education.
Conclusions
Our results valuably extend previous evidence for the existence of at least two distinct subtypes of SAD. A better knowledge of the characteristic differences in prototypic behaviour, personality, coping strategies and comorbidities between the identified (and further) subtypes can contribute to the development of effective prevention interventions and promotes the conceptualization of tailored treatments.
... R. Cloninger et al., 2019). Thus, it might be speculated that these personality traits represent not only priming but also predisposing factors and that, when looking at the polygenetic aspects of DOA, future studies should focus not only on immune related features (Lecendreux et al., 2003;Heidbreder et al., 2016), and on slow-wave related (Zald et al., 2008) or apnea-related genes (Guilleminault et al., 2005), but also on genetic components of human personality (e.g., reward seeking, He et al., 2018). Third, the current study has the advantage to detect personality traits during a period of relative plasticity for the development of personality of an individual (Zohar et al., 2019). ...
Introduction:
Disorders of arousal (DOA) are parasomnias that emerge from incomplete arousal out of Non-Rem Sleep (NREM) and lead to a broad variety of emotional and motor behaviours. Increasing evidence supports the hypothesis that specific psychopathological traits contribute to the multifactorial origin of these phenomena. The aim of the current multicenter study was to compare the personality profile of children and adolescents with and without DOA using the Junior Temperament and Character Inventory (JTCI).
Methods:
We enrolled 36 patients with a diagnosis of DOA (mean age of 11 ± 3 years, 64% males), and 36 healthy age and gender matched control subjects (mean age of 11.2 ± 3.6, years, 67% males). Their parents completed the Paris Arousal Disorder Severity Scale (PADSS), the Sleep Disturbance Scale for Children (SDSC) and the JTCI.
Results:
Patients with DOA reached significantly higher levels compared to their control group in total PADSS (p < 0.0001) and in total SDSC (p < 0.0001). They also displayed higher scores in novelty seeking (p = 0.005), harm avoidance (p = 0.01), self-transcendence (p = 0.006) JTCI subscales, and lower scores on the self-directedness subscale (p = 0.004).
Conclusion:
Our pediatric sample with DOA exhibited specific psychobiological personality traits compared to age and gender matched subjects without DOA. These results shed light on new possible etiopathogenetic mechanisms, as TCI traits have been linked to specific genetic variants and brain circuits, like the reward system. Prospective studies are required to assess the effect of targeted psychological/psychiatric treatment on DOA symptomatology.
... Comings., et al. had identified the specific role of the DA D4 receptor (DRD4) gene in spirituality [10]. The DRD4 gene associates with Novelty-Seeking (NS) [11]. Although they identified a correlation of the DRD4 gene with Self-Transcendence, the association with NS did not emerge in their sample of substance abusers [12]. ...
This commentary explores the neurobiology of spirituality and asks whether it is possible or desirable to apply genetic engineering to increase human spiritual and religious experience - (gene-spirituality) to deal better with the ever-increasing catastrophes that face humanity? Neurological connections between spirituality and reward genes, reward deficiencies (RDS) (hypodopaminergia), the mirror neuron system, and the default mode network are examined. Some interventions from addiction medicine that may be useful to enhance the neuro-spirituality connectome identified as a cornerstone of the Purpose and Meaning of Life as Reward (PMLR) are identified as reasonable targets for interventions to treat RDS and balance DMN activity.
... The data from Western Societies showed that individuals who had the OXTR rs53576 GG genotype or had a spouse with the rs53576 GG genotype reported greater marital satisfaction and greater attachment security than individuals with AA or AG genotypes (Monin et al., 2019). According to other findings, the DRD4E3*7R genetic polymorphism has been negatively correlated with romantic love (Acevedo et al., 2020) and positively with promiscuity (Garcia et al., 2010;He et al., 2018). Our gene candidate associations study, conducted in traditional rural East African population, pointed to similar allele/genotype makers concerning high/ low fertility in men and women. ...
Numerous factors, including family planning and modern contraception, disturb the potential associations between the number of children born and genetic factors in modern Western societies. The current progress of medicine and a relatively high level of well-being make it hard to test the association between children's survival rates and genetic factors in Western societies either. The goal of the current study was to reveal the possible associations between the number of children born and the number of children survived till the age of 5 y. by the time of our study with a set of six genetic polymorphisms associated with serotonin, dopamine, androgen oxytocin behavioral effects; and to test for sex-specific effects of these polymorphisms in a traditional rural sample from Arusha and Singida Districts of Northern Tanzania. The data on 965 healthy individuals (520 men and 415 women) from traditional rural communities with high reproduction profiles were collected. All participants provided information on the number of children born and survived, and other demographic information, as well as buccal epithelium samples for DNA analysis. The data were analyzed using GLM ANCOVA and the APSampler nonparametric methodology. The gene association effects on reproduction and infant survival in men and women were demonstrated. We suggest that sex differences revealed in this study are in line with sexual selection pressure on reproduction and parenting in traditional societies.
... First, several studies have examined moderation between DRD4 (presence/absence of the 7-repeat allele within the Exon 3 48 bp variable number of tandem repeats) and peer influences, including peer preference (Buil, Koot, Olthof, Nelson, & van Lier, 2015), victimization (DiLalla, Bersted, & John, 2015;Kretschmer, Dijkstra, Ormel, Verhults, & Veenstra, 2013), and prosociality (Kretschmer et al., 2013) in relation to adolescent conduct problem behaviors. These analyses were conducted with consideration of the association between DRD4 and novelty and reward seeking behaviors (He, Martin, Zhu, & Liu, 2018;Stice, Yokum, Burger, Epstein, & Smolen, 2012) that may make adolescents more susceptible to negative peer influence. There is some disagreement, however, about the putative susceptibility variant and the chronicity of environmental conditions required to demonstrate sensitivity (Kretschmer et al., 2013;Zandstra, Ormel, Hoekstra, & Hartman, 2018). ...
The most extensively studied influence on adolescent conduct problem behaviors is peers, and the literature points to genetics as one source of individual differences in peer influence. The purpose of this study was to test the hypothesis that an environmental sensitivity genetic index comprised of DRD4, 5‐HTTLPR, and GABRA2 variation would moderate the association between peer and adolescent conduct problems. Latent growth modeling was applied to PROSPER project longitudinal data from adolescents and their peers. Results showed the hypothesis was supported; adolescents with more copies of putative sensitivity alleles were more strongly influenced by their peers. The interaction form was consistent with differential susceptibility in follow‐up analyses. Strengths and weaknesses of genetic aggregates for sensitivity research are discussed.
... The dopamine receptor DRD4-7R gene variant is associated with novelty-seeking (He et al., 2018, meta-analysis;Munafo et al., 2008, meta-analysis), sexual behaviors such as a desire to have children earlier in life (Eisenberg et al., 2007), desire for a wider variety of sexual behaviors (Halley et al., 2016), higher rates of promiscuous behavior, and infidelity (Garcia et al., 2010). The DRD4-7R genetic polymorphism results in reduced binding for dopamine (Asghari et al., 1995), and thus some have speculated that individuals with this genetic variant generally feel less stimulated and crave novelty (He et al., 2018). Although our examination of DRD4-7R was exploratory, prior research studies suggest that this genetic variant is implicated in shortterm pair-bonding strategies (Minkov and Bond, 2015) which are useful for reproduction, but a potential obstacle for relationship maintenance. ...
In Western culture, romantic love is commonly a basis for marriage. Although it is associated with relationship satisfaction, stability, and individual well-being, many couples experience declines in romantic love. In newlyweds, specifically, changes in love predict marital outcomes. However, the biological mechanisms underlying the critical transition to marriage are unknown. Thus, for the first time, we explored the neural and genetic correlates of romantic love in newlyweds. Nineteen first-time newlyweds were scanned (with functional MRI) while viewing face images of the partner versus a familiar acquaintance, around the time of the wedding (T1) and 1 year after (T2). They also provided saliva samples for genetic analysis (AVPR1a rs3, OXTR rs53576, COMT rs4680, and DRD4-7R), and completed self-report measures of relationship quality including the Eros (romantic love) scale. We hypothesized that romantic love is a developed form of the mammalian drive to find, and keep, preferred mates; and that its maintenance is orchestrated by the brain's reward system. Results showed that, at both time points, romantic love maintenance (Eros difference score: T2-T1) was associated with activation of the dopamine-rich substantia nigra in response to face images of the partner. Interactions with vasopressin, oxytocin, and dopamine genes implicated in pair-bonding (AVPR1a rs3, OXTR rs53576, COMT rs4680, and DRD4-7R) also conferred strong activation in the dopamine-rich ventral tegmental area at both time points. Consistent with work highlighting the role of sexual intimacy in relationships, romantic love maintenance showed correlations in the paracentral lobule (genital region) and cortical areas involved in sensory and cognitive processing (occipital, angular gyrus, insular cortex). These findings suggest that romantic love, and its maintenance, are orchestrated by dopamine-, vasopressin- and oxytocin-rich brain regions, as seen in humans and other monogamous animals. We also provide genetic evidence of polymorphisms associated with oxytocin, vasopressin and dopamine function that affect the propensity to sustain romantic love in early stage marriages. We conclude that romantic love maintenance is part of a broad mammalian strategy for reproduction and long-term attachment that is influenced by basic reward circuitry, complex cognitive processes, and genetic factors.
Stress and genotype elicit changes in impulse control in a range of species that are attributable to adaptations in both the central and peripheral nervous system. We examined aspects of this mechanism in the horse by assessing the effect of a dopamine receptor genotype (DRD4) and central dopaminergic tone (measured via spontaneous blink rate [SBR] and behavioral initiation rate [BIR]), on measures of impulsivity, compulsivity (3-choice serial reaction time task) and sympathetic/ parasympathetic system balance (heart rate variability [HRV]). Genotype did not have a significant effect on any of the parameters measured. SBR but not BIR correlated significantly with levels of impulsivity. There was no clear association of HRV parameters with either measures of central dopaminergic activity or impulsivity/compulsivity. Overall, some elements of the data suggest that the horse may be a useful animal model for assessing the genetic and environmental factors that lead to the physiological and behavioral phenotype of human addiction, particularly when considering the relationship between central dopaminergic tone and impulsivity.
Exploration of novel environments has reliably been shown to enhance learning in rodents. More recently, these effects have been replicated in humans using virtual reality: Memory is enhanced after exploration of novel compared to familiar virtual environments. However, exploration of a novel versus familiar environment differs in another aspect. Navigating familiar territory can rely more on habits, while navigating new territory requires active decision-making. This difference in choices could contribute to the positive effects of novelty exploration on memory. In this study, we aimed to investigate this possibility. Participants familiarized with a virtual environment (day 1) and were exposed to this environment again (day 2 or 3) and to a novel environment (day 2 or 3). Participants either actively explored the environments or were passively exposed to the exploration behavior of another participant in virtual reality. After exposure to the environment, participants performed a word-learning task and filled out questionnaires regarding virtual presence and to estimate the novelty seeking personality trait. Mixed models suggested that memory performance was higher after participants actively explored versus were passively exposed to a novel environment, while these effects were reversed for a familiar environment. Bayesian statistics provided further weak evidence that memory performance was influenced by the interaction between novelty and exposure type. Taken together, our findings suggest that active exploration may contribute to novelty-induced memory benefits, but future studies need to confirm this finding.
Sports psychogenetics is a novel field of scientific research that aims to use genetic methods to investigate the nature and origins of individual differences in cognitive abilities and personal traits of athletes. This chapter describes the heritability estimates of psychological traits (e.g., cognitive ability, memory, reaction time, temperament), their potential relationship with success in sport, as well as polymorphisms of genes expressed in the nervous system, which might be associated with athlete status and personality. Despite success in discovery of genetic variants associated with intelligence and personality in non-athletic cohorts (more than 7000 DNA polymorphisms have been identified in candidate-gene or genome-wide association studies, involving large sample sizes), there has been limited progress to date in the field of sports psychogenetics. To date, 16psychogenetics-specific genetic markers have been reported to be associated with predisposition to specific sports (via case-control designs), and 12 markers have been linked with personality traits (via genotype-phenotype designs) in athletes. Future genetic research with large cohorts of athletes, with further validation and replication, will substantially contribute to the discovery of causal genetic variants (i.e., mutations and DNA polymorphisms) that may partly explain the heritability of athlete status and related psychological phenotypes.
Compared the factor structure of the Sensation-Seeking Scale (SSS) in English and American samples, and constructed a new form of the SSS, applicable to both groups. The English Ss consisted of 254 males and 639 females from the Maudsley Twin Register, ages 15–70 yrs. The American sample included 97 male and female undergraduates. Three of the 4 factors showed good cross-national and cross-sex reliability (i.e., significant and reasonably high resemblance between the 4 national and sex symbols). English and American males did not differ on the total SSS score, but American females scored higher than English females. Males in both countries scored higher than females on the total SSS score and on the Thrill and Adventure-Seeking and Disinhibition subscales. Significant age declines occurred for both sexes, particularly on Thrill and Adventure Seeking and Disinhibition. (24 ref)
Human personality traits which can be reliably measured by any of a number of rating scales, show a considerable heritable component. The tridimensional personality questionnaire (TPQ) is one such instrument and was designed by Cloninger to measure four distinct domains of temperament - Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence-that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger proposed that individual variations in the Novelty Seeking trait are mediated by genetic variability in dopamine transmission. Individuals who score higher than average on the TPQ Novelty Seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered and frugal. We now show that higher than average Novelty Seeking test scores in a group of 124 unrelated Israeli subjects are significantly associated with a particular exonic polymorphism, the 7 repeat allele in the locus for the D4 dopamine receptor gene (D4DR). The association of high Novelty Seeking and the 7-repeat allele was independent of ethnicity, sex or age of the subjects. This work, together with the accompanying confirmations in this issue, provides the first replicated association between a specific genetic locus involved in neurotransmission and a normal personality trait.
Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist) and measure the change in neurological indices of novelty processing. In separate drug and placebo sessions, participants completed a von Restorff task. Apomorphine speeded and potentiated the novelty-elicited N2, an Event-Related Potential (ERP) component thought to index early aspects of novelty detection, and caused novel-font words to be better recalled. Apomorphine also decreased the amplitude of the novelty-P3a. An increase in D1/D2 receptor activation thus appears to potentiate neural sensitivity to novel stimuli, causing this content to be better encoded.
Four experiments examined the influence of a stimulus presented after one response in a two-lever choice task. In Experiment
1, food-deprived rats trained on a concurrent variable-interval extinction schedule responded more often on the extinction
lever when such responding periodically produced a visual stimulus than when it did not. In Experiments 2 and 3, a similar
signal-induced enhancement effect was found even when food was delivered randomly with respect to responding on both levers
or when no food was presented. In Experiment 4, a response-contingent visual stimulus elevated responding to the lever on
which it was presented, but an auditory cue suppressed responding. These findings indicate that visual stimuli may possess
intrinsically reinforcing properties for rats.
Previous research has shown inconsistent findings regarding the relations between the functional Val158Met polymorphisms of the catechol-O-methyltransferase (COMT) gene and individual differences in personality traits. This study attempts to overcome some of the weaknesses of previous research, namely, small sample sizes, clinical samples, ethnic stratification, wide age ranges, neglecting sex differences, and single measures of personality traits. A large sample (n = 556, 250 male, 306 female) of healthy Chinese college students (mean age = 20.5 ± 1 years) was given a battery of personality scales, including the temperament and character inventory-revised, the behavioral inhibition system and behavioral approach system scale, the Beck depression inventory, and the Beck anxiety inventory. Factor analysis of the affect-related personality traits revealed two factors that corresponded to positive (PEM) and negative emotionality (NEM). We found a consistent COMT-by-sex interaction effect on affect-related personality traits. Compared with males with Met/Met alleles, males with Val/Val alleles showed significantly higher scores on NEM, but lower scores on PEM. Females, however, showed an opposite but nonsignificant pattern. Our results supported the role of the COMT gene in personality traits for males and contributed to the growing literature on sex differences in gene-behavior connections.
Declarative memory is remarkably adaptive in the way it maintains sensitivity to relative novelty in both unknown and highly familiar environments. However, the neural mechanisms underlying this contextual adaptation are poorly understood. On the basis of emerging links between novelty processing and reinforcement learning mechanisms, we hypothesized that responses to novelty will be adaptively scaled according to expected contextual probabilities of new and familiar events, in the same way that responses to prediction errors for rewards are scaled according to their expected range. Using functional magnetic resonance imaging in humans, we show that the influence of novelty and reward on memory formation in an incidental memory task is adaptively scaled and furthermore that the BOLD signal in orbital prefrontal and medial temporal cortices exhibits concomitant scaled adaptive coding. These findings demonstrate a new mechanism for adjusting gain and sensitivity in declarative memory in accordance with contextual probabilities and expectancies of future events.
Previous phenotypic factor analyses suggest that C. R. Cloninger's Tridimensional Personality Questionnaire (TPQ; 1987c) assesses 4 rather than 3 temperament dimensions. The purpose of this study was to determine whether Cloninger's revised 4-factor model showed incremental validity over his original model and to investigate the convergent and discriminant validity of Cloninger's dimensions in comparison to the personality dimensions proposed by H. J. Eysenck (1981) and J. A. Gray (1970). The sample included 2,420 women and 870 men (aged 50-96) from a volunteer population-based sample of twins. Joint phenotypic factor analyses supported Cloninger's 4-dimensional temperament model. A 4-dimensional genetical factor structure was also confirmed in genetic analyses of the TPQ higher order dimensions in women. For men only 3 genetic factors were necessary to explain the genetic variance among the TPQ dimensions.
Several recent studies, including two in this issue of Molecular Psychiatry, are continuing to explore the relationship between the dopamine D4 receptor repeat polymorphism (D4DR) and Novelty Seeking, a personality trait conspicuous in drug users and alcoholics.
In 1986 and 1987, Cloninger postulated the existence of the heritable behavioral trait of novelty seeking and its putative underpinnings in the dopaminergic systems of the ventral midbrain. Two widely reported studies found significant associations between novelty seeking and the type 4 dopamine receptor gene (DRD4), although a more recent study did not. The authors' objective was to investigate this association in two New Zealand samples.
The authors studied two nonoverlapping samples: subjects in a depression treatment trial (N = 86) and subjects from 14 pedigrees dense with alcoholism (N = 181). DRD4 genotyping was based on a standard protocol.
Novelty seeking and DRD4 were not statistically associated.
In these samples, there was no suggestion that the DRD4 polymorphism contributed to individual differences in the behavioral trait of novelty seeking.
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 (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT x 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR x D4DR (F = 6.18, P = 0.03) and COMT x 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.
It has been reported that the human temperament dimensions of novelty seeking and harm avoidance are associated with polymorphisms in the D(4) dopamine receptor gene (D4DR) and the serotonin-transporter-linked promoter region (5-HTTLPR), respectively. Although these findings are consistent with Cloninger's hypothesized psychobiological model of temperament and character, many studies failed to replicate these findings. In the present study the authors tested whether the psychobiological model taps the genetic architecture of personality by exploring associations between these candidate genes and the dimensions of the Temperament and Character Inventory and by examining its phenotypic structure.
Of the 946 male and female participants in the Baltimore Longitudinal Study of Aging to whom the Temperament and Character Inventory was administered, 587 were genotyped for a polymorphism with a 48-base-pair repeat in the D4DR gene and 425 were genotyped for a 44-base-pair insertion or deletion in the 5-HTTLPR polymorphism.
There was no significant association between D4DR polymorphisms and novelty seeking. The authors also failed to find an association between 5-HTTLPR polymorphisms and harm avoidance. The factor structure of the Temperament and Character Inventory did not reveal the hypothesized phenotypic structure.
This investigation produced no support for the temperament-character model at either the biological or psychological level.
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
A meta-analytical review of 20 studies (n = 3907) of the association between DRD4 polymorphism and novelty seeking suggests the following conclusions: (a) on average, there is no association between DRD4 polymorphism and novelty seeking (average d = 0.06 with 95% CI of +/- 0.09), where 13 reports suggest that the presence of longer alleles is associated with higher novelty seeking scores and seven reports suggest the opposite; (b) there is a true heterogeneity among the studies (ie, unknown moderators do exist) but the strength of the association between DRD4 polymorphism and novelty seeking in the presence of any (unknown) moderator is likely to be weak; (c) search for moderators has not yielded any reliable explanation for the variability among studies. We propose that to find such moderators, theory-driven research for potential interaction, coupled with larger sample sizes should be employed. The growing availability of powerful statistical techniques, high-throughput genotyping and large numbers of polymorphic markers such as single nucleotide polymorphisms makes such proposed studies increasingly feasible.
Sir – The initial findings of an association between the dopamine D4 receptor (DRD4) gene exon III polymorphism and the personality trait Novelty Seeking1,2 prompted a large number of follow-up studies.3 Nevertheless, there is still conflicting evidence whether the presence of the DRD4 exon III 7-repeat allele is associated with higher scores in Novelty Seeking. For example, our group confirmed this association in an earlier work,4 but we did not observe an association between DRD4 exon III and Novelty Seeking in a recent study,5 although both samples were drawn from the same population.
A meta-analysis was conducted on studies reporting data on associations between candidate genes and human personality. Studies reporting data for psychiatric populations (including organic disease and substance abuse) were excluded. A total of 46 studies contributed to the analysis. Pooled data using a fixed-effects model suggested significant associations between the 5HTT LPR, DRD4 c>t, DRD4 length, DRD2 A1/A2, DRD3 A1/A2 polymorphisms and personality traits. A multivariate analysis using a mixed-effects model and including age, sex and predominant ethnicity as covariates was applied to the analyses of 5HTT LPR and DRD4 length polymorphism data. Only the association between the 5HTT LPR polymorphism and avoidance traits remained significant (P=0.038). However, sensitivity analyses excluding data from studies reporting allele frequencies not in Hardy-Weinberg equilibrium and unpublished data resulted in this association no longer being significant. Implications for the design of future association studies of human personality are discussed, including the likely sample sizes that will be required to achieve sufficient power and the potential role of moderating variables such as sex.
Fibromyalgia (FMS) is a common syndrome consisting of diffuse aching, pain, or stiffness in the muscles or joints, accompanied by multiple tender points on examination. FMS patients are characterized by an atypical personality profile, high on harm avoidance and low on novelty seeking. The current study showed a decreased frequency in FMS of a dopamine D4 receptor polymorphism, the 7 repeat, associated in some studies with novelty seeking.
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.
Diverse phenotypic associations with the catechol-O-methyltransferase (COMT) Val158Met polymorphism have been reported. We suggest that some of the complex effects of this polymorphism be understood from the perspective of the tonic-phasic dopamine (DA) hypothesis. We hypothesize that the COMT Met allele (associated with low enzyme activity) results in increased levels of tonic DA and reciprocal reductions in phasic DA in subcortical regions and increased D1 transmission cortically. This pattern of effects is hypothesized to yield increased stability but decreased flexibility of neural network activation states that underlie important aspects of working memory and executive functions; these effects may be beneficial or detrimental depending on the phenotype, a range of endogenous factors, and environmental exigencies. The literature on phenotypic associations of the COMT Val158Met polymorphism is reviewed, highlighting areas where this hypothesis may have explanatory value, and pointing to possible directions for refinement of relevant phenotypes and experimental evaluation of this hypothesis.
The present study provides the first direct molecular genetics support for Gray's Reinforcement Sensitivity Theory (RST), which is one of the most influential biologically oriented personality theories. It was investigated whether the DRD2 TaqIA and the COMT polymorphisms were related to the dimensions of Gray's personality theory, as measured by the Carver and White BIS/BAS scales. In a sample of 295 healthy subjects results revealed significant DRD2xCOMT interactions (i.e. epistasis) for the total BAS scale (related to positive emotionality) and for the subscales Drive (D) and Fun Seeking (FS). High BAS scores were observed if the catabolic enzyme activity and the D2 receptor density as indicated by the two polymorphisms were in disequilibrium, i.e. in the presence of the Val-/A1- (low enzyme activity/high receptor density) or the Val+/A1+ (high enzyme activity/low receptor density) alleles. In a random subsample (n=48), it could be demonstrated that those allele combinations of COMT and DRD2 associated with high BAS scores also had significantly lower prolactin levels under resting conditions, indicating high dopamine activity, compared to those allele combinations with low BAS scores. Furthermore, two-way interactions of DRD2 TaqIAxsmoking status and of the Met allele of COMTxsmoking status on FS and Metxgender on BIS could be shown.
It was recently reported that an interaction of the dopamine D2 receptor (DRD2) and catechol-O-methyltransferase (COMT) influences the behavioural approach system--as measured using Carver and White's Behavioural Inhibition and Behavioural Approach System (BIS/BAS) scales--in a sample of healthy German subjects. The Temperament and Character Inventory (TCI), in particular the novelty seeking (NS) and harm avoidance (HA) scales, correlates moderately with the BIS/BAS measure. This study aimed to examine support for an association of DRD2 and COMT with behavioural activation, using the TCI within two independent samples of depressed outpatients (for both samples n = 146).
Two clinical samples of depressed patients were ascertained to assess the efficacy of two different pharmacotherapy and psychotherapy treatments. Analysis of variance (ANOVA) was used to analyse NS and HA scale and subscale scores with respect to gene loci within each clinical sample. Analysis of covariance were undertaken to examine the association of age and gender with NS and HA scores. An association of age group or gender with gene loci were explored using chi-squared tests, in each sample.
No significant effect of DRD2 or COMT, either independently or as an interaction, on NS or HA scores was observed, within either sample. Whilst age was significantly negatively associated with NS scores, including age in the two- and three-way interactions did not affect the significance of the association of personality with gene loci.
This study suggests that the COMT-DRD2 Equilibrium Model of Positive Emotionality recently proposed by Reuter and his colleagues is not applicable amongst currently depressed individuals, whose behavioural approach and inhibition tendencies have been assessed using the TCI.
The gene encoding cathechol-O-methyltransferase (COMT) contains a common functional missense polymorphism (Val158Met) that regulates dopamine in an allele-dependent manner. A pivotal role of dopamine neurotransmission in the prefrontal cortex has been implicated in drug-seeking behavior and related personality traits, such as sensation seeking, with some evidence for a gender-specific association. Here, we tested the hypothesis that the COMT Val158Met polymorphism modulates the personality dimension, sensation seeking, in a gender-dependent manner. Study sample included 214 male (age 38.1+/-12.6 years) and 218 female (age 36.1+/-13.6 years) healthy volunteers, who were assessed with Zuckerman's sensation-seeking scale and genotyped for the Val158Met polymorphism (dbSNP:rs4680). Univariate analysis of variance showed that the sensation seeking score was significantly affected by a COMT genotype x gender interaction (F=5.330, df=2, p=0.005). The Val158Met polymorphism was associated with the sensation seeking personality trait in women only. The highest scores in the sensation-seeking scale and in three of the four subscales were observed in female subjects with the Val/Val genotype relative to women carrying the Met allele. Our results suggest that high COMT enzyme activity associated with the Val allele predisposes to high sensation seeking scores in female subjects and add to increasing evidence for a gender specific role of COMT in normal and dysfunctional behavior.
Two variants in the dopamine D4 receptor (DRD4) gene have been reported to be associated with human approach-related traits such as novelty seeking and extraversion. However, the strength of evidence for this association remains uncertain.
We conducted a meta-analysis of published studies of the association between the DRD4 gene variable number of tandem repeats (VNTR) and C-521T polymorphisms and human approach-related personality traits, including novelty seeking, extraversion, and impulsivity, restricted to adult samples recruited from nonpsychiatric populations, and extended on this literature by attempting to confirm any evidence of association in a replication sample (n = 309) selected for extreme scores on the extraversion subscale of the Eysenck Personality Questionnaire from a large (n = 40,090) population-based sample.
Our initial meta-analysis supported the association of the DRD4 C-521T polymorphism, but not the VNTR polymorphism, with approach-related traits. This conclusion was qualified by evidence of significant publication bias and the failure to detect association in a replication sample comprising individuals at the extremes of the trait distribution. The association of the C-521T polymorphism observed in our initial meta-analysis was robust to the inclusion of these new data, but our revised meta-analysis indicated that the association was present for measures of novelty seeking and impulsivity but not for measures of extraversion.
The DRD4 gene may be associated with measures of novelty seeking and impulsivity but not extraversion. The association of the C-521T variant with these measures, if genuine, may account for up to 3% of phenotypic variance.
The relationship of various dimensions of temperament, measured by the Tridimensional Personality Questionnaire (TPQ), to polymorphisms of the D2 dopamine receptor (DRD2) and D4 dopamine receptor (DRD4) genes was determined in 119 healthy Caucasian boys who had not yet begun to consume alcohol and other drugs of abuse. Total Novelty Seeking score of the TPQ was significantly higher in boys having, in common, all three minor (A1,B1, and Intron 6 1) alleles of the DRD2 compared to boys without any of these alleles. Boys with the DRD4 7 repeat (7R) allele also had a significantly higher Novelty Seeking score than those without this allele. However, the greatest difference in Novelty Seeking score was found when boys having all three minor DRD2 alleles and the DRD4 7R allele were contrasted to those without any of these alleles. Neither the DRD2 nor the DRD4 polymorphisms differentiated total Harm Avoidance score. Whereas subjects having all three minor DRD2 alleles had a significantly higher Reward Dependence 2 (Persistence) score than subjects without any of these alleles, no significant difference in this personality score was found between subjects with and without the DRD4 7R allele. In conclusion, DRD2 and DRD4 polymorphisms individually associate with Novelty Seeking behavior. However, the combined DRD2 and DRD4 polymorphisms contribute more markedly to this behavior than when these two gene polymorphisms are individually considered. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:257–267, 1998. © 1998 Wiley-Liss, Inc.
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.
In this study, we investigated the association between dopamine receptor D4 (DRD4) exon III polymorphism and novelty seeking in 69 Japanese women. The group of subjects with long allele (≥5 repeats) exhibited significantly elevated novelty seeking scores in comparison with subjects lacking the long allele. By contrast, the scores for harm avoidance, reward dependence, and persistence were statistically indistinguishable in the two group of subjects. With regard to the subscales of novelty seeking, the scores for exploratory excitability and extravagance were significantly higher in subjects with the long allele than in subjects lacking the long allele. However, no significant associations with impulsiveness or disorderliness were recognized. Our results suggest that although long alleles of the polymorphic exon III repeats are low in the Japanese population, there is an association between long alleles of DRD4 exon III polymorphism and novelty seeking. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:469–471, 1999. © 1999 Wiley-Liss, Inc.
This study was designed to assess the association between novelty seeking and D4DR gene polymorphism in the Japanese population. The 48 bp repeat polymorphism in the third exon of the dopamine D4 receptor gene of 153 normal female students was correlated with personality feature results from the Japanese version of Cloninger's Temperament and Character Inventory. The Novelty Seeking subscale of Exploratory Excitability had a significant association with long alleles of the polymorphic exon III repeat sequence of D4DR. Our results suggest that there is an association between long alleles of the polymorphic exon III repeat sequence of D4DR and the personality traits of the Novelty Seeking subscale of Exploratory Excitability, regardless of racial differences in the frequencies of D4DR exon III repeat polymorphism. Am. J. Med. Genet. 74:501–503, 1997. © 1997 Wiley-Liss, Inc.
Although it is well-established that genetic variation is important in causing individual differences in many human personality traits or based on family, twin, and adoption studies, the first reports that specific genetic polymorphisms might influence a normal dimension of personality were only recently published. Specifically, two studies have described significant associations between a dopamine D4 receptor (D4DR) exon III 48-base pair (bp) insertion/deletion polymorphism and the personality traits of novelty-seeking and positive emotional experience [Benjamin et al. (1996): Nat Genet 12:81–84; Ebstein et al. (1996): Nat Genet 12:78–80]. The present study was undertaken to attempt to replicate these important and heuristic initial findings. Personality questionnaires measuring novelty-seeking and positive emotional experience were administered to 306 male and female young adult twins (monozygotic 92 pairs, dizygotic 61 pairs) from the general population, 281 of whom were genotyped for D4DR exon I and III polymorphisms. No significant associations were observed between novelty-seeking or positive emotional experience and these D4DR polymorphisms. This failure to replicate the initial reports seems unlikely to represent measurement or genetic differences across studies, although environmental differences may be possible. Adequate statistical power in the present study suggests that these results are unlikely to be statistical “false negatives” and instead may reduce confidence in the generality of the initial positive findings. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:44–48, 1998. © 1998 Wiley-Liss, Inc.
Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val(158)Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers.
Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val(158)Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls.
Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val(158)Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype.
Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.
Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found.
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.
The present study sought to integrate convergent lines of research on the associations among the dopamine D(4) receptor (DRD4) gene, novelty seeking and drinking behaviors with the overall goal of elucidating genetic influences on problematic drinking in young adulthood. Specifically, this study tested a model in which novelty seeking mediated the relationship between DRD4 variable number of tandem repeats (VNTR) genotype and problematic alcohol use. Participants (n = 90, 40 females) were heavy-drinking college students. Analyses using a structural equation modeling framework suggested that the significant direct path between DRD4 VNTR genotype and problematic alcohol use was reduced to a trend level in the context of a model that included novelty seeking as a mediator, thereby suggesting that the effects of DRD4 VNTR genotype on problematic alcohol use among heavy-drinking young adults were partially mediated by novelty seeking. Cross-group comparisons indicated that the relationships among the model variables were not significantly different in models for men versus women. These results extend recent findings of the association between this polymorphism of the DRD4 receptor gene, problematic alcohol use and novelty seeking. These findings may also help elucidate the specific pathways of risk associated with genetic influences on alcohol use and abuse phenotypes.
Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms. Kinetics of the methylation reaction of dopamine, (-)-noradrenaline, L-dopa, and 3,4-dihydroxybenzoic acid was studied in detail. Here, the catalytic number (Vmax) of S-COMT was somewhat higher than that of MB-COMT for all four substrates. The Km values varied considerably, depending on both substrate and enzyme form. S-COMT showed about 15 times higher Km values for catecholamines than MB-COMT. The distinctive difference between the enzyme forms was also the higher affinity of MB-COMT for the coenzyme S-adenosyl-L-methionine (AdoMet). The average dissociation constants Ks were 3.4 and 20.2 microM for MB-COMT and S-COMT, respectively. Comparison between the kinetic results and the atomic structure of S-COMT is presented, and a revised mechanism for the reaction cycle is discussed. Two recently published human COMT cDNA sequences differed in the position of S-COMT amino acid 108, the residue being either Val-108 [Lundström et al. (1991) DNA Cell. Biol. 10, 181-189] or Met-108 [Bertocci et al. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 1416-1420].(ABSTRACT TRUNCATED AT 250 WORDS)
Ebstein and colleagues have recently reported a significant association between the 7-repeat allele of the dopamine D4 receptor (D4DR) 16 amino acid repeat polymorphism and the personality trait of Novelty Seeking (NS) in 124 Israeli subjects. This study, and another study conducted in the US (although with a different personality measure) that observed a similar association, have generated wide interest in the identification of the genes involved in personality variation. We have determined D4DR genotypes in two groups of Finnish subjects; 193 psychiatrically screened normal controls and 138 alcoholic offenders and assessed NS with the Tridimensional Personality Questionnaire (TPQ). In normals, we find no significant association between NS and the 7-repeat allele despite similar allele frequencies and the use of the same personality measure as Ebstein et al. The group of alcoholic offenders have significantly higher NS than normals, however we fail to replicate the previous association in this group and, in fact, find a significant association in the opposite direction as previously observed. These data suggest that D4DR may require re-evaluation as a candidate gene for personality variation.
Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting protein structure in the D4 dopamine-receptor gene (DRD4) in a sample of 341 American subjects, of whom 224 are of primarily European ancestry and 117 are of primarily African ancestry. These subjects had diagnoses of substance dependence or personality disorder (PD) or were screened to exclude major psychiatric diagnosis. We found that, although the substance-dependent subjects had significantly higher novelty seeking than the control and PD subjects, they did not differ in DRD4*7R allele frequency. There was no association between any DRD4 polymorphism and novelty seeking in any population or diagnostic group, except for a significant association between the DRD4*7R allele and lower novelty seeking among European American females and African American substance abusers. The novelty seeking of subjects heterozygous for a null mutation did not differ from that of subjects with two functional alleles. We conclude that the most likely explanation of these results is that the DRD4 VNTR does not influence directly the trait of novelty seeking, in these samples.
Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients.
The presence of the seven-repeat allele of the VNTR in the exon 3 of the dopamine D4 receptor gene (DRD4) has been associated in healthy subjects to the personality trait of novelty seeking. The present study focuses these observations on a sample of Brazilian male alcoholics, evaluated on the temperament dimensions originally described by Cloninger. The genotypes observed are in agreement with those expected under Hardy-Weinberg equilibrium. Subjects with the seven-repeat allele manifest lower harm avoidance scores. No significant differences between subjects with or without the seven-repeat allele in the scores of novelty seeking or reward dependence were observed. The lack of association between novelty seeking and the DRD4 exon 3 polymorphism is further corroborated by the fact that the comorbid antisocial personality disorder is not associated to the presence of the seven-repeat allele. These results could be explained by a biological connection between the personality dimensions of novelty seeking and harm avoidance.
Dopamine is an important neurotransmitter involved in motor control, endocrine function, reward, cognition and emotion. Dopamine receptors belong to the superfamily of G protein-coupled receptors and play a crucial role in mediating the diverse effects of dopamine in the central nervous system (CNS). The dopaminergic system is implicated in disorders such as Parkinson's disease and addiction, and is the major target for antipsychotic medication in the treatment of schizophrenia. Molecular cloning studies a decade ago revealed the existence of five different dopamine receptor subtypes in mammalian species. While the presence of the abundantly expressed dopamine D(1) and D(2) receptors was predicted from biochemical and pharmacological work, the cloning of the less abundant dopamine D(3), D(4) and D(5) receptors was not anticipated. The identification of these novel dopamine receptor family members posed a challenge with respect to determining their precise physiological roles and identifying their potential as therapeutic targets for dopamine-related disorders. This review is focused on the accomplishments of one decade of research on the dopamine D(4) receptor. New insights into the biochemistry of the dopamine D(4) receptor include the discovery that this G protein-coupled receptor can directly interact with SH3 domains. At the physiological level, converging evidence from transgenic mouse work and human genetic studies suggests that this receptor has a role in exploratory behavior and as a genetic susceptibility factor for attention deficit hyperactivity disorder.
Recently, different research groups reported conflicting results with regard to an association of dopamine 4 receptor (DRD4) genotypes and the personality dimension of novelty seeking (NS). High scores for NS seemed to be associated with long alleles of a DRD4 polymorphism. Furthermore, an association between personality traits and the dopamine 2 (DRD2) receptor gene was reported. NS and persistence (PS) high scores seemed to be associated with alleles of DRD2. We examined 109 (78 female and 31 male) normal healthy individuals using Cloninger's Temperament and Character Inventory (TCI) in order to replicate these findings. We genotyped a 48 base pair variable number of tandem repeats (from two to eight repeats) polymorphism in the third exon of DRD4 and a Cys311Ser polymorphism in exon 7 of DRD2. We tested alleles and genotypes of DRD4 (allele 7 absent or present; genotype 4,4 versus 4,7), and Ser/Cys and Cys/Cys genotypes of DRD2 for associations with TCI values. NS and the alleles and genotypes of DRD4 did not show any association. In associating the genotypes of DRD2 with TCI scales (NS, harm avoidance, reward dependence and PS), we also found no association. Recent findings associating NS with DRD4 could not be replicated. With regard to DRD2, we tested a different polymorphism as published recently and could not find an association of TCI scales with the gene. The present results therefore do not provide evidence that the DRD2 and DRD4 receptor genes contribute a common and relevant effect to personality traits.
The seven-factor model of personality developed by Cloninger and colleagues describes personality as a function of developmental aspects of character superimposed on heritable dimensions of temperament. The objective of this study was to determine whether this model could be applied to early childhood. We tested a preschool version of the Temperament and Character Inventory (the preschool TCI) in 305 children aged 2-5 years. Exploratory factor analysis provided support for the presence of distinct domains of temperament (comprising four factors) and character (comprising three factors). The preschool TCI demonstrated high internal consistency for each of the seven factors (Cronbach's alpha values: 0.70-0.93). Inter-individual differences in novelty seeking, reward dependence and cooperativeness were highly preserved (Pearson's r values 0.75, 0.64 and 0.80, respectively) in 29 subjects who were studied over a 3-year period from toddlerhood to early school age. Future studies are warranted to test the extent to which early childhood measurements of the seven factors might predict the development of personality disorders.
Studies of the association between polymorphisms within and near the dopamine D4 receptor (DRD4) gene and novelty seeking (NS) have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship holds. We conducted three meta-analyses of existing studies to provide formal statistical measures of the strength of the DRD4-NS relationship. Results provided no support for a relationship between NS and the presence of the 7-repeat allele of the VNTR polymorphism. A small positive effect, however, was found for long repeats of the same polymorphism. The most promising findings were obtained for the relationship with the -521 C/T promoter polymorphism, for which the analysis showed an effect size of 0.32. The positive findings are consistent with a polygenic model of influence on fundamental personality dimensions.
To examine the relationship among nicotine, alcohol, and marijuana use; level of sensation seeking (SS); and pubertal development.
Subjects were early and middle adolescent males and females recruited from a psychiatric clinic (n = 77) and two general pediatric clinics (n = 131). SS was measured by using the Sensation Seeking Scale for Children. Pubertal development was measured with a modified Pubertal Development Scale that was completed by the adolescent and his/her parent about the adolescent. Adolescent self-reports of nicotine, alcohol, and marijuana use were also obtained using questionnaires.
SS was higher in males and females who reported nicotine and alcohol use and in males who reported marijuana use. SS was positively associated with pubertal development in males and females, even when controlling for age. Furthermore, SS mediated the relationship of pubertal development and drug use in males and females.
The observation that SS mediates the relationship between pubertal development and drug use in males and females may contribute to understanding changes in drug use that are seen during adolescence. In addition, SS is associated with drug use and is easily measured in a variety of clinical settings.
Polymorphism in exon III of the dopamine D4 receptor (DRD4) gene has been implicated to be associated with the human personality trait of novelty seeking (NS). For this study, we have investigated the possible association between 48-bp VNTR in exon III and -521 C/T SNP of the DRD4 and personality traits among young ( approximately 14 years of age) Korean female population. We found that the interaction between the two alleles of DRD4 polymorphism, 48-bp VNTR and -521 C/T, were significantly high on NS (F = 4.88, P = 0.029) and persistence (P) (F = 5.05, P = 0.027) personality scores, suggesting that the variants of DRD4 gene influence the NS and P (persistent) personality traits. When analyzed independently, however, the two different alleles of DRD4 polymorphisms, 48-bp VNTR and -521 C/T, there was no direct correlation with the personality traits.
The correlation between the D4 dopamine receptor gene (DRD4) and the D2 dopamine receptor gene (DRD2) polymorphisms was investigated with personality traits. For this study, homogeneous population consisting of 243 young alcohol- and drug-naive Koreans who were blood-unrelated with a mean age (+/-SD) of 13.87 (+/-0.30) years old was analyzed for the DRD4 and the DRD2 polymorphisms with their personality trait by Temperament and character inventory (TCI). The association between Novelty seeking (NS) score and DRD4 long alleles was only observed among the female subjects (t = 2.11, P = 0.037), but not in the male counter part. Female subjects who carried the DRD2 less frequent alleles (TaqI A1, TaqI B1, and Intron6 1) showed higher RD4 scores (dependence vs. independence) of Reward dependence (RD) than those without these alleles (P < 0.05). There was no interaction between DRD4 and DRD2 on the personality traits. These results, thus, confirmed the previous findings in which the long repeats of the DRD4-exon III polymorphism are related to NS personality trait, and also suggested that the DRD2 less frequent alleles were also associated with the reward-dependent trait.
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.
Catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) are both involved in the degradation of various biogenic amines which have been hypothesized to have a relationship with personality traits. The present study investigated the possible relationships between the genotypes of COMT Val158Met and MAOA-uVNTR polymorphisms and personality traits measured by the Temperament and Character Inventory (TCI). We recruited 286 normal, unrelated Korean subjects (138 males and 148 females). There were no associations between the COMT Val158Met genotypes or the TCI subscales in the male subjects. However, a significant correlation was observed between the COMT genotype and harm avoidance (HA, F=6.0, p=0.003) in females. Post hoc analyses showed that the subjects with the Met/Met genotype had the lowest mean HA (HA=13.8+/-5.7, p=0.02), Val/Met group had an intermediate mean HA score (HA=16.3+/-7.0, p=0.02), and Val/Val group had the highest mean HA value (HA=19.6+/-7.0, p=0.02). There were no associations between the MAOA-uVNTR and the TCI subscales in either the male or female subjects. These results suggest that genetic variants of the COMT Val158Met gene may play a role in HA in Korean females but not in males.
Previous research suggests that personality traits, particularly novelty seeking (NS), increase the risk of substance abuse. One possible explanation to account for this association relates to common genetic factors. The aim of this study was to examine whether allelic variants of the dopamine D4 receptor gene (DRD4) are associated with alcohol use in adolescents and to determine the extent to which these links are mediated by NS.
Three hundred three adolescents (144 male participants, 159 female participants, approximately 15 years old) from a high-risk community sample completed self-report questionnaires measuring alcohol intake and temperament (Junior Temperament and Character Inventory [JTCI]). DNA was genotyped for the DRD4 exon III polymorphism.
Male participants carrying the 7-repeat allele of DRD4 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking than male participants without this allele. Higher levels of NS were associated with higher alcohol intake in both genders. Multiple regression analyses support the role of NS in mediating the relationship between DRD4 and heavy drinking in male adolescents but not in female adolescents.
These findings extend previous work highlighting the significance of personality traits as a mediating factor between genetic susceptibility and substance use during the period of early experimental use.
Dopamine transmission is known to play an important role in the reinforcement system of the brain. Studies have identified dopamine system genes whose polymorphic variants have been linked with the intensity of psychological traits reflecting the tendency to form behaviors characterized by impulsivity and the need for additional stimulation. The aim of the present work was to seek associations between polymorphisms in the catechol-O-methyltransferase (COMT) and D4 dopamine receptor (DRD4) genes and personality traits in the Russian population. Studies of 130 subjects showed that carriers of the Met/Met genotype of the COMT gene had a greater intensity of the novelty-seeking trait than carriers of the Val/Val and Val/Met genotypes, though this association was seen only in women. In addition, the presence of the C allele of the DRD4 gene in carriers of the Met/Met genotype showed high levels of extraversion and hypomania. These results are consistent with current theoretical concepts of the regulation of dopamine transmission in the brain.