Dopaminergic system genes in childhood aggression: Possible role for DRD2

Abstract

Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. Objective. We examined selected members of the dopaminergic system genes for association with child aggression. Method. We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity. Results. Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children. Conclusions. Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children.     

Association analysis of exon III and exon I polymorphisms of the dopamine D4 receptor locus in Mexican psychotic patients

In this study, we investigated whether polymorphisms of the dopamine D4 receptor (DRD4) gene were associated with psychotic symptomatology rather than with a unique diagnosis such as schizophrenia. A number of association studies between the DRD4 gene 48 bp-VNTR polymorphism at exon 3 and psychotic disorders have been reported, but the results have been controversial. Both 48 bp-VNTR and the 12 bp-VNTR (at exon 1) polymorphisms of this gene were analyzed in a group of 149 unrelated Mexican subjects with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depression and bipolar disorder, both with psychotic symptoms, brief psychotic disorder, delusional disorder and non-specific psychotic disorder, and in 169 individuals free of psychiatric illnesses. There were no differences in allele or genotype frequencies between groups for the 12 bp-VNTR polymorphisms. However, a significant excess of "rare" alleles (3-, 5-, 6- and 8-48 bp repeats alleles) was found in the group of psychotics. Moreover, haplotypes 3-A1, 5-A1, 6-A1 and 8-A1 were significantly more frequently associated with cases. This positive association supports a role of this molecule as a genetic risk factor in psychotic disorders.     

DRD3 and DAT1 genes in schizophrenia: an association study

OBJECTIVE: To investigate the role of the dopamine receptor 3 (DRD3) and transporter 1 (DAT1) genes in schizophrenia or in modulating its phenotype. METHODS: a Ser9Gly polymorphism in codon 9 of the DRD3 and a VNTR polymorphism in the DAT1genes were examined in two groups of schizophrenic patients, one of excellent neuroleptic responders (N=42) and one of nonresponders (N=64). A group of healthy volunteers screened for major psychiatric disorders was also included (N=89). In addition, age at onset of psychotic symptoms, attention performance and family loading for schizophrenia spectrum disorders were compared between patients with different genotypes in the DRD3 and DAT1 genes. RESULTS: No significant differences in the allelic distribution of the DRD3 and DAT1 polymorphisms were detected between schizophrenic patients and controls. A trend toward an excess of DRD3 genotype Gly/Gly was observed in neuroleptic nonresponder schizophrenic patients compared to controls (chi(2)=3. 30, df=1, p=0.07). No significant differences in age at onset of psychotic symptoms, attention task performance or family loading for schizophrenia spectrum disorders were observed between groups with different DRD3 and DAT1 genotypes. CONCLUSION: These results do not support the role of either of these genes in increasing susceptibility to schizophrenia or in modulating its phenotype in the studied population.     

Association of variants in DRD2 and GRM3 with motor and cognitive function in first-episode psychosis

Similar smooth pursuit eye tracking dysfunctions are present across psychotic disorders. They include pursuit initiation and maintenance deficits that implicate different functional brain systems. This candidate gene study examined psychosis-related genotypes regulating dopamine and glutamate neurotransmission in relation to these pursuit deficits. One hundred and thirty-eight untreated first-episode patients with a psychotic disorder were genotyped for four markers in DRD2 and four markers in GRM3. The magnitude of eye movement abnormality in patients was defined in relation to performance of matched healthy controls (N = 130). Eighty three patients were followed after 6 weeks of antipsychotic treatment. At baseline, patients with a ?141C deletion in DRD2 rs1799732 had slower initiation eye velocity and longer pursuit latency than CC insertion carriers. Further, GRM3 rs274622_CC carriers had poorer pursuit maintenance than T-carriers. Antipsychotic treatment resulted in prolonged pursuit latency in DRD2 rs1799732_CC insertion carriers and a decline in pursuit maintenance in GRM3 rs6465084_GG carriers. The present study demonstrates for the first time that neurophysiological measures of motor and neurocognitive deficits in patients with psychotic disorders have different associations with genes regulating dopamine and glutamate systems, respectively. Alterations in striatal D2 receptor activity through the ?141C Ins/Del polymorphism could contribute to pursuit initiation deficits in psychotic disorders. Alterations in GRM3 coding for the mGluR3 protein may impair pursuit maintenance by compromising higher perceptual and cognitive processes that depend on optimal glutamate signaling in corticocortical circuits. DRD2 and GRM3 genotypes also selectively modulated the severity of adverse motor and neurocognitive changes resulting from antipsychotic treatment.     

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.     

Association study of MAO-A and DRD4 genes in schizophrenic patients with aggressive behavior

Genes involved in dopamine neurotransmission are interesting candidates to be analyzed in schizophrenia and aggressive behavior. Therefore, we analyzed the functional polymorphisms of the dopamine receptor D4 (DRD4) and monoamine oxidase A (MAO-A) genes in a sample of 71 schizophrenic patients assessed with the Overt Aggression Scale to measure aggressive behavior. CLUMP analysis of the DRD4 48-bp repeat-exon III polymorphism in schizophrenic patients showed significant differences between the aggressive behavior and the nonaggressive groups (T1 = 18.77, d.f. = 6, p = 0.0046; T3 = 6.54, p = 0.0195). However, analysis of the promoter polymorphism of the MAO-A gene revealed no significant association between aggressive and nonaggressive patients. Finally, analysis of Overt Aggression Scale dimensions exhibited significant differences for the DRD4 and MAO-A genes. Our preliminary findings suggest that the DRD4 and MAO-A genes may be involved in aggressive schizophrenic patients.     

Genetic variants of dopamine receptor D4 and psychopathology.

There is much evidence to indicate that the dopamine receptor D4 (DRD4) gene is involved in psychiatric disorders. We investigated the correlation between DRD4 gene polymorphism and the psychopathology of major psychoses, independently of diagnoses. Some 461 inpatients affected by major psychoses were assessed by the Operational Criteria checklist for psychotic illness and typed for DRD4 variants. The four symptomatologic factors-mania, depression, delusion, and disorganization-were used as phenotype definitions. DRD4 Exon 3 long allele variants were associated with high delusional scores, with the most significant difference between alleles 2 and 7 (p = 0.004). DRD4 variants may, therefore, constitute a liability factor for development of delusional symptomatology in patients with major psychoses.     

Influences of a DRD2 polymorphism on updating of long‐term memory representations and caudate BOLD activity: Magnification in aging

A number of genetic polymorphisms are related to individual differences in cognitive performance. Striatal dopamine (DA) functions, associated with cognitive performance, are linked to the TaqIA polymorphism of the DRD2/ANKK1 gene. In humans, presence of an A1 allele of the DRD2/ANKK1‐TaqIA polymorphism is related to reduced density of striatal DA D2 receptors. The resource‐modulation hypothesis assumes that aging‐related losses of neurochemical and structural brain resources modulate the extent to which genetic variations affect cognitive functioning. Here, we tested this hypothesis using functional MRI during long‐term memory (LTM) updating in younger and older carriers and noncarriers of the A1‐allele of the TaqIa polymorphism. We demonstrate that older A1‐carriers have worse memory performance, specifically during LTM updating, compared to noncarriers. Moreover, A1‐carriers exhibited less blood oxygen level‐dependent (BOLD) activation in left caudate nucleus, a region critical to updating. This effect was only seen in older adults, suggesting magnification of genetic effects on functional brain activity in aging. Further, a positive relationship between caudate BOLD activation and updating performance among non‐A1 carriers indicated that caudate activation was behaviorally relevant. These results demonstrate a link between the DRD2/ANKK1‐TaqIA polymorphism and neurocognitive deficits related to LTM updating, and provide novel evidence that this effect is magnified in aging. Hum Brain Mapp 36:1325–1334, 2015. © 2014 Wiley Periodicals, Inc.     

Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings

Macrophages are one of HIV-1’s principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3’s binding to DA, would be more likely to develop CI. Cochran–Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.     

Antidepressive response to sleep deprivation in unipolar depression is not associated with dopamine D3 receptor genotype

The psychostimulant theory of antidepressive sleep deprivation (SD) proposes a contribution of dopamine D3 receptors (DRD3) in the limbic system to the antidepressant effects of SD. Neuroendocrinological studies suggest a positive correlation of clinical response to SD and cortisol secretion. We hypothesized that the clinical response to SD and amount of cortisol secretion upon SD is associated with the 1-1 genotype of the Bal1 polymorphism of DRD3 on exon 1. In this study, aiming at evaluating the feasibility of screening large patient samples, 52 inpatients (19 males/33 females) with unipolar depression and a score of 18 or more on the 21-item Hamilton Depression Rating Scale were treated with 1 night of total SD. We found that 31% of our patients responded to SD. There was no association between response to SD and the genotype of the DRD3 Bal1 polymorphism (p < 0.879). There was also no association between increase in cortisol secretion after SD and DRD3 genotypes (p < 1.000) in a subgroup of patients. Statistical power analysis ruled out a major effect of the DRD3 Bal1 polymorphism on clinical response to SD. These results suggest that the DRD3 Bal1 polymorphism is not a promising lead to be followed up in larger patient samples.     

Evidence for epistasis between the 5-HTTLPR and the dopamine D4 receptor polymorphisms in externalizing behavior among 15-year-olds

The present study aimed to clarify the functional role of genes in the dopamine and serotonin systems by examining whether polymorphisms in these genes are related to adolescent externalizing behavior either alone or in interaction with each other. Participants were selected from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 298 adolescents (144 males, 154 females) completed the Youth Self Report, 296 primary caregivers the Child Behavior Checklist and 253 teachers the Teacher Report Form. DNA was genotyped for the DRD4 exon III VNTR and the 5-HTTLPR polymorphisms. Results revealed that individuals with the DRD4 7r allele reported significantly more externalizing behavior than carriers of other variants. In addition, a significant interaction emerged, indicating that adolescents carrying two copies of the 5-HTTLPR short allele and the DRD4 7r variant scored highest on aggressive and/or delinquent behavior compared to other genotypes. This result suggests an effect of 5-HTTLPR on externalizing behavior in the presence of DRD4 7r but no effect in its absence.     

Association of a Schizophrenia Risk Variant at the DRD2 Locus With Antipsychotic Treatment Response in First-Episode Psychosis

Findings from the Psychiatric Genomics Consortium genome-wide association study (GWAS) showed that variation at the DRD2 locus is associated with schizophrenia risk. However, the functional significance of rs2514218, the top DRD2 single nucleotide polymorphism in the GWAS, is unknown. Dopamine D2 receptor binding is a common mechanism of action for all antipsychotic drugs, and DRD2 variants were related to antipsychotic response in previous studies. The present study examined whether rs2514218 genotype could predict antipsychotic response, including efficacy and adverse events, in a cohort of patients with first episode of psychosis treated with either risperidone or aripiprazole for 12 weeks. Subjects were genotyped using the Illumina Infinium HumanOmniExpressExome array platform. After standard quality control, data from 100 subjects (49 randomly assigned to treatment with aripiprazole and 51 assigned to risperidone) was available for analysis. Subjects were assessed for psychotic symptomatology and medication-related adverse events weekly for 4 weeks, then biweekly for 8 weeks. Linear mixed model analysis revealed that the homozygotes for the risk (C) allele at rs2514218 had significantly greater reduction in positive symptoms during 12 weeks of treatment compared to the T allele carriers. In the aripiprazole group, C/C homozygotes also reported more akathisia than the T allele carriers, while in the risperidone group, male T allele carriers demonstrated greater prolactin elevations compared to male C/C homozygotes. These findings suggest that the schizophrenia risk variant at the DRD2 locus (or another variant in close proximity) is associated with observable differences in response to treatments which reduce striatal dopamine signaling.Key words: antipsychotic, pharmacogenetics, DRD2     

An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia

Summary. Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed.     

Association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and tardive dyskinesia in Chinese schizophrenic patients

It has been suggested that dopamine D3 receptor (DRD3) may have important implications for antipsychotic-induced tardive dyskinesia (TD). Previous studies have demonstrated an association between a serine to glycine polymorphism in the first exon of the DRD3 gene and TD; however, the results have been inconsistent. Therefore, we have replicated these studies using a Chinese sample population. A total of 115 schizophrenic patients from chronic wards were assessed for TD severity using the Abnormal Involuntary Movements Scale (AIMS) and were subsequently genotyped for the DRD3 polymorphism. The mean AIMS score for patients carrying the heterozygote (DRD3(ser-gly)) was significantly greater than for those with the homozygotes (DRD3(ser-ser) and DRD3(gly-gly)). Our results are in line with a previous report, the results of which suggest that the presence of the DRD3(ser-gly) genotype may be a risk factor for the development of TD in patients treated with antipsychotics.     

Genetic background of ADHD: population studies, genes of the catecholamine system

Attention-deficit hyperactivity disorder (ADHD) begins in early childhood. In this article we review the studies supporting a genetic background of this disorder. ADHD occurs in 3-10% of the general population. Family studies reveal a 5 times more likely frequency of ADHD among first-degree relatives than in the general population. Monozygotic twin concordance rate for ADHD is 81%, whereas for dizygotic twins it is 29%. One of the ADHD predisposing factors is dopaminergic neurotransmission abnormality. According to other studies there is a relationship between polymorphism of dopamine transporter gene (DAT), dopamine receptors genes: DRD2, DRD3, DRD4, DRD5, dopamine-beta-hydroxylase gene (DBH) and catechol-O-methyltransferase gene (COMT) and ADHD. In other articles authors describe abnormalities of the serotonergic system, such as the polymorphism of the serotonin transporter gene (5HTT/SERT), serotonin receptors genes 5HT2A and 5HT1B in the development ofADHD. Another possible factor in ADHD background is the dysregulation of the adrenergic system. The most frequently studied is the connection between polymorphism of norepinephrine transporter gene (NET), adrenergic receptors genes: alpha 2A (ADRA2A), alpha 1C (ADRA1C), alpha 2C and monoamine oxidase A gene (MAO-A).     

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

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

A meta-analysis of the association between DRD4 polymorphism and novelty seeking

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.     

Sexual Trauma,the Dopamine D4 Receptor,and Suicidal Ideation Among Hospitalized Adolescents: A Preliminary Investigation

Though an association exists between sexual trauma and adolescent suicidal thoughts and behaviors (STBs), not all adolescents with a sexual assault history develop STBs. The present study examined whether carrier status of the DRD4 VNTR polymorphism (DRD4 L vs. DRD4S) moderated the relationship between sexual trauma and STBs in a sample of psychiatrically hospitalized adolescents. A total of 76 psychiatrically hospitalized adolescents provided saliva samples for genotyping procedures and completed assessment measures. Using hierarchical regression analyses, results indicated that DRD4 L carriers with a sexual trauma history reported significantly more severe suicidal ideation than DRD4S homozygotes. There was no interaction evident for the prediction of suicide attempts. To our knowledge, this is the first study to provide preliminary support for synergistic effects of sexual trauma, DRD4, and severity of SI in adolescents. Further studies of the relationship between sexual trauma, DRD4, and STBs utilizing larger samples are needed.     

Living with schizophrenia: caring for a person with a severe mental illness

Data from a survey of a total population of patients with schizophrenia or schizoaffective disorder were used to examine the relationship between patient behaviours and the experience of caregiving. Carers were more distressed by depressed behaviours in the patient than any other type of behaviour, including behaviour associated with florid psychotic episodes. The number of patient needs met by the caregiver was also associated with a negative appraisal of caregiving. A comparison of patients who were living with an informal carer and those who were living alone or in hostel accommodation showed that the former group were less likely than the latter to have been either an inpatient or a day patient during the previous year. Accepted: 19 December 1997     

Genetic polymorphisms and personality in healthy adults: a systematic review and meta-analysis

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.