DRD4 7R Allele Research Articles

Abstract 5216: The effect of polymorphisms in DAT1 and DRD4 on dietary intake during chemotherapy for childhood leukemia

Abstract Outcomes of acute lymphoblastic leukemia (ALL) are associated with both host and environmental factors. We hypothesized that there is also an interaction between them, with genetic variants influencing dietary choices. The dopamine transporter 1 (DAT1) and D4 subtype of the dopamine receptor (DRD4) genes are polymorphic, with a variable number of nucleotide repeats (VNTR) that affect dopaminergic neurotransmission, and reward circuitry for food cravings. Specifically, the 9-tandem repeats (9R) allele of DAT1 and the 7-tandem repeats (7R) allele of DRD4 are risk factors for eating disorders or undereating behavior in children. The goal of this study was to determine whether these polymorphisms are associated with altered dietary intake during therapy for childhood ALL. DNA was isolated from peripheral blood mononuclear cells collected from 439 children being treated on Dana Farber Cancer Institute ALL Consortium Protocol 05-001 (NCT00400946). Target alleles in DAT1 and DRD4 were determined using PCR product length analysis. Each subject was classified as having either zero or at least one copy of the target alleles. Dietary intake was previously determined using food frequency questionnaires collected at three timepoints: time of diagnosis, end of induction, and continuation therapy. As previously published dietary composition in fat and carbohydrate differed significantly among three timepoints. There was no significant difference between those with or without the target alleles in DAT1 or DRD4 in percent from fat or percent from carbohydrate at any of the three timepoints. However, significant differences were observed when dietary intake was compared to the Dietary Reference Intake (DRI). Notably, a greater portion of male participants with DAT1 9R polymorphism had fat consumption below the DRI at the time of diagnosis. On the contrary, significantly decreased portion of females with DAT1 9R had fat consumption below the DRI during continuation therapy. When compared to normative values, a significantly increased number of children had total calorie consumption below DRI during induction therapy. The DRD4 7R polymorphism was associated with fat intake below DRI during induction therapy in males. However, neither DAT1 nor DRD4 polymorphisms were related to variation in carbohydrates consumption. In addition, a greater portion of participants that carry both DAT1 and DRD4 polymorphism exhibited a trend toward undereating behavior in fat intake compared to the controls. Our results are the first to indicate that DAT1 and DRD4 polymorphisms are associated with altered dietary intake during chemotherapy for childhood ALL. Future study will further elucidate whether this modulation is associated with changes in their body weight, BMI, glucose level, and disease relapse. Citation Format: Jing Wen, Arul Duggimpudi, Shengguo Li, Elena Ladas, Kara M. Kelly, Peter D. Cole. The effect of polymorphisms in DAT1 and DRD4 on dietary intake during chemotherapy for childhood leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5216.

The effect of the 7R allele at the DRD4 locus on risk tolerance is independent of background risk in Senegalese fishermen

It has been shown that living in risky environments, as well as having a risky occupation, can moderate risk-tolerance. Despite the involvement of dopamine in the expectation of reward described by neurobiologists, a GWAS study was not able to demonstrate a genetic contribution of genes involved in the dopaminergic pathway in risk attitudes and gene candidate studies gave contrasting results. We test the possibility that a genetic effect of the DRD4-7R allele in risk-taking behavior could be modulated by environmental factors. We show that the increase in risk-tolerance due to the 7R allele is independent of the environmental risk in two populations in Northern Senegal, one of which is exposed to a very high risk due to dangerous fishing.

The effects of increased dopamine-levels on attentional control during reading and reading comprehension

The aim of the present study was to gain insight into the neurobiological processes, particularly the dopaminergic processes, underlying attentional control during reading and reading comprehension. In order to test the effects of increased levels of dopamine (DA) in the brain, female university students (N = 80), half of them being carriers of the DRD4-7R allele and half of them not, participated in a double-blind placebo-controlled within-subjects experiment in which they were orally administered levodopa or a placebo before reading a text. After reading the text, participants reported on their attentional control during reading and completed comprehension questions. Pharmacologically increasing DA levels in the brain negatively influenced reading comprehension. This effect was moderate (ηp2 = .13). No interaction effects of condition and DRD4 genotype were found, for either attentional control or reading comprehension. Exploratory analyses showed that increased DA levels in the brain positively influenced fluctuations in attentional control, but only in a group of slow readers. No effects of increased DA were found for the two other attentional control measures used in the present study and no effects of increased DA on attentional control were found for fast readers. Results are discussed from the perspective of the inverted U-shape theory and the possible dopamine-related mechanisms.

Reduced Prefrontal Gyrification in Carriers of the Dopamine D4 Receptor 7-Repeat Allele With Attention Deficit/Hyperactivity Disorder: A Preliminary Report.

Objective: Structural and functional abnormalities have been noted in the prefrontal cortex of individuals with neurodevelopmental disorders such as attention deficit/hyperactivity disorder (ADHD). Cortical thickness and gyrification, both of which have been reported as abnormal in the prefrontal cortex in ADHD, are thought to be modulated by genetic influences during neural development. This study aimed to investigate the effects of a polymorphism of the dopamine DRD4 gene (the 7-repeat (7R) “risk” allele) on thickness and gyrification as distinct parameters of prefrontal cortical structure in children with ADHD. Method: Structural images and genetic samples were obtained from 49 children aged 9–15 years (25 with ADHD and 24 matched controls), and measures of cortical thickness and gyrification for inferior, middle, and superior frontal cortex were calculated. Results: A significant interaction between diagnosis and genotype on prefrontal gyrification was observed, largely driven by reduced inferior frontal gyrification in patients who carried the DRD4 7R allele. Furthermore, inferior frontal gyrification—but not thickness—related to everyday executive functioning in 7R allele carriers across groups. Conclusions: Prefrontal gyrification is reduced in children with ADHD who also carry the DRD4 7R allele, and it relates to critical functional skills in the executive domain in carriers of the risk allele. More broadly, these effects highlight the importance of considering precise neurodevelopmental mechanisms through which risk alleles influence cortical neurogenesis and migration.

Effects of DRD2 splicing-regulatory polymorphism and DRD4 48bp VNTR on crack cocaine addiction.

There is evidence that dopamine receptors D2 (DRD2) and D4 (DRD4) polymorphisms may influence substance use disorders (SUD) susceptibility both individually and through their influence in the formation of DRD2-DRD4 heteromers. The dopaminergic role on the vulnerability to addiction appears to be influenced by sex. A cross-sectional study with 307 crack cocaine addicts and 770 controls was conducted. The influence of DRD2 rs2283265 and DRD4 48bp VNTR in exon 3 variants, as well as their interaction on crack cocaine addiction susceptibility and severity were evaluated in women and men separately. An association between the DRD2 T allele and crack cocaine addiction was found in women. In this same group, interaction analysis demonstrated that the presence of DRD2-T allele and concomitant absence of DRD4-7R allele were associated with risk for crack cocaine addiction. No influence of DRD2 and DRD4 variants was observed in men regarding addiction severity. This study reinforces the role of dopaminergic genes in externalizing behaviors, especially the influence of DRD2-DRD4 interaction on SUD. This is the fourth sample that independently associated the DRD2-DRD4 interaction with SUD itself or related disorders. In addition, our findings point out to a potential difference of dopaminergic neurotransmission across sex influencing addiction susceptibility.

Relations between three dopaminergic system genes, school attachment, and adolescent delinquency.

Both environmental factors and genetic variation, particularly in genes responsible for the dopaminergic system such as DRD4, DRD2, and DAT1 (SLC6A3), affect adolescent delinquency. The school context, despite its developmental importance, has been overlooked in gene-environment research. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (NICHD ECCYD), this study examined key interactions between school attachment and (a) each of the DRD4, DRD2, and DAT1 (SLC6A3) genotypes; and (b) a polygenic score. Results indicate that there is a main effect of school attachment, unlike genetic variation, on delinquency. Interestingly, there are important interactive effects of school attachment and dopaminergic genotypes on delinquency. Carriers of the DRD2-A1 allele were differentially affected by both positive and negative school environments, whereas DAT1-10R carriers fared the same as 9R homozygotes in poorer and moderate school environments, but fared disproportionately better in more positive environments. Contrary to expectations, youth without the DRD4-7R allele were particularly affected by the school environment. These findings contribute to the literature considering the roles of both context and genes in delinquency research, and inform our understanding of the individual-level traits that influence sensitivity to particular contexts. (PsycINFO Database Record

A DRD4 gene by maternal sensitivity interaction predicts risk for overweight or obesity in two independent cohorts of preschool children.

Recent evidence suggests that early exposure to low maternal sensitivity is a risk factor for obesity in children and adolescents. A separate line of study shows that the seven-repeat (7R) allele of the dopamine-4 receptor gene (DRD4) increases susceptibility to environmental factors including maternal sensitivity. The current study integrates these lines of work by examining whether preschoolers carrying the 7R allele are more vulnerable to low maternal sensitivity as it relates to overweight/obesity risk. The Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) project in Canada was used as the discovery cohort (N=203), while the Generation R study in the Netherlands was used as a replication sample (N=270). Regression models to predict both continuous BMI z-scores and membership in any higher BMI category based on established World Health Organization (WHO) cutoffs for 48months of age were completed. In both cohorts, there was a significant maternal sensitivity by DRD4 by sex interaction predicting higher body mass indices and/or obesity risk. As hypothesized, post hoc testing revealed an inverse relationship between maternal sensitivity and body mass indices in 7R allele carriers relative to noncarriers. This finding was strongest in girls in the Canadian cohort and in boys in the Dutch cohort. Many children who carry the 7R allele of DRD4 appear to be more influenced by maternal sensitivity as it relates to overweight/obesity risk, consistent with a plasticity effect. Given the relatively small sample sizes available for these analyses, further replications will be needed to confirm and extend these results.

Dopamine Receptor Gene DRD4 7-Repeat Allele X Maternal Sensitivity Interaction on Child Externalizing Behavior Problems: Independent Replication of Effects at 18 Months

The DRD4 VNTR has been associated with child behavior problems in interaction with maternal insensitivity in European and American cohorts of preschoolers, with the 7-repeat (7R) allele associated with greater problems. We sought to replicate and expand these findings by examining effects on reports of child behavior problems at 18 months. A 63 family sample with data for observed maternal sensitivity ratings, DRD4 VNTR genotype, and maternal report of child behavior problems at 18-months was used in this preliminary analysis. Maternal sensitivity was measured at 6-months of age using laboratory observational measures (free-play and a teaching task). Maternal report of toddler behavior was obtained at 18-months via the standard Child Behavior Checklist, and infant genotype on the DRD4 VNTR was obtained using PCR. Infants carrying the DRD4 7R allele showed greater effects of maternal insensitivity than non-carriers for behavioral problems at 18-months. We replicated previous findings of association of infant DRD4 x maternal sensitivity interactions with child Externalizing problems in the European-ancestry sample (N = 42) in a median split of maternal sensitivity (p = .00011, eta2 = .329) and in regression analyses controlling for maternal age, maternal depression, and child gender in European ancestry (B = -3.4, SE 1.33, p = .01) and the total sample (B = -2.2, SE 1.02, p = .02). Exploratory analyses also found evidence of DRD4 x maternal sensitivity interaction with the CBCL ADHD scale. These findings replicate in an independent cohort DRD4 x maternal insensitivity interaction effect on child externalizing behavior problems at 18 months, further supporting the role of the DRD4 genotype in differential sensitivity to parenting.

Age and DRD4 Genotype Moderate Associations Between Stimulant Treatment History and Cortex Structure in Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) has been associated with dopaminergic imbalance and subtle volume decreases in the brain. Stimulants acutely enhance dopaminergic neurotransmission. Long-term effects of prolonged manipulation of the dopaminergic system on brain structure remain poorly understood; they could be beneficial or unfavorable and could be moderated by common genetic variants and/or age. In a large observational ADHD cohort study (N= 316), the effects of cumulative stimulant treatment, genotype (for DAT1 haplotype and DRD4 variants), and treatment-by-genotype interactions on striatal, frontal, and hippocampal volumes and their interactions with age were evaluated. No main effects of treatment were found. Associations between treatment and bilateral frontal and left hippocampal volume depended on DRD4 genotype and age. At a younger age and lower treatment levels, but not at a younger age and higher treatment levels, carriers of the DRD4 7R allele showed decreased frontal cortex volumes. At an older age, carriers and non-carriers showed smaller frontal volumes irrespective of treatment history. Left hippocampal volume was similar to that in controls at average treatment levels and increased with treatment only in carriers of the DRD4 risk allele and at a younger age. No interaction effects were found in the striatum. Carriers of the DRD4 risk allele at a younger age might be sensitive to cortical remodeling after stimulant treatment. The cross-sectional nature of this study warrants cautious interpretation of age effects. The present findings, although of small effect size, might ultimately contribute to optimal care for individuals with ADHD.

Interacting effects of maternal responsiveness, infant regulatory problems and dopamine D4 receptor gene in the development of dysregulation during childhood: A longitudinal analysis

Recent longitudinal studies have indicated that affective and behavioral dysregulation in childhood is associated with an increased risk for various negative outcomes in later life. However, few studies to date have examined early mechanisms preceding dysregulation during early childhood. Aim of this study was to elucidate early mechanisms relating to dysregulation in later life using data from an epidemiological cohort study on the long-term outcome of early risk factors from birth to adulthood. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness was evaluated by trained raters. Infant regulatory problems were assessed on the basis of a parent interview and direct observation by trained raters. At age 8 and 11 years, 290 children (139 males) were rated on the Child Behavior Checklist (CBCL). Additionally, participants were genotyped for the dopamine D4 receptor (DRD4) exon 3 VNTR polymorphism. A significant three-way interaction between maternal responsiveness, DRD4 genotype and infant regulatory problems was detected predicting the CBCL-dysregulation profile (CBCL-DP). Carriers of the DRD4 7r allele with regulatory problems at age 3 months showed significantly more behavior problems associated with the CBCL-DP during childhood when exposed to less maternal responsiveness. In contrast, no effect of maternal responsiveness was observed in DRD4 7r carriers without infant regulatory problems and in non-carriers of the DRD4 7r allele. This prospective longitudinal study extends earlier findings regarding the association of the CBCL-DP with early parenting and later psychopathology, introducing both DRD4 genotype and infant regulatory problems as important moderators.

Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence

Insensitive and unresponsive caregiving during infancy has been linked to externalizing behavior problems during childhood and adolescence. The 7-repeat (7r) allele of the dopamine D4 receptor (DRD4) gene has meta-analytically been associated with a heightened susceptibility to adverse as well as supportive environments. In the present study, we examined long-term effects of early maternal care, DRD4 genotype and the interaction thereof on externalizing and internalizing psychopathology during adolescence. As part of an ongoing epidemiological cohort study, early maternal care was assessed at child's age 3 months during a nursing and playing situation. In a sample of 296 offspring, externalizing and internalizing symptoms were assessed using a psychiatric interview conducted at age 15 years. Parents additionally filled out a questionnaire on their children's psychopathic behaviors. Results indicated that adolescents with the DRD4 7r allele who experienced less responsive and stimulating early maternal care exhibited more symptoms of ADHD and CD/ODD as well as higher levels of psychopathic behavior. In accordance with the hypothesis of differential susceptibility, 7r allele carriers showed fewer ADHD symptoms and lower levels of psychopathic behavior when exposed to especially beneficial early caregiving. In contrast, individuals without the DRD4 7r allele proved to be insensitive to the effects of early maternal care. This study replicates earlier findings with regard to an interaction between DRD4 genotype and early caregiving on externalizing behavior problems in preschoolers. It is the first one to imply continuity of this effect until adolescence.

Association between the seven-repeat allele of the dopamine-4 receptor gene (DRD4) and spontaneous food intake in pre-school children

Background: Studies in adults show associations between the hypofunctional seven-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), increased eating behaviour and/or obesity, particularly in females. We examined whether 7R is associated with total caloric intake and/or food choices in pre-schoolers. Methods: 150 four-year-old children taking part in a birth cohort study in Canada were administered a snack test meal in a laboratory setting. Mothers also filled out a food frequency questionnaire to address childrens’ habitual food consumption. Total caloric and individual macronutrient intakes during the snack meal and specific types of foods as reported in the food diaries were compared across 7R allele carriers vs. non-carriers, using current BMI as a co-variate. Results: We found significant sex by genotype interactions for fat and protein intake during the snack test. Post hoc testing revealed that in girls, but not boys, 7R carriers ate more fat and protein than did non-carriers. Based on the food diaries, across both sexes, 7R carriers consumed more portions of ice cream and less vegetables, eggs, nuts and whole bread, suggesting a less healthy pattern of habitual food consumption. Conclusion: The 7R allele of DRD4 influences macronutrient intakes and specific food choices as early as four years of age. The specific pattern of results further suggests that prior associations between the 7R allele and adult overeating/obesity may originate in food choices observable in the preschool years. Longitudinal follow-up of these children will help establish the relevance of these findings for obesity risk and prevention.

The association between creativity and 7R polymorphism in the dopamine receptor D4 gene (DRD4)

Creativity can be defined as the ability to produce responses that are both novel and appropriate. One way to assess creativity is to measure divergent thinking (DT) abilities that involve generating multiple novel and meaningful responses to open-ended questions. DT abilities have been shown to be associated with dopaminergic (DA) activity, and impaired DT has been reported in populations with DA dysfunctions. Given the strong association between DT and the DA system, the current study examined a group of healthy individuals (N = 185) to determine the role of repeat polymorphism in exon3 of the DRD4 gene in creativity. The results show that individuals carrying the DRD4-7R allele scored significantly lower on tests of DT, particularly on the flexibility dimension of DT, compared to non-carriers. The current findings link creative cognition to the DA system and suggest that DA dysfunctions in neurological and psychiatric disorders may account for impaired creativity and cognitive flexibility in these individuals.

Dopamine Genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and Executive Function: Their Interaction with Obesity

Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions.

Gene-Environment Interaction and the Intergenerational Transmission of Parenting: Testing the Differential-Susceptibility Hypothesis

The current study evaluated the differential-susceptibility hypothesis in explaining the intergenerational transmission of parenting, using data from the National Longitudinal Study of Adolescent Health (Add Health). Exposure to maternal parenting was measured prospectively when respondents were adolescents and parental stress was measured when they were parents themselves, some 14 years later, on average. Cumulative-genetic plasticity was measured by dominantly coding the presence of putative plasticity alleles from four genes: the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, and the short allele of 5HTTLPR. Results showed that the more plasticity alleles individuals carried (range 0-4), the more that parenting experienced in adolescence predicted future parenting experience. Those respondents with the most plasticity alleles not only experienced the highest levels of parental stress when exposed to negative maternal parenting in adolescence but the lowest levels when exposed to positive maternal parenting in adolescence. These results indicate that differential susceptibility is operative in the case of the intergenerational transmission of parenting, which could explain why estimates of such transmission have proven so modest in studies which fail to consider GXE interactions.

DRD4 genotype moderates the impact of parental problems on unresolved loss or trauma

In the current study we tested whether the dopamine receptor D4 (DRD4) genotype moderates the association of experienced parental problems during childhood (e.g., parental depression, marital discord) with unresolved loss or trauma during the Adult Attachment Interview. To test the specificity of this moderation the role of the serotonin transporter gene promoter (5-HTTLPR) was also examined. Subjects were 124 adopted adults (mean age 39 years). Participants with the DRD4-7 repeat (7R) allele who experienced parental problems had the highest scores for unresolved loss or trauma whereas participants with DRD4-7R who did not experience parental problems showed the lowest ratings. Among participants without DRD4-7R, the parental problems during childhood did not make a difference. 5-HTTLPR did not moderate the relation between parental problems and unresolved loss or trauma. Our study shows heightened susceptibility to environmental influences for carriers of the DRD4-7R allele, and suggests that the interplay between specific dopamine-related genes and family contexts leads to more or less successful coping with adverse childhood experiences.

Cumulative-genetic plasticity, parenting and adolescent self-regulation

The capacity to control or regulate one's emotions, cognitions and behavior is central to competent functioning, with limitations in these abilities associated with developmental problems. Parenting appears to influence such self-regulation. Here the differential-susceptibility hypothesis is tested that the more putative 'plasticity alleles' adolescents carry, the more positively and negatively influenced they will be by, respectively, supportive and unsupportive parenting. One thousand, five hundred and eighty-six (1586) adolescents (n = 754 males; n = 832 females) enrolled in the American Add Health project were scored in terms of how many of 5 putative 'plasticity alleles' they carried - the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, the short allele of 5HTTLPR, and the 2R/3R alleles of MAOA. Then the effect of the resultant index (ranging from 0 to 5) of cumulative-genetic plasticity in moderating effects of parenting on adolescent self-regulation was evaluated. Consistent with differential susceptibility, the more plasticity alleles males (but not females) carried, the more and less self-regulation they manifested under, respectively, supportive and unsupportive parenting conditions. Adolescent males appear to vary for genetic reasons in their susceptibility to parenting vis-à-vis self-regulation, perhaps due to epistatic and/or epigenetic processes. G×E research may benefit from compositing candidate genes. To afford comparative evaluation of differential-susceptibility vs. diathesis-stress models of environmental action, future G×E work should focus on positive as well as negative environmental conditions and developmental outcomes.

Meta‐analysis of the heterogeneity in association of DRD4 7‐repeat allele and AD/HD: Stronger association with AD/HD combined type

The purpose of this meta-analysis was to examine whether association studies between attention deficit/hyperactivity disorder (AD/HD) and the dopamine receptor 4 gene 7-repeat (DRD4 7R) allele vary systematically based on study characteristics. A total of 27 empirical studies with 28 distinct samples using either case-control or family-based association analyses were included. Consistent with previous meta-analytic work [Gizer et al. (2009), Hum Genet 126:51-90], the DRD4 7R allele was associated with AD/HD across studies (OR = 1.33; 95% CI = 1.16-1.53, z = 4.04, P = 0.00005) and there was significant systematic variability among studies (Q = 54.24; P = 0.001; I(2) = 50.22). To account for the variability among studies, sample and study level covariates were examined. No differences in overall effect size emerged between family-based and case-control studies. However, the risk allele frequency in the control population accounted for a significant portion of the variance in overall effect size within case-control studies. In addition, evidence for the association between the DRD4 7R allele and distinct AD/HD subtypes emerged across family-based and case-control studies. The proportion of AD/HD, combined type individuals within the AD/HD sample was associated with a significant increase in the magnitude of association between the DRD4 7R allele and AD/HD. Conversely, an increase in the proportion of AD/HD, predominantly inattentive type individuals within the AD/HD sample was associated with a decrease in study effect size. Implications regarding AD/HD etiological and phenotypic heterogeneity are discussed.

A Season-of-Birth/DRD4 Interaction Predicts Maximal Body Mass Index in Women with Bulimia Nervosa

We have earlier reported that season of birth interacts with the hypofunctional 7-repeat (7R) allele of the dopamine-4 receptor gene (DRD4) to promote weight gain and obesity in women with seasonal affective disorder (SAD). This study examined whether this gene-environment interaction influences body weight regulation in women with bulimia nervosa (BN). In 188 female probands with BN, we performed an analysis of covariance predicting maximum lifetime body mass index (BMI) using season-of-birth, DRD4 genotype (7R present/absent), and past history of anorexia nervosa (yes/no) as independent variables, and age at maximum weight as the co-variate. Consistent with our SAD study, the birth-season x DRD4 interaction was a significant predictor of maximal BMI. Although in SAD, the spring-birth/7R+ group had markedly elevated maximal BMIs and high rates of obesity, in this BN sample, the fall-birth/7R+ group exhibited the highest BMI values (N=17: mean maximal BMI=28.2 kg/m(2) (SE 0.9) vs 25.2 kg/ m(2) (SE 0.3) for all other probands combined (N=171); p=0.002). The lifetime rate of obesity (BMI>30) was also higher in the fall-birth/7R+ vs 'other' group (29.9 vs 8.8%, respectively, p=0.008). These data offer further evidence that season of birth interacts with the 7R allele of DRD4 to influence body weight regulation in female overeating populations.

From Regulatory Problems in Infancy to Attention-Deficit/Hyperactivity Disorder in Childhood: A Moderating Role for the Dopamine D4 Receptor Gene?

To examine whether the dopamine receptor D4 gene (DRD4) exon III VNTR moderates the risk of infants with regulatory disorders for developing attention-deficit/hyperactivity disorder (ADHD) later in childhood. In a prospective longitudinal study of children at risk for later psychopathology, 300 participants were assessed for regulatory problems in infancy, DRD4 genotype, and ADHD symptoms and diagnoses from childhood to adolescence. To examine a potential moderating effect on ADHD measures, linear and logistic regressions were computed. Models were fit for the main effects of the DRD4 genotype (presence or absence of the 7r allele) and regulatory problems (presence or absence), with the addition of the interaction term. All models were controlled for sex, family adversity, and obstetric risk status. In children without the DRD4-7r allele, a history of regulatory problems in infancy was unrelated to later ADHD. But in children with regulatory problems in infancy, the additional presence of the DRD4-7r allele increased the risk for ADHD in childhood. The DRD4 genotype seems to moderate the association between regulatory problems in infancy and later ADHD. A replication study is needed before further conclusions can be drawn, however.