7-repeat Carriers Research Articles

Chronic Stressors and Adolescents\u2019 Externalizing Problems: Genetic Moderation by Dopamine Receptor D4. The TRAILS Study

The existing literature does not provide consistent evidence that carriers of the Dopamine D4 Receptor 7-repeat allele are more sensitive to adverse environmental influences, resulting in enhanced externalizing problems, compared to noncarriers. One explanation is that the adverse influences examined in prior studies were not severe, chronic, or distressing enough to reveal individual differences in sensitivity reflected by DRD4–7R. This study examined whether the 7-repeat allele moderated the association between chronic stressors capturing multiple stressful aspects of individuals’ lives and externalizing problems in adolescence. We expected that chronic stressor levels would be associated with externalizing levels only in 7-repeat carriers. Using Linear Mixed Models, we analyzed data from 1621 Dutch adolescents (52.2% boys), obtained in three measurement waves (mean age approximately 11, 13.5, and 16 years) from the TRacking Adolescents’ Individual Lives Survey (TRAILS) population-based birth cohort and the parallel clinic-referred cohort. Across informants, we found that higher levels of chronic stressors were related to higher externalizing levels in 7-repeat carriers but not in noncarriers, as hypothesized. Although previous studies on the 7-repeat allele as a moderator of environmental influences on adolescents’ externalizing problems have not convincingly demonstrated individual differences in sensitivity to adverse environmental influences, our findings suggest that adolescent carriers of the Dopamine D4 Receptor 7-repeat allele are more sensitive to chronic, multi-context stressors than noncarriers.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

Adolescent behavioral and neural reward sensitivity: a test of the differential susceptibility theory.

Little is known about the causes of individual differences in reward sensitivity. We investigated gene–environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes.

Season of birth, the dopamine D4 receptor gene and emotional eating in males and females. Evidence of a genetic plasticity factor?

Emotional eating has a female preponderance and an understanding of possible genetic and environmental underpinnings is still in the early stages. The current study focuses on the possible role of the dopamine D4 receptor (DRD4) ‘plasticity’ gene in emotional eating and the possible moderator effects of sex and season of birth therein. We tested this in two samples (n = 93 and n = 586) of male and female Caucasian adults by genotyping DRD4 and assessing self-reported emotional eating. Participants were defined as high risk carriers if they had at least one long (7-repeat) allele, which confers hypo-function to DRD4. We also ran analyses that grouped 2- and 7-repeat carriers together. In the first sample there only was a moderator effect of sex. In the second sample there also was a 3 way interaction between season of birth, sex and genotype. In line with the idea that the Drd4 gene functions as a plasticity gene that affects the sensitivity to environmental influences, the moderator effect of sex was only found for the participants born in fall. Only in females the hypo-functional variants of DRD4 were associated with significantly higher degrees of emotional eating. Furthermore, the sex × genotype effects were somewhat stronger when the 2-repeat allele was grouped together with the 7-repeat allele. Our data suggest that DRD4 hypo-functional genetic variants are associated with emotional eating, only in females.

DRD4 polymorphism moderates the effect of alcohol consumption on social bonding.

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse.

Dopamine D4 Receptor Exon III Polymorphism, Adverse Life Events and Personality Traits in a Nonclinical German Adult Sample

Personality and temperament embrace a wide area of both psychological and behavioral processes which are also based on disposition. A functional polymorphism in exon III of the dopamine D4 receptor gene (DRD4) has been a highly suspect genetic marker for personality in spite of ambiguous results. The present study aimed to further elucidate the relationship between DRD4, negative life events and personality in a representative nonclinical sample. Hundred sixty-seven Germans completed the NEO Five-Factor Inventory, the Tridimensional Personality Questionnaire and the California Adult Q-Sort. A factor analysis revealed 3 factors: emotional stability, social orientation and impulsivity. DNA from buccal cells was genotyped for the DRD4 variable-number tandem-repeat exon III polymorphism with respect to presence versus absence of the DRD4 7-repeat allele. Adverse life events were assessed by means of the Adverse Life Events Scale. Men carrying the DRD4 7-repeat allele were more impulsive than those without. Male 7-repeat carriers were more emotionally instable than others, but only when they experienced a large amount of negative life events. No genotype-personality relationships were found for women. The results indicate gender-specific influences of the DRD4 gene on human behavior and invite researchers to further investigate gene-environment correlations on personality traits.

Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity

Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsivity consists of two dissociable components that previous studies have failed to separate: functional and dysfunctional impulsivity. We compared participants with a genetic predisposition to have relatively high striatal DA levels (DAT1 9-repeat carriers, DRD2 C957T T/T homozygotes, and DRD4 7-repeat carriers) with participants with other genetic predispositions. We predicted that the first group would show high scores of dysfunctional, but not functional, self-reported impulsivity and greater difficulty in inhibiting a behavioral response to a stop-signal, a behavioral measure of impulsivity. In a sample of 130 healthy adults, we studied the relation between DAT1, DRD4, and C957T polymorphism at the DRD2 gene (polymorphisms related to striatal DA) and catechol-Omethyltransferase (COMT) Val158Met (a polymorphism related to frontal DA) on self-reported dysfunctional and functional impulsivity, assessed by the Dickman impulsivity inventory (DII), and the efficiency of inhibitory control, assessed by the stop-signal paradigm. DRD2 C957T T/T homozygotes and DRD4 7-repeat carriers indeed had significantly higher scores on self-reported dysfunctional, but not functional, impulsivity. T/T homozygotes were also less efficient in inhibiting prepotent responses. Our findings support the claim that dopaminergic variation affects dysfunctional impulsivity. This is in line with the notion that the over-supply of striatal DA might weaken inhibitory pathways, thereby enhancing the activation of, and the competition between responses.

A Birth-Season/DRD4 Gene Interaction Predicts Weight Gain and Obesity in Women with Seasonal Affective Disorder: A Seasonal Thrifty Phenotype Hypothesis

We have recently described an association between the hypofunctional 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), weight gain, and obesity in women with seasonal affective disorder (SAD). In the current study, we examined whether season-of-birth might interact with the 7R allele to influence body weight regulation in SAD. In 182 female probands with SAD, we performed an analysis of covariance predicting maximum lifetime body mass index (BMI) with both the exon-3 variable number of tandem repeat polymorphism of DRD4 and season-of-birth as independent variables, and age as the covariate. The overall model was highly significant (F = 4.42, df = 8, 173, p < 0.0001) with season-of-birth predicting maximal lifetime BMI both on its own and in its interaction with the 7R allele. The latter finding was attributable to 7-repeat carriers born in the spring (N = 17), who had a mean maximal lifetime BMI of 33.7 kg/m2 (SD 8.6), compared to 26.7 kg/m2 (SD 5.4) for all other probands combined (N = 165) (F = 20.01, df = 1, 179, p < 0.0001). The lifetime rate of obesity (maximal BMI > 30 kg/m2) was also significantly higher in the 7R/spring birth group (9/17=52.9% vs 32/165=19.4%; chi2 = 9.94, df = 1, p = 0.002; odds ratio = 4.68, 95% CI = 1.67-13.07). These data may reflect a novel gene-environment interaction, during early brain development, which establishes an increased risk for obesity in women with SAD. Although the mechanism for season-of-birth effects in psychiatric disorders is unknown, a characteristic pattern of melatonin exposure during the second and third trimesters may be of particular relevance in this study population. We speculate that these data may reflect the vestigial expression of a seasonal thrifty phenotype that contributed to the positive selection of the 7R allele over the past 40,000 years.