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James M Swanson - One of the best experts on this subject based on the ideXlab platform.
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association between Dopamine D4 Receptor polymorphism and age related changes in brain glucose metabolism
PLOS ONE, 2013Co-Authors: Nora D Volkow, Dardo Tomasi, Genejack Wang, Frank Telang, Joanna S Fowler, Rita Z Goldstein, Nelly Klein, Christopher Wong, James M SwansonAbstract:Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the Dopamine Receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22–55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R−, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = −0.52), temporal (r = −0.51) and striatal regions (r = −0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R− groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism.
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etiologic subtypes of attention deficit hyperactivity disorder brain imaging molecular genetic and environmental factors and the Dopamine hypothesis
Neuropsychology Review, 2007Co-Authors: James M Swanson, Joel T. Nigg, Nora D Volkow, Marcel Kinsbourne, Bruce P Lanphear, Gerry A Stefanatos, Eric Taylor, B J Casey, Xavier F Castellanos, Pathik D WadhwaAbstract:Multiple theories of Attention-Deficit/Hyper- activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the Dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of Dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of Dopamine deficits based on the recent literature that (1) confirms abnormalities in Dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on Dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the Dopamine system (higher-than-normal Dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of Dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the Dopamine Receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of Dopamine deficits based on recent studies of (1) toxic substances that may affect the Dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in Dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of Dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve Dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.
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the genetic architecture of selection at the human Dopamine Receptor D4 drD4 gene locus
American Journal of Human Genetics, 2004Co-Authors: Eric T Wang, Yuanchun Ding, Deborah L Grady, Judith R Kidd, Kenneth K Kidd, Pamela Flodman, James M Swanson, Oliver A Ryder, M A Spence, Robert K MoyzisAbstract:Associations of the seven-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (∼40,000–50,000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between Receptor variants.
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high prevalence of rare Dopamine Receptor D4 alleles in children diagnosed with attention deficit hyperactivity disorder
Molecular Psychiatry, 2003Co-Authors: Deborah L Grady, Yuanchun Ding, Pamela Flodman, Sabrina Schuck, James M Swanson, Eric T Wang, M A Spence, Han Chang Chi, Moyra Smith, Robert K MoyzisAbstract:Associations have been reported of the 7-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.
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evidence of positive selection acting at the human Dopamine Receptor D4 gene locus
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Yuanchun Ding, Deborah L Grady, Atsuyuki Morishima, Judith R Kidd, Kenneth K Kidd, Pamela Flodman, Anne M Spence, Sabrina Schuck, James M Swanson, Yaping ZhangAbstract:Associations have been reported of the seven-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2–11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R–6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5–10-fold “younger” than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.
James L Kennedy - One of the best experts on this subject based on the ideXlab platform.
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prenatal maternal depression and child serotonin transporter linked polymorphic region 5 httlpr and Dopamine Receptor D4 drD4 genotype predict negative emotionality from 3 to 36 months
Development and Psychopathology, 2017Co-Authors: Cathryn Gordon Green, Vanessa Babineau, Alexia Jolicoeurmartineau, Andreeanne Bouvetteturcot, Klaus Minde, Roberto B Sassi, Martin Standre, Normand Carrey, Leslie Atkinson, James L KennedyAbstract:Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother-infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the Dopamine Receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire-Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis-stress model at 36 months.
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5 untranslated region of the Dopamine D4 Receptor gene and attention deficit hyperactivity disorder
American Journal of Medical Genetics, 2001Co-Authors: Cathy L Barr, Yu Feng, Karen Wigg, Russell Schachar, Rosemary Tannock, Wendy Roberts, Molly Malone, James L KennedyAbstract:Recently the molecular genetic basis of attention-deficit hyperactivity disorder (ADHD) has been the focus of a number of studies with the majority of these investigating the role of Dopamine system genes. A great deal of attention has been focused on the possible involvement of the Dopamine D4 Receptor gene (DRD4) following a report of an association of ADHD with the allele containing seven copies of the 48-bp repeat in the third exon. In this paper we extended the search for the molecular explanation for the observed association by testing three polymorphisms in the region 5' to the Dopamine Receptor D4 gene transcription start site for linkage to ADHD. We specifically targeted polymorphisms in the region 5' to the start site of transcription as DNA variants in this region could alter the transcription level of the gene and hence the phenotype. We did not observe significant evidence for biased transmission of any of the alleles at these three polymorphisms to ADHD probands using the transmission disequilibrium test. We conclude that these three polymorphisms are not related to the ADHD phenotype.
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Association of the Dopamine Receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach
Molecular Psychiatry, 1998Co-Authors: James M Swanson, G A Sunohara, Lillie Williams, Gerald J Lahoste, Timothy Wigal, Marc Lerner, James L Kennedy, Regino R, Fineberg E, Sharon B WigalAbstract:Previously in this journal, we reported an association of the Dopamine D4 Receptor gene (DRD4) and attention deficit hyperactivity disorder (ADHD). In a population-association (case-control) study of 39 children with a refined phenotype of ADHD and 39 ethnically matched controls, we observed an increased percentage of the 7 repeat allele (29% vs 12%) and the 7+ genotype (49% vs 21%) in the ADHD group compared to the control group. In a replication and an extension of our initial study, we recruited another sample of ADHD subjects and found percentages of the 7 repeat allele (28%) and the 7+ genotype (48%) consistent with our previous findings. We used a family-based approach to evaluate a predicted association of DRD4 and ADHD based on a test of allele transmission focused on the 7 repeat allele. We identified 52 families based on the diagnosis of the refined phenotype of ADHD in the proband and the availability of DNA from both biological parents as well as the proband. Haplotype relative risk (HRR) analysis was performed to test our a priori hypothesis and produced significant results (chi-square = 4.65, P < 0.035). This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD.
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association of the Dopamine Receptor D4 drD4 gene with a refined phenotype of attention deficit hyperactivity disorder adhd a family based approach
Molecular Psychiatry, 1998Co-Authors: James M Swanson, G A Sunohara, R Regino, E Fineberg, Lillie Williams, Gerald J Lahoste, Timothy Wigal, Marc Lerner, James L Kennedy, Sharon B WigalAbstract:Association of the Dopamine Receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach
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a hypervariable segment in the human Dopamine Receptor D4 drD4 gene
Human Molecular Genetics, 1993Co-Authors: Jay B Lichter, James L Kennedy, Kenneth K Kidd, Cathy L Barr, Kenneth James LivakAbstract:: The human Dopamine D4 Receptor contains a novel polymorphism within the putative third cytoplasmic loop of the protein. The polymorphism is characterized by a varying number of direct imperfect 48-bp repeats in the gene. Pharmacological characterization has suggested that this Receptor is the site through which the atypical neuroleptic clozapine exerts its antipsychotic action and that some polymorphic variants display different pharmacological properties. Further analysis of the repeat region using innovative technologies indicates that the alleles vary not only in the number of repeats (2-8 or 10 repeat units) but also in the sequence of the repeats and the order in which they appear. In 178 unrelated chromosomes we have identified 19 different repeats in 25 different haplotypes coding for 18 different predicted amino acid sequences, making this one of the most variable functional proteins currently described.
Yuanchun Ding - One of the best experts on this subject based on the ideXlab platform.
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the genetic architecture of selection at the human Dopamine Receptor D4 drD4 gene locus
American Journal of Human Genetics, 2004Co-Authors: Eric T Wang, Yuanchun Ding, Deborah L Grady, Judith R Kidd, Kenneth K Kidd, Pamela Flodman, James M Swanson, Oliver A Ryder, M A Spence, Robert K MoyzisAbstract:Associations of the seven-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (∼40,000–50,000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between Receptor variants.
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high prevalence of rare Dopamine Receptor D4 alleles in children diagnosed with attention deficit hyperactivity disorder
Molecular Psychiatry, 2003Co-Authors: Deborah L Grady, Yuanchun Ding, Pamela Flodman, Sabrina Schuck, James M Swanson, Eric T Wang, M A Spence, Han Chang Chi, Moyra Smith, Robert K MoyzisAbstract:Associations have been reported of the 7-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.
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evidence of positive selection acting at the human Dopamine Receptor D4 gene locus
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Yuanchun Ding, Deborah L Grady, Atsuyuki Morishima, Judith R Kidd, Kenneth K Kidd, Pamela Flodman, Anne M Spence, Sabrina Schuck, James M Swanson, Yaping ZhangAbstract:Associations have been reported of the seven-repeat (7R) allele of the human Dopamine Receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2–11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R–6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5–10-fold “younger” than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.
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attention deficit hyperactivity disorder children with a 7 repeat allele of the Dopamine Receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention
Proceedings of the National Academy of Sciences of the United States of America, 2000Co-Authors: Yuanchun Ding, Pamela Flodman, Anne M Spence, Sabrina Schuck, James M Swanson, Jaap Oosterlaan, Michael Andrew Murias, Michael WasdellAbstract:An association of the Dopamine Receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.
Richard P. Ebstein - One of the best experts on this subject based on the ideXlab platform.
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the association between creativity and 7r polymorphism in the Dopamine Receptor D4 gene drD4
Frontiers in Human Neuroscience, 2013Co-Authors: Naama Mayseless, Richard P. Ebstein, Florina Uzefovsky, Idan Shalev, Simone G ShamaytsooryAbstract: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 activity, and impaired DT has been reported in populations with Dopaminergic dysfunctions. Given the strong association between DT and the Dopaminergic system, the current study examined a group of healthy individuals (N=185) to determine the role of the repeat polymorphism in exon3 of the DRD4 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 Dopaminergic system and suggest that Dopaminergic dysfunctions in neurological and psychiatric disorders may account for impaired creativity and cognitive flexibility in these individuals.
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Heritability of children's prosocial behavior and differential susceptibility to parenting by variation in the Dopamine Receptor D4 gene
Development and Psychopathology, 2011Co-Authors: Ariel Knafo, Salomon Israel, Richard P. EbsteinAbstract:Theoretical considerations and new empirical evidence suggest that children's development cannot simply be explained by either genes or environment but that their interaction is important to understanding child behavior. In particular, a genetic polymorphism, the exon III repeat region of the Dopamine Receptor D4, has been the focus of interest regarding differential susceptibility to parental influence. To study environmental and genetic influences on children's prosocial behavior, 168 twin pairs (mean age = 44 months) participated in an experiment that assessed prosocial behavior via three measures: compliant prosocial behavior elicited in response to social requests, self-initiated prosocial behavior enacted voluntarily, and mothers' rating of children's behavior. Genetic effects accounted for 34% to 53% of the variance in prosocial behavior. The rest of the variance was accounted for by nonshared environment and error. Parenting measures of maternal positivity, negativity, and unexplained punishment did not correlate significantly with children's prosocial behavior. However, when parenting was stratified by presence or absence of the child's Dopamine Receptor D4 7-repeat allele in an overlapping sample of 167 children to model differential susceptibility to parental influence, a richer picture emerged. Positive parenting related meaningfully to mother-rated prosocial behavior, and unexplained punishment related positively to self-initiated prosocial behavior, but only among children carrying the 7-repeat allele. The findings demonstrate that a molecular genetic strategy, based on genotyping of common polymorphisms and combined with a classic twin approach, provides a richer description of how genes and environment interact to shape children's behavior, and allows for the identification of differential sensitivity to parental influence.
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Dopamine Receptor D4 polymorphism predicts the effect of l dopa on gambling behavior
Biological Psychiatry, 2010Co-Authors: Christoph Eisenegger, Richard P. Ebstein, Daria Knoch, Lorena R R Gianotti, Peter S Sandor, Ernst FehrAbstract:Background There is ample evidence that a subgroup of Parkinson's disease patients who are treated with Dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between Dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the Dopamine Receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of Dopaminergic stimulation on gambling behavior in healthy subjects. Methods We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration. Results Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after Dopaminergic stimulation. Conclusions These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a Dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.
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association between tridimensional personality questionnaire tpq traits and three functional polymorphisms Dopamine Receptor D4 drD4 serotonin transporter promoter region 5 httlpr and catechol o methyltransferase comt
Molecular Psychiatry, 2000Co-Authors: Jonathan Benjamin, Yamima Osher, Moshe Kotler, Inga Gritsenko, Lubov Nemanov, R H Belmaker, Richard P. EbsteinAbstract:Dopamine D4 Receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT × 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR × D4DR (F = 6.18, P = 0.03) and COMT × 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults.
Marinus H. Van Ijzendoorn - One of the best experts on this subject based on the ideXlab platform.
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maternal care of heterozygous Dopamine Receptor D4 knockout mice differential susceptibility to early life rearing conditions
Genes Brain and Behavior, 2020Co-Authors: Marinus H. Van Ijzendoorn, Jelle Knop, Marian J Bakermanskranenburg, Marian Joels, Rixt Van Der VeenAbstract:The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy Dopamine Receptor D4 (DRD4) 7-repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed DrD4+/− mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2-14. Puberty onset was examined from P24 to P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of DrD4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared DrD4+/− mice exhibited the lowest and CN reared DrD4+/− mice the highest levels of licking/grooming. These results indicate that both genetic and early-environmental factors play an important role in shaping maternal care of the offspring for better and for worse.
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Differential susceptibility to rearing environment depending on Dopamine-related genes: New evidence and a meta-analysis
Development and Psychopathology, 2011Co-Authors: Marian J. Bakermans-kranenburg, Marinus H. Van IjzendoornAbstract:In the current paper we present new empirical data and meta-analytic evidence for the role of Dopamine-related genes as a susceptibility factor interacting with the rearing environment for better and for worse, that is, increasing children’s susceptibility to both the adverse effects of unsupportive environments and the beneficial effects of supportive rearing. In Study 1 we examined the readiness of 91 7-year-old children to donate their money to a charity (UNICEF). We tested whether the association between attachment and donating behavior was moderated by the presence of the Dopamine Receptor D4 (DRD4) 7-repeat allele. The attachment story completion task was used to assess attachment as an index of the quality of the rearing environment. Children with secure attachment representations donated more but only if they had the DRD4 7-repeat allele. In Study 2 we present the results of a meta-analysis of gene– environment studies on children up to 10 years of age involving Dopamine-related genes (Dopamine Receptor D2, DRD4, Dopamine transporter). The cumulative negative effects of these “risk genes” and adverse rearing environments have been stressed, but potentially cumulative positive effects of these same genes interacting with positive rearing environments remained largely unnoticed. We examined the associations between negative and positive rearing environments and developmental outcomes as moderated by Dopamine-related gene polymorphisms. Children with the less efficient Dopamine-related genes did worse in negative environments than the comparisons without the “genetic risk,” but they also profited most from positive environments. Finding sa re discussed in light of evolutionary theory, and illustrated with some practical implications of differential susceptibility.
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Effects of an attachment-based intervention on daily cortisol moderated by Dopamine Receptor D4: a randomized control trial on 1- to 3-year-olds screened for externalizing behavior.
Development and Psychopathology, 2008Co-Authors: Marian J. Bakermans-kranenburg, Marinus H. Van Ijzendoorn, Judi Mesman, Lenneke R. A. Alink, Femmie JufferAbstract:The effect of the Video-Feedback Intervention to Promote Positive Parenting and Sensitive Discipline (VIPP-SD) on daily cortisol production was tested in a randomized controlled trial with 130 families with 1- to 3-year-old children screened for their relatively high levels of externalizing behavior. Six 1.5-hr intervention sessions focusing on maternal sensitivity and discipline were conducted with individual families at their homes. Children in the intervention group showed lower cortisol levels, with a moderating role of the Dopamine Receptor D4 (DRD4) VNTR exon III polymorphism. The VIPP-SD program proved to be effective in decreasing daily cortisol production in children with the DRD4 7-repeat allele, but not in children without the DRD4 7-repeat allele. Our findings indicate that children are differentially susceptible to intervention effects dependent on the presence of the 7-repeat DRD4 allele.