DRD4 Genotype Research Articles

ADHD symptoms across adolescence: the role of the family and school climate and the DRD4 and 5-HTTLPR genotype

We examined bidirectional relations between attention-deficit/hyperactivity disorder (ADHD) symptoms and family and school climate, and the possible role of DRD4 and/or 5-HTTLPR genotypes herein. Three-wave longitudinal data of 1860 adolescents (mean ages 11, 13.5, and 16 years) from the general population and clinic-referred cohort of TRacking Adolescents’ Individual Lives Survey were used. Using a multigroup Random Intercept Cross-Lagged Panel Model, we tested between-person (i.e., stable trait levels) and within-person (i.e., causal processes) associations across ADHD symptoms, family and school climate, and the extent to which these depended on genotype. Findings indicated no influence of genotype. Results did show significant between-person differences (ADHD symptoms with family climate r = .38; and school climate r = .23, p values < .001), indicating that higher stable levels of ADHD symptoms were associated with a less favorable family and school climate. Regarding within-person causal processes, ADHD symptoms predicted a less favorable family climate in early adolescence (β = .16, p < .01), while ADHD symptoms predicted a more favorable family climate in the later phase of adolescence (β = − .11, p < .01), a finding which we explain by normative developmental changes during adolescence. Overall, this study showed that negative associations between ADHD symptoms and both family and school climate are largely explained by stable between-person differences. We recommend applying the Random Intercept Cross-Lagged Path Model to developmental data to tease stable associations and change processes apart.

59 Genotypic effects of a Dopamine receptor type-2 SNP on growth and semen quality in beef bulls exposed to a dopamine agonist

Abstract Ergot alkaloids (EA) share similar structural properties to neurotransmitters and are able to elicit physiological responses in cattle that consume them by binding receptors such as the Dopamine type-2 receptor (DRD2). A single nucleotide polymorphism (SNP) in DRD2, previously found to be correlated to prolactin (PRL) serum concentrations was evaluated for impact on growth traits and semen quality parameters. Yearling beef bulls were allowed to graze a diet containing (E+) (n = 41) or lacking EA (E-) (n = 43) over a four-year study. Blood samples and semen were collected every 21 or 28 d. Semen motility, morphology, body condition score (BCS), and scrotal circumference (SC) were recorded. Prolactin (PRL) serum concentrations were assessed by radioimmunoassay (RIA). Bulls were sacrificed from the first year at the end of a 126-day period or 60 days after removal of treatment. Testicles and epididymis were collected and immunohistochemistry was performed on testis, epididymis, and sperm cells. Tissues and cells were incubated in the presence or absence of primary antibody against DRD2 with a DAPI counterstain. Isolation of DNA was performed on sperm pellets from semen collected using DNAzol (Thermo Fisher Scientific, Waltham, MA, USA). Amplification of the DRD2 SNP region was performed by PCR and resulting products were assessed for genotype through restriction fragment length polymorphism (RFLP) analysis. These data show the presence of DRD2 in the testis, epididymis, and sperm cells; however, semen quality and growth traits did not differ across DRD2 genotype or treatment. Body condition (P = 0.0009), SC (P = 0.0053), and semen velocity (P = 0.0398) differed across period. As expected, consumption of EA resulted in decreased prolactin serum concentrations (P = 0.0240).

30 Genotypic effects of a Dopamine receptor type-2 SNP on growth and semen quality in beef bulls exposed to a dopamine agonist

Abstract Ergot alkaloids (EA) share similar structural properties to neurotransmitters and are able to elicit physiological responses in cattle that consume them by binding receptors such as the Dopamine type-2 receptor (DRD2). A single nucleotide polymorphism (SNP) in DRD2, previously found to be correlated to prolactin (PRL) serum concentrations was evaluated for impact on growth traits and semen quality parameters. Yearling beef bulls were allowed to graze a diet containing (E+) (n = 41) or lacking EA (E-) (n = 43) over a four-year study. Blood samples and semen were collected every 21 or 28 d. Semen motility, morphology, body condition score (BCS) and scrotal circumference (SC) were recorded. Prolactin (PRL) serum concentrations were assessed by radioimmunoassay (RIA). Bulls were sacrificed from the first year at the end of a 126-day period or 60 days after removal of treatment. Testicles and epididymis were collected and immunohistochemistry was performed on testis, epididymis, and sperm cells. Tissues and cells were incubated in the presence or absence of primary antibody against DRD2 with a DAPI counterstain. Isolation of DNA was performed on sperm pellets from semen collected using DNAzol (Thermo Fisher Scientific, Waltham, MA, USA). Amplification of the DRD2 SNP region was performed by PCR and resulting products were assessed for genotype through restriction fragment length polymorphism (RFLP) analysis. These data show the presence of DRD2 in the testis, epididymis, and sperm cells; however, semen quality and growth traits did not differ across DRD2 genotype or treatment. Body condition (P = 0.0009), SC (P = 0.0053), and semen velocity (P = 0.0398) differed across period. As expected, consumption of EA resulted in decreased prolactin serum concentrations (P = 0.0240)

Bovine dopamine type-2 receptor SNP has no effect on growth, semen characteristics and prolactin concentrations in beef bulls treated with a dopamine agonist

A dopamine type-2 receptor (DRD2) SNP, previously found to be correlated with serum prolactin (PRL) concentrations in cattle, was evaluated for impact on growth traits, serum prolactin concentration, and semen quality. Over a four-year period, yearling beef bulls were allowed diets containing or lacking ergot alkaloids (EA). Every 21 or 28 d semen was collected for semen motility and morphology assessment and blood samples were collected to measure serum PRL concentrations. In addition, body condition score and scrotal circumference were evaluated. Serum PRL concentrations were assessed using a radioimmunoassay. In the first year, all bulls were sacrificed at the end of a 126-day study. Testicles and epididymis were collected at the end of the study or 60 days after removal from treatment. Immunohistochemistry was performed on testis, epididymis, and sperm cells, incubated with or without a primary antibody for DRD2 and counterstained with DAPI. Isolation of DNA was performed on sperm pellets using DNAzol (Thermo Fisher Scientific, Waltham, MA, USA) methods. Polymerase chain reaction was performed to amplify the region of the DRD2 gene containing the SNP of interest. The products were subjected to restriction fragment length polymorphism analysis. Further, all samples were subjected to genotyping using a custom Taqman genotyping assay (Applied Biosystems, Foster city, CA, USA). The presence of DRD2 was detected in the testis, epididymis, and sperm cells. The DRD2 genotype was not associated with semen quality, serum PRL, or growth traits. Consumption of EA resulted in lesser PRL serum concentrations but had no effect on values for other variable examined.

The association between perinatal hypoxia exposure and externalizing symptoms and children's decision making in conditions of uncertainty is moderated by DRD2 genotype.

Variants of the DRD2 Taq1A polymorphism, which have been shown to result in functional differences in dopamine D2 receptors (D2R), have been linked to various externalizing outcomes in adults. However, the neurobiological processes that contribute to these associations are not well understood. The current study investigates gene×environment effects on teacher-rated externalizing behaviors and probabilistic decision making in a sample of 333 children (age 9) enrolled in an ongoing longitudinal study. Findings indicate that externalizing behaviors increased as a function of hypoxic exposure only among individuals carrying the A1 (A1+) allele. Results also indicate that willingness to pursue reward under conditions of maximum uncertainty (50% probability) decreased as a function of hypoxic exposure only among A1- individuals. Among A1 carriers, no association between probability decision making and hypoxic exposure emerged. These findings suggest that hypoxia could influence neural development through different biological pathways depending on D2 receptor genotype, and provide insight into the development of individual differences in behavior and decision making.

Interaction Effects between the Cumulative Genetic Score and Psychosocial Stressor on Self-Reported Drinking Urge and Implicit Attentional Bias for Alcohol: A Human Laboratory Study.

The current candidate gene and environment interaction (cGxE) study examined whether the effects of an experimentally manipulated psychosocial stressor on self-reported drinking urge and implicit attentional bias for alcohol cues differ as a function of a cumulative genetic score of 5-HTTLPR, MAO-A, DRD4, DAT1 and DRD2 genotypes. The current study also examined whether salivary alpha-amylase level or self-reported anxiety state mediate these cGxE effects. Individuals with high cumulative genetic risk score of the five monoamergic genotypes showed greater attentional bias toward alcohol cues when exposed to a psychosocial stressor than when not exposed. Frequent binge-drinking Caucasian young adults (N = 105; mean age = 19; 61% male) completed both the control condition and stress condition (using the Trier Social Stress Test) in order. Regarding attentional bias, individuals with high and medium cumulative genetic risk scores showed greater attentional bias toward alcohol stimuli in the stress condition than in the control condition, whereas, those with low genetic risk scores showed greater attentional bias toward alcohol stimuli in the control condition than in the stress condition. No mediating roles of salivary alpha-amylase and anxiety state in the cGxE effect were found. Regarding self-reported drinking urge, individuals with high cumulative genetic score reported greater drinking urge than those with low genetic score regardless of experimental conditions. Although replication is necessary, the findings suggest that the association of a psychosocial stressor on implicit (but not explicit, self-reported) alcohol outcomes may differ as a function of the collective effects of five monoamine genes.

Minute‐to‐minute trajectories of child unresponsiveness and parent sensitivity in parent–child interactions: The role of DRD4

AbstractElevated and persistent childhood unresponsiveness to others (not responding to cues from others during interactions) may be due to a combination of early environmental and biological influences. However, little is known about how sensitive parenting may influence minute‐to‐minute changes in child unresponsiveness. The present study examines trajectories of child unresponsiveness to parent and parent sensitivity across a 10‐minute parent–child interaction, and also examines variation by children's DRD4 genotype. Child unresponsiveness and parent sensitivity were assessed minute by minute for 246 twins during a puzzle task. Latent growth curve models demonstrated that increasing trajectories of child unresponsiveness and decreasing trajectories of parent sensitivity were associated across the 10‐minute interaction. When examined by genotype, this association was present only for children with the DRD4 7‐repeat allele (the putative ‘risk’ allele). In addition, initial levels of parent sensitivity predicted trajectories of child unresponsiveness only in children with a DRD4 7‐repeat allele. This examination of gene‐environment interaction illustrates the value of considering both genotype and the parenting environment in consideration of preschool children's development of unresponsive behavior. It also supports the importance of investigating the interplay between minute‐level parenting and child behavior in explaining child development.

A systematic review: Candidate gene and environment interaction on alcohol use and misuse among adolescents and young adults.

Youth drinking is a pervasive public health concern with serious negative developmental implications. Candidate gene and environment interaction studies (cGxE) show that environmental effects on drinking behaviors may differ by individuals' genotypes. Yet little is known about whether genetic and environmental effects on drinking behaviors are developmentally specific. This systematic review evaluated 42 cGxE studies of drinking in adolescence and young adulthood. Although there are mixed findings, studies of cGxE effects involving DRD4, 5-HTTLPR, DRD2, and OPRM1 genotypes showed relatively consistent patterns. The effects of under-controlled environments (eg, low levels of parental monitoring) on early and middle adolescent drinking appeared to differ across DRD2 or OPRM1 genotypes. Effects of alcohol-facilitating environments (eg, heavy drinking peers) on late adolescent and young adult drinking appeared to differ across DRD4 or OPRM1 genotypes. Interactions between 5-HTTLPR genotype with stressful environments (eg, negative life events) were found throughout adolescence and young adulthood, although there were some inconsistencies regarding the risk-conferring allele. There was limited evidence for other cGxE effects due to the small number of studies. This review suggests that GxE findings may advance our knowledge regarding which developmentally specific conditions result in the expression of candidate genes that influence youth alcohol use and misuse. However, since a significant number of studies had small sample sizes and most studies had small effect sizes, findings need replication across independent studies with large samples. (Am J Addict 2018;XX:1-19).

Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1β) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1β levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence.

Relations between early maternal sensitivity and toddler self-regulation: Exploring variation by oxytocin and dopamine D2 receptor genes.

Gene-by-environment interactions between maternal sensitivity during infancy and child oxytocin receptor gene (OXTR rs53576) and D2 dopamine receptor gene (DRD2 TaqIA, rs1822497) genotypes were explored as predictors of toddlers' well-regulated behavioral and physiological responses to maternal compliance demands. Maternal sensitivity was assessed across a range of mother-child interactions when children were 6months and 1year of age (N=186), and toddler self-regulatory responses were assessed through compliance and vagal withdrawal during a toy clean-up task when children were 2years of age. Sensitivity-by-OXTR interactions suggested two diathesis-stress patterns, predicting compliance for the GG genotype group, and predicting physiological regulation for the AA/AG genotype group. A main effect for DRD2 genotype indicated that children with an A1 allele displayed less-compliant behavior in toddlerhood. These results suggest that genetic differences may contribute to variation both in risk for self-regulatory difficulties, and in relations between maternal sensitivity and children's responses to compliance demands at different levels of analysis.

DRD4 exon 3 genotype and ADHD: Randomised pharmacodynamic investigation of treatment response to methylphenidate

Objectives: Dopamine plays an important role in modulating attention and motor behaviours, dimensions altered in attention deficit/hyperactivity disorder (ADHD). Numerous association studies have linked dopamine receptor 4 (DRD4) to increased risk of ADHD. This study investigated the effect of DRD4 exon 3 polymorphism on child behaviours in response to treatment with methylphenidate.Methods: A total of 374 children diagnosed with ADHD (ages 6–12 years) were evaluated under three experimental conditions: baseline, placebo and MPH (0.5 mg/kg/day). This was a 2-week prospective within-subject, placebo-controlled, crossover trial. The Conners’ Global Index for parents and for teachers was used to evaluate the behaviours of the children. One-way repeated measures analysis of variance was used to test the effect of the interaction between DRD4 genotype and experimental conditions.Results: A significant interaction between DRD4 genotype and treatment was detected when the child’s behaviour was evaluated by the parents (P = 0.035, effect size of 0.014), driven by a better treatment response in children homozygous for long 7-repeat allele.Conclusions: According to the parent assessment, children homozygous for the long 7-repeat allele were more responsive to experimental condition. This is the largest pharmacogenetic investigation of the effect of DRD4 exon 3 polymorphism in childhood ADHD.Trial Registration: clinicaltrials.gov, identifier NCT00483106.

The dopamine D4 receptor gene, birth weight, maternal depression, maternal attention, and the prediction of disorganized attachment at 36 months of age: A prospective gene × environment analysis

BackgroundEfforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. MethodsOur sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother–child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 genotype was obtained with buccal swabs and categorized according to the presence of the 7-repeat allele. Maternal depression was assessed with the Center for Epidemiologic Studies Depression Scale at the prenatal, 6-, 12-, and 24-month assessments. Maternal attention was measured at 6-months using a videotaped session of a 20-min non-feeding interaction. Attachment was assessed at 36-months using the Strange Situation Procedure. ResultsThe presence of the DRD4 7-repeat allele was associated with less disorganized attachment, β=−1.11, OR=0.33, p=0.0008. Maternal looking away frequency showed significant interactions with maternal depression at the prenatal assessment, β=0.003, OR=1.003, p=0.023, and at 24 months, β=0.004, OR=1.004, p=0.021, as at both time points, women suffering from depression and with frequent looking away behavior had an increased probability of disorganized attachment in their child, while those with less looking away behavior had a decreased probability of disorganized attachment in their child at 36 months. ConclusionsOur models support the contribution of biological and multiple environmental factors in the complex prediction of disorganized attachment at 36 months.

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation

A mother’s cortisol secretion is importantly associated with her own mental health and her infant’s cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother’s history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion.

Genotypes are related to neurocognitive performance but not concussion history in collegiate student-athletes

BackgroundSingle-nucleotide polymorphisms (SNPs) of neurologically relevant genes play a role in concussions from increasing susceptibility or hampering cognitive performance.ObjectiveThe purpose of this study was to investigate the effects of polymorphisms of APOE, APOE promoter, COMT and DRD2 on baseline neurocognitive function and concussion history in collegiate student-athletes.DesignCross-sectional.SettingCollegiate campus in North Carolina.Participants262 (194 males, 68 females) collegiate student-athletes.Assessment of risk factorsBuccal mucosa swabs were collected from participants. SNP genotyping was run on all samples to determine APOE, APOE promoter, COMT, and DRD2 genotypes. Participants were split into three groups based on their genotypes for each gene.Outcome measuresParticipants completed the Immediate Post-Concussion Assessment and Cognitive Testing neurocognitive assessment which generated composite scores on Verbal Memory, Visual Memory, Visuomotor Speed, and Reaction Time as well as Impulse ControlResultsNone of the genotype variables influenced number of concussions (p&gt;0.05). MANOVA analysis determined no differences for APOE promoter and DRD2 genotypes (p&gt;0.05). There were statistical differences for APOE for Visuomotor composite (APOE-e3 (m=41.2, %95 CI [40.8, 42.1]) vs e4 (m=39.1, %95 CI [37.8, 40.5], p=0.017) and Reaction Time (APOE-e4 (m=0.62, %95 CI [0.60, 0.64]) was different than both e2 (m=0.57, %95 CI [0.54, 0.60] and e3(m=0.58, %95 CI [0.56, 0.59], p&lt;0.005). There were also differences for COMT for Impulse Control (Val/Val (m=6.2 %95 CI [5.4, 7.1]) was different Val/Met (m=4.7, %95 CI [4.1, 5.2] and Met/Met (m=4.7, %95 CI [3.8, 5.6], p&lt;0.02).ConclusionsAPOE and COMT single nucleotide polymorphisms lead to significant differences in neurocognitive performance at baseline but not concussion history.Competing interestsNone.

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.

Association between genetic variation in the dopamine system and motor recovery after stroke.

The dopamine system plays a key role in motor learning and neuroplasticity. Several studies have studied the efficacy of dopaminergic drugs in enhancing motor recovery after stroke, but the effects are controversial. Although genetic variations in plasticity-related genes influence each individual's capacity for recovery after stroke, limited studies have investigated the effects of polymorphism of dopamine-related genes. We aimed to investigate the association between motor recovery in stroke patients and polymorphisms in the dopamine-related genes catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), DRD2, and DRD3. We enrolled 74 patients with first-ever stroke (42 males, 32 females, mean age: 61.4±14.1 y). During admission, blood samples were collected, and the genotypes of COMT, DRD1, DRD2, and DRD3 were analyzed. The primary outcome was assessed with Fugl-Meyer Assessment (FMA) at 1 week, 3 months, and 6 months after stroke; secondary outcomes were assessed with Functional Independence Measure (FIM) and mini-mental state examination at 3 and 6 months after stroke. The association between polymorphisms and functional outcome was analyzed. There were no significant associations between COMT polymorphisms and FMA or FIM scores at 1 week after stroke or between DRD1, DRD2, or DRD3 genotypes and FMA or FIM scores at any point. COMT genotypes were significantly associated with FMA and FIM at 3 months (p < 0.01 and p < 0.05, respectively) and at 6 months (p < 0.01 and p < 0.05, respectively). These data suggest that genetic variation of dopamine-related genes may affect motor recovery after stroke and that COMT polymorphism could be useful for predicting motor recovery.

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

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.

Genetics and Other Risk Factors for Past Concussions in Active-Duty Soldiers.

Risk factors for concussion in active-duty military service members are poorly understood. The present study examined the association between self-reported concussion history and genetics (apolipoprotein E [APOE], brain-derived neurotrophic factor [BDNF], and D2 dopamine receptor genes [DRD2]), trait personality measures (impulsive-sensation seeking and trait aggression-hostility), and current alcohol use. The sample included 458 soldiers who were preparing to deploy for Operation Iraqi Freedom/Operation Enduring Freedom. For those with the BDNF Met/Met genotype, 57.9% (11/19) had a history of one or more prior concussions, compared with 35.6% (154/432) of those with other BDNF genotypes (p = 0.049, odds ratio [OR] = 2.48). APOE and DRD2 genotypes were not associated with risk for past concussions. Those with the BDNF Met/Met genotype also reported greater aggression and hostility personality characteristics. When combined in a predictive model, prior military deployments, being male, and having the BDNF Met/Met genotype were independently associated with increased lifetime history of concussions in active-duty soldiers. Replication in larger independent samples is necessary to have more confidence in both the positive and negative genetic associations reported in this study.

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.