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A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention deficit hyperactivity disorder
Abstract
The association between the 10-repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta-analysis of the association between the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40-base pair VNTR polymorphism in the3'-UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype-based haplotype relative risk (HHRR) studies, and 6 case-control-based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case-control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05-1.30, chi-square = 8.11, df = 1, P = 0.004), but not in HHRR and case-control studies. The 10-repeat allele of a VNTR polymorphism in the 3'-UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta-analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.
... The meta-analysis of the family-based association studies was divided into two parts: TDT and HRR. For the TDT study, every included study provided a 2-by-2 transmission disequilibrium table that classifies heterozygous parental alleles (informative meioses) based on the passing status (Ser9 allele passed to the schizophrenic offspring) and data type (the number of observed passing vs. the number of theoretic passing) [37]. For one informative meiosis, the expected transmitted number that the allele is transmitted from heterozygous parents to the proband is 0.5 and the expected untransmitted number that the allele is not transmitted from heterozygous parents to proband is also 0.5. ...
... For one informative meiosis, the expected transmitted number that the allele is transmitted from heterozygous parents to the proband is 0.5 and the expected untransmitted number that the allele is not transmitted from heterozygous parents to proband is also 0.5. For the HRR studies, every included study provided a 2-by-2 HRR table that classifies parental alleles by type of allele (Ser9 or Gly9) and passing status (passed to the offspring with schizophrenia or not) [37]. The Q test was used to measure the heterogeneity among the included studies and P < 0.05 indicated the presence of heterogeneity [38,39]. ...
... Moreover, subgroup analysis were conducted by ethnicity (i.e., East Asian, Caucasian, and other populations) and diagnostic criteria (i.e., DSM-III-R, DSM-IV, and CCMD-III). In addition, the funnel plot was generated to evaluate publication bias according to the previous study [37]. ...
Background:
Previous studies found that Ser9Gly (rs6280) might be involved in the occurrence of schizophrenia. However, no consist conclusion has yet been achieved. Compared to the case-control study, the family-based study took into account stratification bias. Thus, we conducted a meta-analysis of family-based studies to measure a pooled effect size of the association between Ser9Gly and the risk of schizophrenia.
Methods:
The relevant family-based studies were screened using the electronic databases by the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the correction between Ser9Gly polymorphism and schizophrenia susceptibility. Subgroup analysis was performed by stratification of ethnicity (i.e., East Asian, Caucasian, and other populations). Additionally, publication bias was evaluated by the funnel plot.
Results:
After literature searching, a total of 13 family-based association studies were included, which contained 11 transmission disequilibrium test (TDT) studies with 1219 informative meiosis and 5 haplotype-based haplotype relative risk (HRR) studies. No statistical significance of the heterogeneity was detected in TDT and HRR studies. Thus, the pooled effect size was calculated under the fixed effect model. The results found that the association was significantly protective in East Asian in TDT studies (204 informative meiosis, OR = 0.744, 95% CI = 0.564-0.980, Z-value = - 2.104, p = 0.035).
Conclusions:
The meta-analysis based on the family study found a protective association of Ser9Gly in East Asian. In future, large sample molecular epidemiology studies are needed to validate our findings.
... Findings of the three meta-analyses carried out so far support the involvement of the DA system genes in ADHD liability variation (Li et al. 2006;Maher et al. 2002;Yang et al. 2007). However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association (Yang et al. 2007). ...
... Findings of the three meta-analyses carried out so far support the involvement of the DA system genes in ADHD liability variation (Li et al. 2006;Maher et al. 2002;Yang et al. 2007). However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association (Yang et al. 2007). Furthermore, it should be noted that 5HT, norepinephrine, GABA, opioid, and cannabinoid neurons all modify DA metabolism and DA neurons (Comings and Blum 2000). ...
Abnormal dopamine (DA) transporter functioning has long been suspected to be involved in attention-deficit hyperactivity disorder (ADHD). My extensive search on theories concerning ADHD included: CENTRAL, MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Complementary and Alternative Medicine-specific databases, Informit, JST, plus grey literature and trial registries from inception to May 2010. A new understanding of ADHD pathophysiology is required. DA-deficit theory of ADHD is insufficient to cover critical aspects of ADHD pathology and medication. The dominance of this theory discourages the human and financial investments needed to explore alternative theories and has caused an evident bias in health and drug policies. A combined theory of altered DA and serotonin (5HT), deficit DA, and weakened prefrontal cortex (PFC) circuits may serve as a good alternate to DA-theory alone. This combined theory may influence the future of drug polices, pharmaceutical investments, treatment options, and drug developments.
... Not surprisingly, DA signaling dysfunction has been implicated in many neurological and psychiatric disorders including Parkinson's disease (Lees et al., 2009), schizophrenia (Howes and Kapur, 2009), bipolar disorder (BPD) (Ashok et al., 2017) and addiction (Hyman et al., 2006). In humans, the robust expansion and synapse formation of DA pathways during early postnatal development, which continues through adolescence (Larsen et al., 2020;Rothmond et al., 2012;Webster et al., 2011), aligns with proposals that dopaminergic perturbations contribute to neurodevelopmental disorders, notably, attention-deficit/ hyperactivity disorder (ADHD) (Gizer et al., 2009;Mazei-Robison et al., 2005;Yang et al., 2007) and autism spectrum disorder (ASD) (Hamilton et al., 2013;Pavăl, 2017). As reviewed below, evidence indicates that dysregulation of developmental DA signalling impacts brain function at the molecular, circuit and behavioral levels, with long-lasting effects on physiology and behavior that can persist throughout adulthood. ...
... In support for changes in developmental DA actions as impacting risk for neurobehavioral disorders, several human genetic studies have demonstrated an association between polymorphisms in dopaminergic genes and such conditions. Thus, polymorphisms in multiple DA receptors as well as DAT have been associated with risk for ADHD (Kustanovich et al., 2004;Mazei-Robison et al., 2008RibaséS et al., 2012;Wu et al., 2012;Yang et al., 2007). Correspondingly, alterations in the density of DA receptors in several brain regions of ADHD patients have been reported (reviewed on Prince, 2008) and gene x environment interactions for DAT and DA receptors with maternal use of alcohol and nicotine have been found (Brookes et al., 2006;Cortese, 2012;Neuman et al., 2007). ...
Dopamine (DA) signaling is critical to the modulation of multiple brain functions including locomotion, reinforcement, attention and cognition. The literature provides strong evidence that altered DA availability and actions can impact normal neurodevelopment, with both early and enduring consequences on anatomy, physiology and behavior. An appreciation for the developmental contributions of DA signaling to brain development is needed to guide efforts to preclude and remedy neurobehavioral disorders, such as attention-deficit/hyperactivity disorder, addiction, bipolar disorder, schizophrenia and autism spectrum disorder, each of which exhibits links to DA via genetic, cellular and/or pharmacological findings. In this review, we highlight research pursued in preclinical models that use genetic and pharmacological approaches to manipulate DA signaling at sensitive developmental stages, leading to changes at molecular, circuit and/or behavioral levels. We discuss how these alterations can be aligned with traits displayed by neuropsychiatric diseases. Lastly, we review human studies that evaluate contributions of developmental perturbations of DA systems to increased risk for neuropsychiatric disorders.
... Naturally, our third aim was to then examine if any of these genes might also be related to those second-order traits we found in our related study to influence variation in ELE. In view of earlier research cited above on a possible role of DAT1 and DRD4 in life expectancy, we hypothesized that polymorphisms of those genes that previously related to ADHD (Wu et al., 2012;Yang et al., 2007) would also be related to ELE here. We did not have an explicit hypothesis concerning the role of DBH Taq1 polymorphisms in ELE but explored it here because of its role, like the other genes, in dopamine signaling and metabolism and potential association with ADHD (Nyman et al., 2007). ...
... Participants voluntarily gave blood samples from which we genotyped four candidate genes that were believed to pose some risk for ADHD in prior research at the time of this follow-up evaluation (Nyman et al., 2007;Wu et al., 2012;Yang et al., 2007). These were the dopamine 4 receptor density gene (DRD4) VNTRs ≥7 repeats versus ≤6 repeats, the dopamine 1 transporter gene (DAT1) VNTR of 9 or 10 repeat allele pairings (rs28363170), the dopamine beta-hydroxylase gene (DBH) TaqI alleles for A1 and A2 polymorphisms (rs2519152), and the orphan nuclear receptor involved in dopamine cell development in the ventral tegmental area NR4A2 (Nurr 1). ...
ADHD is associated with an elevated risk of mortality and reduced estimated life expectancy (ELE) by adulthood. Reduced life expectancy is substantially related to the trait of behavioral disinhibition; a correlate of both ADHD and of several dopamine genes related to dopamine signaling and metabolism. We therefore hypothesized that several ADHD risk genes related to dopamine might also be predictive of reduced ELE. Using a longitudinal study of 131 hyperactive children and 71 control cases followed to young adulthood, we examined whether several polymorphisms involving DRD4, DAT1, and DBH were related to ELE. The homozygous 9/9 allele of DAT1 and the heterozygous allele of DBH TaqI were associated with 5‐ and 2‐year reductions, respectively, in total ELE. They did not operate on ELE through any relationships to ADHD specifically or behavioral disinhibition more generally. Instead, they showed links to alcohol use (DBH), reduced education, smoking, and reduced exercise (DAT1) employed in the computation of ELE. We conclude that polymorphisms of two dopamine genes are linked to reductions in ELE independently of their association with ADHD.
... In the present study, we were able to extend this observation, further discovering that the amounts of methylation are also correlated with DAT-aAbs titers, depending on genotype, and hence with ADHD symptoms' severity or with likelihood to respond positively to treatment. There is extensive literature with discordant results on the involvement of 3′-UTR VNTR polymorphism of DAT in ADHD [17,31,79] as far as severity is concerned but also for likelihood to respond after treatment [47,64]. These studies indicate that the 3′ VNTR might not be the functional site itself, but it could act as a tagging marker for an alternative functional site that contributes to the ADHD phenotype [79]. ...
... There is extensive literature with discordant results on the involvement of 3′-UTR VNTR polymorphism of DAT in ADHD [17,31,79] as far as severity is concerned but also for likelihood to respond after treatment [47,64]. These studies indicate that the 3′ VNTR might not be the functional site itself, but it could act as a tagging marker for an alternative functional site that contributes to the ADHD phenotype [79]. It is, however, quite new to find a role for the 5′-UTR in general and for specific CpG methylation sites in particular, especially as it is clearly a function of VNTR at 3′-UTR; therefore, we deal with factors residing thousands of base pairs apart. ...
In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.
... In particular, the 10-repeat allele has been associated with greater expression of the gene compared to the 9-repeat allele (Fuke et al., 2001), a relation that appears to be positively associated with the number (either none, one, or two) of 10r alleles (Mill et al., 2002). Moreover, density of the DAT binding site is about 50% higher for carriers of the 10r allele, a phenotype that functionally translates into less availability of DA in the synaptic space, and hence hypoactivity of the DA pathways (VanNess et al., 2005;Yang et al., 2007). ...
... At the cognitive and behavioral levels, a large bulk of clinical studies have linked DAT functioning and variations of the SLC6A3/DAT1 gene to ADHD. For instance, several studies have reported an increased density of DAT in children and adults diagnosed with ADHD (Cheon et al., 2003;Krause et al., 2003) and meta-analytic studies have found significant associations between the 10r allele of the DAT1 and ADHD (Yang et al., 2007;Gizer et al., 2009; although see Rommelse et al., 2008 for contradictory results). Neuroimaging studies have also shown that homozygosity for the 10r allele is associated with reduced cortical thickness in the prefrontal cortex in children and adolescents diagnosed with ADHD (Fernández-Jaén et al., 2015). ...
Development of self-regulation, the capacity to voluntarily modulate thoughts, emotions and actions is strongly related to the maturation of the dopamine-mediated executive attention network (EAN). The attention control processes associated with the EAN greatly overlap with efficiency of the executive functions and are correlated with measures of effortful control. Regulation of dopamine levels within the EAN, particularly in the basal ganglia is carried out by the action of dopamine transporters. In humans, the SLC6A3/DAT1 gene carries out the synthesis of the DAT protein. The 10-repeat allele has been associated with an enhanced expression of the gene and has been related to ADHD symptoms. Little is known about the impact of DAT1 variations on children's capacity to self-regulate in contexts that impose particular demands of regulatory control such as the school or home. This study defines a multi-domain phenotype of self-regulation and examines whether variations of the DAT1 gene accounts for individual differences in performance in 4–5 year old children. Results show that presence of the 10r allele is related to a diminished ability to exert voluntary regulation of reactivity. These findings shed light on the neurobiological mechanisms underlying individual differences in self-regulation during childhood.
... 22,23 This result is intriguing, given that 3 meta-analyses have reported a small but significant association between the 10R allele and genetic susceptibility to ADHD. 6,7,24 Despite all data from the literature demonstrating that ADHD traits are normally distributed in the population, a recent study suggested a different genetic architecture for ADHD and ADHD traits. 25 In this context, genes identified as risk factors for a full categorical diagnosis of ADHD would not necessarily be associated with ADHD traits in the general population. ...
... 9, 10 We chose the DAT1 10R allele as the reference based on the results of previous meta-analyses. 6,7,24 Other alleles (3R, 5R, 6R, 7R, 8R, 9R, 11R, and 12R) were pooled owing to low frequency. ...
Background:
Attention-deficit/hyperactivity disorder (ADHD) symptoms are dimensionally distributed in the population. This study aimed to assess the role of the catechol-O-methyltransferase (COMT) and of the dopamine transporter (DAT1) genes on ADHD symptoms in the general population.
Methods:
We investigated 4101 individuals from the 1993 Pelotas Birth Cohort Study using the parent version of the Strengths and Difficulties Questionnaire (SDQ) at ages 11 and 15 years. The SDQ hyperactivity/inattention scores were the main outcomes.
Results:
Linear regression analyses demonstrated that the increasing number of COMT158Val and DAT1 10R alleles significantly predicted increasing SDQ hyperactivity/inattention scores in boys at both 11 and 15 years of age (β coefficient = 0.049, t = 2.189, p = 0.029, R2 = 0.012, and β coefficient = 0.064, t = 2.832, p = 0.005, R2 = 0.008, respectively). The presence of both COMT158Val and DAT1 10R alleles was also associated with full categorical ADHD diagnosis at 18 years of age in boys (χ2 = 4.561, p = 0.033, odds ratio 2.473, 95% confidence interval 1.048-5.838) from this cohort. We did not observe these associations in girls.
Limitations:
Our analyses of SDQ hyperactivity/inattention scores were not corrected for SDQ scores of conduct problems because these variables were highly correlated.
Conclusion:
This study demonstrates a role for COMT and DAT1 genes on hyperactivity/inattention symptoms and provides further support for ADHD as the extreme of traits that vary in the population. It also confirms previous evidence for sexual dimorphism on COMT and DAT1 gene expression.
... Intron 8 VNTR Associated with clinical ADHD in meta-analysis [Gizer et al., 2009]. Altered gene expression DAT1 3 0 UTR VNTR Associated with clinical ADHD in meta-analyses [Yang et al., 2007;Gizer et al., 2009]. ...
... Nineteen polymorphisms were selected on the basis of previous reports of association with ADHD [Bobb et al., 2005;Domschke et al., 2005;Sheehan et al., 2005;Xu et al., 2005Xu et al., , 2007Xu et al., , 2008Brookes et al., 2006;Li et al., 2006;Kim et al., 2007Kim et al., , 2008Yang et al., 2007;Lasky-Su et al., 2008a,b;Lesch et al., 2008;Ribases et al., 2008Ribases et al., , 2009Gizer et al., 2009]. SNPs associated with ADHD in these studies were included from the following genes: cadherin 13 (CDH13), ciliary neurotrophic factor receptor (CNTFR), DRD4, HTR1B, serotonin receptor (HTR2A), monoamine oxidase A (MAOA), norepinephrine transporter (SLC6A2), SLC6A3, SNAP-25, and tryptophan hydroxylase 2 (TPH2). ...
Family and twin studies have identified endophenotypes that capture familial and genetic risk in attention-deficit/hyperactivity disorder (ADHD), but it remains unclear if they lie on the causal pathway. Here, we illustrate a stepwise approach to identifying intermediate phenotypes. First, we use previous quantitative genetic findings to delineate the expected pattern of genetically correlated phenotypes. Second, we identify overlapping genetic associations with ADHD-related quantitative traits. Finally, we test for the mediating role of associated endophenotypes. We applied this approach to a sample of 1,312 twins aged 7-10. Based on previous twin model-fitting analyses, we selected hyperactivity-impulsivity, inattention, reading difficulties (RD), reaction time variability (RTV) and commission errors (CE), and tested for association with selected ADHD risk alleles. For nominally significant associations with both a symptom and a cognitive variable, matching the expected pattern based on previous genetic correlations, we performed mediation analysis to distinguish pleiotropic from mediating effects. The strongest association was observed for the rs7984966 SNP in the serotonin receptor gene (HTR2A), and RTV (P=0.007; unadjusted for multiple testing). Mediation analysis suggested that CE (38%) and RTV (44%) substantially mediated the association between inattention and the T-allele of SNP rs3785157 in the norepinephrine transporter gene (SLC6A2) and the T-allele of SNP rs7984966 in HTR2A, respectively. The SNPs tag risk-haplotypes but are not thought to be functionally significant. While these exploratory findings are preliminary, requiring replication, this study demonstrates the value of this approach that can be adapted to the investigation of multiple genetic markers and polygenic risk scores. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
... It has been suggested that the development of ADHD and associated behavioral disorders might be caused by abnormalities in the functioning of the plasma membrane DA transporter (DAT). A significant association between ADHD and the gene encoding the DAT was demonstrated (Mill et al., 2005;Yang et al., 2007), and altered DAT expression in the striatum of patients with ADHD symptoms was shown (Madras et al., 2005). Furthermore, it is well known that patients with ADHD react favorably to therapy with Ritalin (methylphenidate) and Adderall (amphetamine), which target DAT (Dresel et al., 2000). ...
Attention deficit hyperactivity disorder (ADHD) is believed to be connected with a high level of hyperactivity caused by alterations of the control of dopaminergic transmission in the brain. The strain of hyperdopaminergic dopamine transporter knockout (DAT-KO) rats represents an optimal model for investigating ADHD-related pathological mechanisms. The goal of this work was to study the influence of the overactivated dopamine system in the brain on a motor cognitive task fulfillment. The DAT-KO rats were trained to learn an object recognition task and store it in long-term memory. We found that DAT-KO rats can learn to move an object and retrieve food from the rewarded familiar objects and not to move the non-rewarded novel objects. However, we observed that the time of task performance and the distances traveled were significantly increased in DAT-KO rats in comparison with wild-type controls. Both groups of rats explored the novel objects longer than the familiar cubes. However, unlike controls, DAT-KO rats explored novel objects significantly longer and with fewer errors, since they preferred not to move the non-rewarded novel objects. After a 3 months’ interval that followed the training period, they were able to retain the learned skills in memory and to efficiently retrieve them. The data obtained indicate that DAT-KO rats have a deficiency in learning the cognitive task, but their hyperactivity does not prevent the ability to learn a non-spatial cognitive task under the presentation of novel stimuli. The longer exploration of novel objects during training may ensure persistent learning of the task paradigm. These findings may serve as a base for developing new ADHD learning paradigms.
... Zhang et al. 2008;Neckameyer and White 1993;Riemensperger et al. 2011) . An imbalance in dopamine levels due to altered DAT function is associated with various neurological disorders and addiction in humans (Yang et al. 2007;S.-I. Ueno 2003) . ...
Geneticists use olfactory conditioning in Drosophila to identify learning genes; however, little is known about how these genes are integrated into short-term memory (STM) pathways. Here, we investigated the hypothesis that the STM evidence base is weak. We performed systematic review and meta-analysis of the field. Using metrics to quantify variation between discovery articles and follow-up studies, we found that seven genes were both highly replicated, and highly reproducible. However, ~80% of STM genes have never been replicated. While only a few studies investigated interactions, the reviewed genes could account for >1000% memory. This large summed effect size could indicate irreproducibility, many shared pathways, or that current assay protocols lack the specificity needed to identify core plasticity genes. Mechanistic theories of memory will require the convergence of evidence from system, circuit, cellular, molecular, and genetic experiments; systematic data synthesis is an essential tool for integrated neuroscience.
... Finally, dopaminergic genes seem important to understanding genetic risk for antisocial behavior and psychopathy. Early research found that dopamine regulating genes such as DAT1 and dopamine beta-hydroxylase (DβH) are associated with low behavioral control and aggression (Caspi et al., 2003;Guo et al., 2010;Li et al., 2006;Moffitt, 2005;Yang et al., 2007), whereas other research has found that the DRD3 is positively associated with impulsivity (Retz et al., 2003). The dopamine receptor genes, especially DRD4, have shown a generally positive relationship with antisocial behavior, despite the complex relationship between dopamine and cognitive functioning (Daigle, 2010). ...
Psychopathy is of great interest to criminologists, given its consistent association with violence, offending, and antisocial behavior. However, the etiology of psychopathy, particularly in terms of a gene × environment (G×E) interaction, has had little examination in the literature. One study has examined the direct and interactive effects of two genotypes (MAOA, 5-HTT) and childhood trauma on psychopathic traits using a high-risk forensic sample of adult males, and identified G×E interactions that may help us understand this complex phenotype. However, given the difficulties replicating G×E research, particularly with antisocial phenotypes, this study conducts a replication and expansion of prior research by examining direct and interactive effects of three genotypes (MAOA, 5-HTT, DRD4) and childhood trauma on psychopathy using a high-risk community sample of males and females. Results only partially support prior findings, illustrating the need for additional replication research in the biopsychosocial and epigenetic arenas.
... DTDS symptomatology is directly caused by impaired DAT functioning due to various loss-of-function mutations found in SLC6A3 DAT gene [9][10][11]. The DAT gene mutations are also associated with ADHD, and there are indications that DAT expression level in the striatum of such patients might be affected [12][13][14][15]. Furthermore, a functional mutation in the gene SLC6A3 that codes DAT was found in patients with ADHD and early Parkinson symptoms [16]. ...
Understanding the role of the dopamine system in learning and memory processes is very important for uncovering central mechanisms underlying complex behavioral responses that can be impaired in patients with neuropsychiatric disorders caused by dopamine system dysfunction. One of the most useful animal models for dopaminergic dysregulation is the strain of dopamine transporter knockout (DAT-KO) rats that have no dopamine re-uptake and thus elevated extracellular dopamine levels. It is known that dopamine is involved in various cognitive processes such as learning, memory and attention. This investigation was focused on the ability of DAT-KO rats to learn and perform a behavioral task in the 8-arm radial maze test. It was found that DAT-KO rats are able to learn the behavioral task, but the level of task performance did not reach that of WT group. The behavioral tactics used by animals during training significantly differ in mutants. The behavioral tactics used by DAT-KO rats involved perseverations and resulted in worse task fulfillment in comparison to wild-type controls. The data obtained indicate that deficient dopamine reuptake results in an impairment of working memory and perseverative behavioral tactics in DAT-KO rats.
... Many studies have investigated the association of this VNTR with ADHD, but with highly variable results. The 10R/10R genotype of SLC6A3 is thought to be a risk factor for ADHD in children 31 , the 9R/9R genotype is associated with persistent ADHD in adulthood 32 . Barkley et al. 33 reported 9R/10R genotype as reliably associated with symptoms of ADHD (hyperactivity, impulsivity, externalizing and pervasive behavioral problems in both children and adolescents) 33 . ...
Neuropharmacological and human clinical studies have suggested that the brain dopaminergic system is substantively involved in normal and pathological phenotypes of attention. Dopamine transporter gene (SLC6A3) was proposed as a candidate gene for Attention-Deficit/Hyperactivity Disorder (ADHD). We investigated the effect of the SLC6A3 variants on cognitive performance in ADHD and healthy children and teenagers. Participants completed cognitive tasks measuring attentional switching, selective and sustained attention, and effectiveness of alerting, orienting and executive attention. We estimated the effects of 40 bp variable number of tandem repeat (VNTR) polymorphism located in the 3′ untranslated region (3′ UTR) (9-repeat vs 10-repeat allele) of the SLC6A3 gene, ADHD diagnosis, age, and their interactions as predictors of cognitive performance. ADHD children demonstrated deficits in most of the examined attention processes, persistent within the examined age range (9–16 years). No significant effects were observed for the interaction of ADHD and the SLC6A3 polymorphism, but the results revealed a significant main effect of SLC6A3 genotype in the entire research sample. Subjects carrying 9R allele performed the switching task significantly worse in comparison to children with 10R/10R or 10R/11R genotype. SLC6A3 polymorphism moderated age-related improvements in orienting and attentional switching. Results suggest that SLC6A3 genotype influence these attentional/cognitive functions which deficits are not the key symptoms in ADHD.
... Polymorphisms of dopamine transporter gene SLC6A3 have been associated with altered transcriptional activity of dopamine transporter and thus have been investigated and associated with attention deficit hyperactivity disorder, schizophrenia, and Parkinson's disease. [5,6] Another regulator of dopamine levels is catechol-o-methyl transferase (COMT) which has been considered as a treatment target of cognitive symptoms in schizophrenia. Because of its function in the prefrontal cortex, COMT became a gene candidate in genetic association studies for schizophrenia. ...
Context:
Schizophrenia has been associated with disorder of the dopamine system, which is downregulated by projections of the serotonin pathway. Dopamine and serotonin levels are regulated by a system of transporters and enzymes. In this research, dopamine transporter polymorphism (DAT-VNTR), serotonin transporter polymorphism (5-HTTLPR), monoamine oxidase A (MAOA-uVNTR), and catechol-o-methyl transferase (COMT Val158Met) polymorphisms have been investigated.
Aims:
The aim of this study was to asses frequencies of these polymorphisms in the healthy control group and patients and to asses association with schizophrenia.
Settings and design:
Three hundred and fourteen healthy volunteers and 306 schizophrenia patients were included. Schizophrenia was diagnosed by Diagnostic and Statistical Manual-IV of the American Psychiatric Association, and mini international neuropsychiatric interview questionnaire was used for screening of healthy population.
Materials and methods:
Genotyping was performed using polymerase chain reaction (PCR) reaction followed by gel electrophoresis and PCR-restriction fragment length polymorphism.
Statistical analysis:
Categorical data were analyzed using the Chi-square test, age between subgroups was compared using the Mann-Whitney test, and all polymorphisms were tested for Hardy-Weinberg equilibrium. Logistic regression analysis was used to set the prediction model of schizophrenia.
Results:
Difference in genotype distribution was observed for COMT Val158Met in female and DAT-VNTR polymorphism in overall sample P = 0.021 and P = 0.028, respectively. Statistically significant association of MAOA-uVNTR and schizophrenia was observed after adjustment for anamnestic predictors of disease. P = 0.010, 80.45% participants were correctly classified.
Conclusion:
Our results suggest an association of MAOA-uVNTR polymorphism with schizophrenia. The difference in the distribution of COMT Val158Met and DAT-VNTR polymorphism support the involvement of dopamine system components in the pathogenesis of schizophrenia.
... . Implication dans le trouble de déficit d'attention avec hyperactivitéDepuis plus de 20 ans, le disfonctionnement de DAT a été beaucoup étudié lors de recherches sur le TDAH(328). En 1995, Cook et ses collègues ont rapporté qu'un polymorphisme sur la partie non codante du gène de DAT entrainait un risque accru de développer le TDAH(329).Par la suite, d'autres études ont confirmé ces résultats(329)(330)(331). Alors que les bases moléculaires de cette association ne sont pas claires, il a été démontré que ce polymorphisme peut impacter l'expression du gène de DAT(332,333). ...
La mélatonine est une neurohormone produite principalement par la glande pinéale de manière circadienne et agissant par l’activation de deux récepteurs couplés aux protéines G (RCPGs) appelés MT1 et MT2. La mélatonine régule de nombreuses fonctions physiologiques importantes. La régulation des niveaux de dopamine (DA) et de glucose en font partie mais nous ne savons pas clairement comment la mélatonine les régule.Les niveaux de DA extracellulaire sont principalement régulés par son transporteur (DAT) responsable de sa recapture dans les neurones présynaptiques afin de prévenir d’une hyperactivation des récepteurs dopaminergiques. Par conséquent, nous avons vérifié le rôle de DAT dans la régulation du système dopaminergique par le système mélatoninergique. Nous avons montré qu’en interagissant avec la forme immature non-glycosylée de DAT, MT1 et MT2 le retiennent dans le réticulum endoplasmique régulant ainsi son expression à la surface cellulaire et donc la recapture de la DA. De la même manière, les souris déficientes en MT1 ou MT2 ont montré une augmentation de la recapture de la DA dans les synaptosomes de striatum et une baisse de l’hypermotilité induite par l’amphétamine. Dans ce projet nous avons ainsi révélé un nouveau lien entre les systèmes mélatoninergiques et dopaminergiques basé sur la formation de complexes moléculaires entre les récepteurs de la mélatonine et DAT.Afin de mieux comprendre le rôle de la mélatonine dans la régulation des niveaux de glucose, nous avons ensuite étudié l’implication de variants génétiques de MT2 dans le développement du diabète de type 2 (DT2). Des études antérieures avaient montré que des variants naturels défectueux fonctionnellement étaient associés à un risque de développer le DT2. Afin de déterminer plus précisément les propriétés défectueuses en lien avec le DT2, nous avons mesuré l’activation spontanée et celle induite par la mélatonine de 40 variants MT2. Nous avons ainsi montré que des défauts d’activation des protéines Gαi et Gαz induite par la mélatonine et de recrutement spontané de la βarrestine-2 sont significativement reliés à un risque de développer le DT2. Les résultats expérimentaux corrélaient avec les prédictions de l’analyse sur le score d’évolution. Ce travail permettra de nouvelles avancées dans la recherche de traitements personnalisés pour les personnes portants les mutations sur MT2 afin qu’il retrouve une réponse non défectueuse.Le séquençage de 9393 personnes a permis l’identification de 32 variants naturels MT1. Le récepteur MT1 sauvage et les variants ont ainsi été caractérisés grâce aux techniques de transfert d’énergie par résonnance de bioluminescence (BRET). Nous avons montré que MT1 active les protéines Gαi/o, Gα12 et Gα15 et recrute la βarrestine-2. L’analyse des résultats par factorisation matricielle non linéaire a révélé l’existence de 5 clusters caractérisés par différents profils de signalisation. La modélisation 3D par homologie de MT1 a permis de déterminer l’impact de chaque variant sur l’activation du récepteur et ses interactions avec les protéines G et la βarrestine-2. Ce projet a ainsi permis de démontrer que des variants naturels sont très intéressant afin de comprendre les mécanismes d’action des RCPGs. En résumé, ce travail contribue à la compréhension des fonctions des récepteurs à la mélatonine et souligne leur importance dans la régulation du système dopaminergique et de l’homéostasie glucidique. Nos résultats offrent de nouvelles perspectives dans la recherche de nouveaux traitements personnalisés pour les patients souffrant d’un dérèglement du système dopaminergique ou de DT2.
... DNA repeats influence chromatin organization, gene activity, and regulation of DNA metabolic processes. Alleles of genes carrying altered minisatellites have been correlated with a number of severe diseases, such as progressive myoclonus epilepsy [9], insulin-dependent diabetes mellitus [10], attention-deficit hyperactivity disorder [11], asthma [12], ulcerative colitis [13] and several cancer subtypes [14][15][16]. Expansions in trinucleotide repeats in humans can cause Huntington's disease, myotonic dystrophy, spinocerebellar ataxia, and many other neurodegenerative disorders [17][18][19]. ...
Faithful replication and repair of DNA lesions ensure genome maintenance. During replication in eukaryotic cells, DNA is unwound by the CMG helicase complex, which is composed of three major components: the Cdc45 protein, Mcm2-7, and the GINS complex. The CMG in complex with DNA polymerase epsilon (CMG-E) participates in the establishment and progression of the replisome. Impaired functioning of the CMG-E was shown to induce genomic instability and promote the development of various diseases. Therefore, CMG-E components play important roles as caretakers of the genome. In Saccharomyces cerevisiae, the GINS complex is composed of the Psf1, Psf2, Psf3, and Sld5 essential subunits. The Psf1-1 mutant form fails to interact with Psf3, resulting in impaired replisome assembly and chromosome replication. Here, we show increased instability of repeat tracts (mononucleotide, dinucleotide, trinucleotide and longer) in yeast psf1-1 mutants. To identify the mechanisms underlying this effect, we analyzed repeated sequence instability using derivatives of psf1-1 strains lacking genes involved in translesion synthesis, recombination, or mismatch repair. Among these derivatives, deletion of RAD52, RAD51, MMS2, POL32, or PIF1 significantly decreased DNA repeat instability. These results, together with the observed increased amounts of single-stranded DNA regions and Rfa1 foci suggest that recombinational mechanisms make important contributions to repeat tract instability in psf1-1 cells. We propose that defective functioning of the CMG-E complex in psf1-1 cells impairs the progression of DNA replication what increases the contribution of repair mechanisms such as template switch and break-induced replication. These processes require sequence homology search which in case of a repeated DNA tract may result in misalignment leading to its expansion or contraction.
... The 10-repeat (10R) and ninerepeat (9R) alleles of this VNTR are the most frequently occurring (Vandenbergh et al., 1992). Although several studies have reported a significant association between the DAT1 3′ UTR 10R allele and ADHD (Cook et al., 1995;Faraone et al., 2005;Yang et al., 2007), others have suggested that it may be the 9R allele that is preferentially transmitted in individuals with ADHD (Franke et al., 2008) and a meta-analysis found no evidence of association with ADHD and the DAT1 VNTR polymorphism (Li, Sham, Owen, & He, 2006). The functional effect of DAT1 polymorphism was also unclear. ...
... One of these VNTRs (rs28363170), located on the dopamine transporter gene (SLC6A3 / DAT1) in the 3′ untranslated region (UTR), with the 10-and 9-repeat alleles that are most common (Doucette-Stamm et al. 1995), were found to be associated with ADHD. In particular, the 10-repeat allele was described in several meta-analyses to associate with child and adolescent ADHD, though with a rather low effect size and in most cases with high heterogeneity between studies due to clinical phenotyping, age and ethnicity (Gizer et al. 2009;Yang et al. 2007). Nevertheless, further studies kept looking into the association between DAT1 gene and ADHD, also due to significant linkage findings with the chromosomal location 5p13 containing the gene and ADHD (Friedel et al. 2007). ...
Attention-deficit hyperactivity disorder (ADHD) has been postulated to associate with dopaminergic dysfunction, including the dopamine transporter (DAT1). Several meta-analyses showed small but significant association between the 10-repeat allele in the DAT1 gene in 3'-untranslated region variant number tandem repeat polymorphism and child and adolescent ADHD, whereas in adult ADHD the 9-repeat allele was suggested to confer as risk allele. Interestingly, recent evidence indicated that the long-allele variants (10 repeats and longer) might confer to lower expression of the transporter in comparison to the short-allele. Therefore, we assessed here the association in samples consisting of families with child and adolescent ADHD as well as a case-control sample, using either the 10- versus 9-repeat or the long- versus short-allele approach. Following, we conducted a systematic review and meta-analysis, including family and case-control studies, using the two aforementioned approaches as well as stratifying to age and ethnicity. The first approach (10-repeat) resulted in nominal significant association in child and adolescent ADHD (OR 1.1050 p = 0.0128), that became significant stratifying to European population (OR 1.1301 p = 0.0085). The second approach (long-allele) resulted in significant association with the whole ADHD population (OR 1.1046 p = 0.0048), followed by significant association for child and adolescent ADHD (OR 1.1602 p = 0.0006) and in Caucasian and in European child and adolescent ADHD (OR 1.1310 p = 0.0114; OR 1.1661 p = 0.0061; respectively). We were not able to confirm the association reported in adults using both approaches. In conclusion, we found further indication for a possible DAT1 gene involvement; however, further studies should be conducted with stringent phenotyping to reduce heterogeneity, a limitation observed in most included studies.
... A meta-analysis of the literature (Yang et al. 2007) on the neurotransmitter dopamine, DAT1, which has previously been associated with the expression of ADHD symptoms (including inefficient executive function, inattention, and impulsivity), revealed a weak, but statistically significant association between the gene and the disorder. Specifically, individuals inherit one of the two alleles (forms) of this gene, DAT1 10 or DAT1 9. ...
The full text of this article may be found here: http://rdcu.be/ytuG
From the first mention of impairments in attention in the scientific literature by the Scottish physician Alexander Crichton in 1798, the correlation between educational attainment and learning has been persistently noted. Since then, the impact of attention deficits on school achievement has been a central component in a significant portion of research, despite continual disagreements within the scientific community on identification, diagnosis, and efficacious interventions to address core symptoms of what is now referred to as Attention Deficit-Hyperactivity Disorder (ADHD). This article provides the historical context in which the construct of ADHD was developed, as well as a discussion of two commonly used interventions to address symptoms of ADHD (e.g., pharmaceuticals and the use of electroencephalographic [EEG] operant conditioning, or “neurofeedback.”). While use of pharmaceutical interventions is relegated only to medical professionals, neurofeedback may have the potential to be used by highly trained special educators and school psychologists in academic settings.
... The 10R allele has also been consistently implicated in increased susceptibility to attention deficit disorder (ADD) (Cook et al., 1995;Gill, Daly, Heron, Hawi, & Fitzgerald, 1997;Gizer, Ficks, & Waldman, 2009;Kebir, Tabbane, Sengupta, & Joober, 2009;Newman et al., 2014). Although it remains unclear whether this association is mediated by the dopamine or dopamine transporter levels (Yang et al., 2007), it suggests that homozygous 10R allele carriers are more likely than others to exhibit poor attentional processing, e.g. difficulty filtering out irrelevant sensory stimuli, which is a key symptom of ADD (American Psychiatric Association, 2000). ...
Studies testing the benefits of enriching smoking-cessation video ads with “attention grabbing” sensory features have yielded variable results. Dopamine transporter gene (DAT1) has been implicated in attention deficits. We hypothesized that DAT1 polymorphism is partially responsible for this variability. Using functional magnetic resonance imaging, we examined brain responses to videos high or low in “attention grabbing” features, indexed by “message sensation value” (MSV), in 53 smokers genotyped for DAT1. Compared to other smokers, 10/10 homozygotes showed greater neural response to High- vs. Low-MSV smoking-cessation videos in two a priori regions of interest: the right temporoparietal junction and the right ventrolateral prefrontal cortex. These regions are known to underlie stimulus-driven attentional processing. Exploratory analysis showed that the right temporoparietal response positively predicted follow-up smoking behavior indexed by urine cotinine. Our findings suggest that responses to “attention grabbing” features in smoking-cessation messages is affected by the DAT1 genotype.
... Initially, Cook et al. (1995) reported that the VNTR polymorphism in the 3 0 untranslated region of the DAT-1 allele conferred significant risk for developing ADHD. Other independent studies including a meta-analysis confirmed this result (Gill et al., 1997;Chen et al., 2003;Yang et al., 2007). While the precise molecular basis for this association is unclear, it has been shown that the VNTR polymorphism can impact expression of the DAT gene (Michelhaugh et al., 2001;Mill et al., 2002). ...
Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are two regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move transmitter efficiently throughout the neuron. The accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine. This article is protected by copyright. All rights reserved.
... Transports dopamine out of the synapse VNTR; shorter allele is risk; 10+repeats=L ; <10 repeats=S/risk Meta-analyses: Brookes et al. 2006;Jonas and Markon 2014;Li et al. 2006;Maher et al. 2002;Stapleton et al. 2007;Yang et al. 2007 Dopamine D2 Receptor (DRD2) Encodes D2 subtype of the dopamine receptor, activated by dopamine SNP, A1 or A2; A1 allele is risk Meta-analyses: Bakermans-Kranenburg and van Ijzendoorn 2011;Lopez et al. 2005;Ohmoto et al. 2013;Zhang et al. 2014;Zou et al. 2012 Notes. VNTR = Variable Number of Tandem Repeats, SNP = Single Nucleotide Polymorphism. ...
Abstract
This study presents results from a collaboration across five longitudinal studies seeking to test and replicate models of gene–environment interplay in the development of substance use and externalizing disorders (SUDs, EXT). We describe an overview of our conceptual models, plan for gene–environment interplay analyses, and present main effects results evaluating six candidate genes potentially relevant to SUDs and EXT (MAOA, 5-HTTLPR, COMT, DRD2, DAT1, and DRD4). All samples included rich longitudinal and phenotypic measurements from childhood/adolescence (ages 5–13) through early adulthood (ages 25–33); sample sizes ranged from 3487 in the test sample, to ~600–1000 in the replication samples. Phenotypes included lifetime symptom counts of SUDs (nicotine, alcohol and cannabis), adult antisocial behavior, and an aggregate externalizing disorder composite. Covariates included the first 10 ancestral principal components computed using all autosomal markers in subjects across the data sets, and age at the most recent assessment. Sex, ancestry, and exposure effects were thoroughly evaluated. After correcting for multiple testing, only one significant main effect was found in the test sample, but it was not replicated. Implications for subsequent gene–environment interplay analyses are discussed.
... However, the results remain ambiguous, which probably is attributable to sampling bias, different diagnostic criteria of alcoholism, low statistical power, the variability of the selection of AD cases, or some combination thereof. Significantly, accumulating evidence has indicated that association studies based on small samples have insufficient statistical power, causing pronouncedly contradictory findings (Yang et al., 2007). A Fig. 2 . ...
Background:
Although many studies have analyzed the association of 3'-untranslated region variable-number tandem repeat (VNTR) polymorphism in SLC6A3 with alcohol dependence (AD), the results remain controversial. This study aimed to determine whether this variant indeed has any genetic effect on AD by integrating 17 reported studies with 5,929 participants included.
Methods:
The A9-dominant genetic model that considers A9-repeat and non-A9 repeat as 2 genotypes and compared their frequencies in alcoholics with that in controls was adopted. Considering the potential influence of ethnicity, differences in diagnostic criteria of AD, and alcoholic subgroups, stratified meta-analyses were conducted. There existed no evidence for the presence of heterogeneity among the studied samples, indicating the results under the fixed-effects model are acceptable.
Results:
We found a significant association of VNTR A9 genotypes with AD in all ethnic populations (pooled odds ratio [OR] 1.12; 95% confidence interval [CI] 1.00, 1.25; p = 0.045) and the Caucasian population (pooled OR 1.15; 95% CI 1.01, 1.31; p = 0.036). We also found VNTR A9 genotypes to be significantly associated with alcoholism as defined by the DSM-IV criteria (pooled OR 1.18; 95% CI 1.03, 1.36; p = 0.02). Further, we found a significant association between VNTR A9 genotypes and alcoholism associated with alcohol withdrawal seizure or delirium tremens (pooled OR 1.55; 95% CI 1.24, 1.92; p = 1.0 × 10(-4) ). In all these meta-analyses, no evidence of publication bias was detected.
Conclusions:
We concluded that the VNTR polymorphism has an important role in the etiology of AD, and individuals with at least 1 A9 allele are more likely to be dependent on alcohol than persons carrying the non-A9 allele.
... Table 2 also summarizes the results of the genetic association analysis. The variant analysis was conducted in the DHS -Mind cohort to evaluate the association of dopaminergic and other literaturesupported polymorphisms with cognitive performance adjusting for age, sex, T2D status, and education Assuming an additive model with the 10 repeat allele as the risk allele (Yang et al. 2007), the DAT1 VNTR was not significantly associated with any cognitive phenotypes ( Table 2). The most suggestive association was with poorer performance (i.e., higher score) on the Stroop-IV, which measures difficulty in color-naming due to interference of the conflicting printed words known as the stroop effect (P = 0.253; b = 0.029). ...
Background:
There is an established association between type 2 diabetes and accelerated cognitive decline. The exact mechanism linking type 2 diabetes and reduced cognitive function is less clear. The monoamine system, which is extensively involved in cognition, can be altered by type 2 diabetes status. Thus, this study hypothesized that sequence variants in genes linked to dopamine metabolism and associated pathways are associated with cognitive function as assessed by the Digit Symbol Substitution Task, the Modified Mini-Mental State Examination, the Stroop Task, the Rey Auditory-Verbal Learning Task, and the Controlled Oral Word Association Task for Phonemic and Semantic Fluency in the Diabetes Heart Study, a type 2 diabetes-enriched familial cohort (n = 893).
Methods:
To determine the effects of candidate variants on cognitive performance, genetic association analyses were performed on the well-documented variable number tandem repeat located in the 3' untranslated region of the dopamine transporter, as well as on single-nucleotide polymorphisms covering genes in the dopaminergic pathway, the insulin signaling pathway, and the convergence of both. Next, polymorphisms in loci of interest with strong evidence for involvement in dopamine processing were extracted from genetic datasets available in a subset of the cohort (n = 572) derived from Affymetrix(®) Genome-Wide Human SNP Array 5.0 and 1000 Genomes imputation from this array.
Results:
The candidate gene analysis revealed one variant from the DOPA decarboxylase gene, rs10499695, to be associated with poorer performance on a subset of Rey Auditory-Verbal Learning Task measuring retroactive interference (P = 0.001, β = -0.45). Secondary analysis of genome-wide and imputed data uncovered another DOPA decarboxylase variant, rs62445903, also associated with retroactive interference (P = 7.21 × 10(-7), β = 0.3). These data suggest a role for dopaminergic genes, specifically a gene involved in regulation of dopamine synthesis, in cognitive performance in type 2 diabetes.
Neurodevelopmental disorders (NDDs) represent a group of heterogeneous disabilities characterized by impaired cognition, memory, learning abilities, self-control, and psychomotor skills. NDDs encompass many rare genetic syndromes and heritable genetic conditions such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Understanding the molecular etiology and pathophysiological mechanisms of NDDs is challenging, mainly owing to the genetic and phenotypic heterogeneity of these conditions and the fact that both heritable and environmental factors influence NDD risk. Despite the complex genetic architecture of NDDs, emerging evidence suggests that proteins involved in NDDs converge on common pathways, including synaptic function, chromatin remodeling, and mTOR. In-depth insight of the recent advancements in genomic technologies has enabled the identification of genetic mutations underlying NDDs and uncovered mechanisms behind these pathways that point towards treatment options. In this chapter, the authors review the available literature to compile a comprehensive set of genes and proteins underlying NDDs and identify signaling pathways involved in various NDDs.KeywordsNeurodevelopmental disordersAttention-deficit hyperactivity disorderAutism spectrum disorderIntellectual disabilityGenetic mutationsWhole-exome sequencingChromatin remodelingSynaptic functionTranscriptional pathwaysSignaling pathways
Child genotype is an important biologically based indicator of sensitivity to the effects of parental behavior on children’s executive function (EF) in early childhood, birth to age 5. While evidence for gene × parental behavior interactions on children’s early EF is growing, researchers have called the quality of evidence provided by gene × environment interaction studies into question. For this reason, this review comprehensively examined the literature and evaluated the evidence for gene × parental behavior interactions on children’s early EF abilities. Psychology and psychiatry databases were searched for published peer-reviewed studies. A total of 18 studies met inclusion criteria. Twenty-nine of 89 (33%) examined interactions were significant. However, a p-curve analysis did not find the significant interactions to be of evidential value. A high rate of false positives, due to the continued use of candidate gene and haplotype measures of child genotype and small sample sizes, likely contributed to the high rate of significant interactions and low evidential value. The use of contemporary molecular genetic measures and larger sample sizes are necessary to advance our understanding of child genotype as a moderator of parental effects on children’s EF during early childhood and the biopsychosocial mechanisms underlying children’s EF development during this critical period. Without these changes, future research is likely to be stymied by the same limitations as current research.
Child genotype is an important biologically based individual difference conferring differential sensitivity to the effect of parental behavior. This study explored dopaminergic polygenic composite × parental behavior interactions in relation to young children’s executive function. Participants were 135 36-month-old children and their mothers drawn from a prospective cohort followed longitudinally from pregnancy. A polygenic composite was created based on the number of COMT, DAT1 , DRD2 , and DRD4 alleles associated with increased reward sensitivity children carried. Maternal negative reactivity and responsiveness were coded during a series of structured mother–child interactions. Executive function was operationalized as self-control and working memory/inhibitory control. Path analysis supported a polygenic composite by negative reactivity interaction for self-control. The nature of the interaction was one of diathesis-stress, such that higher negative reactivity was associated with poorer self-control for children with higher polygenic composite scores. This result suggests that children with a higher number of alleles may be more vulnerable to the negative effect of negative reactivity. Negative reactivity may increase the risk for developing behavior problems in this population via an association with poorer self-control. Due to the small sample size, these initial findings should be treated with caution until they are replicated in a larger independent sample.
Alterations in dopamine (DA) reuptake are involved in several psychiatric disorders whose symptoms can be investigated in knock out rats for the DA transporter (DAT-KO). Recent studies evidenced the role of epigenetic DAT modulation in depressive-like behavior. Accordingly, we used heterozygous (HET) rats born from both HET parents (termed MIX-HET), compared to HET rats born from WT-mother and KO-father (MAT-HET), implementing the role of maternal care on DAT modulation. We developed a "sudden fright" paradigm (based on dark-light test) to study reaction to fearful inputs in the DAT-KO, MAT-HET, MIX-HET, and WT groups. Rats could freely explore the whole 3-chambers apparatus; then, they were gently confined in one room where they experienced the fright; finally, they could freely move again. As expected, after the fearful stimulus only MAT-HET rats showed a different behavior consisting of avoidance towards the fear-associated chamber, compared to WT rats. Furthermore, ex-vivo immuno-fluorescence reveals higher prefrontal DAT levels in MAT-HET compared to MIX-HET and WT rats. Immuno-fluorescence shows also a different histone deacetylase (HDAC) enzymes concentration. Since HDAC concentration could modulate gene expression, within MAT-HET fore brain, the enhanced expression of DAT could well impair the corticostriatal-thalamic circuit, thus causing aberrant avoidance behavior (observed only in MAT-HET rats). DAT expression seems to be linked to a simply different breeding condition, which points to a reduced care by HET dams for epigenetic regulation. This could imply significant prefronto-cortical influences onto the emotional processes: hence an excessively frightful response, even to mild stressful agents, may draw developmental trajectories toward anxious and depressed-like behavior.
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioural in the children. Genetic factor is known one of the factors which contributed in ADHD development. VNTR polymorphism in 3’UTR exon 15 of DAT1 gene and exon 3 of DRD4 gene are reported to be associated in ADHD. In this study we examine the association of ADHD with VNTR polymorphism of DAT1 and DRD4 gene in Indonesian children. Sixty-five ADHD children and 70 normal children (6- 13 years of age), were included in the study, we matched by age and gender. ADHD was diagnosed by DSM-IV. We performed a casecontrol study to found the association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes. The 10-repeat allele of DAT1 and 2-repeat allele of DRD4 were higher in Indonesian children. Although the frequency of these allele was higher, but it was similar both in ADHD and control groups. Neither DAT1 nor DRD4 gene showed showed significant difference in genotype distribution and frequency allele between both groups (p > 0.05). No association between ADHD and VNTR polymorphism of DAT1 and DRD4 genes found in Indonesian children. This data suggest that DAT1 and DRD4 do not contribute to etiology of ADHD in Indonesian children. Further studies are needed to clarify association between VNTR polymorphism of DAT1 and DRD4 genetic with ADHD of Indonesian children in larger sample size and family based study.
Causal factors of psychiatric diseases are unclear, due to gene×environment interactions. Evaluation of consequences, after a dopamine-transporter (DAT) gene knock-out (DAT-KO), has enhanced understanding the pathological dynamics of several brain disorders, such as Attention-Deficit/Hyperactivity and Bipolar-Affective disorders. Recently, our attention has shifted to DAT hypo-functional (heterozygous, HET) rodents: HET dams display less maternal care and HET females display marked hypo-locomotion if cared by HET dams (Mariano et al., 2019). We assessed phenotypes of male DAT-heterozygous rats as a function of their parents: we compared "maternal" origin (MAT-HET, obtained by breeding KO-male rats with WT-female dams) to "mixed" origin (MIX-HET, obtained by classical breeding, both heterozygous parents) of the allele. MAT-HET subjects had significantly longer rhythms of daily locomotor activity than MIX-HET and WT-control subjects. Furthermore, acute methylphenidate (MPH: 0, 1, 2 mg/kg) revealed elevated threshold for locomotor stimulation in MAT-HETs, with no response to the lower dose. Finally, by Porsolt-Test, MAT-HETs showed enhanced escape-seeking (diving) with more transitions towards behavioral despair (floating). When comparing both MAT- and MIX-HET to WT-control rats, decreased levels of DAT and HDAC4 were evident in the ventral-striatum; moreover, with respect to MIX-HET subjects, MAT-HET ones displayed increased DAT density in dorsal-striatum. MAT-HET rats displayed region-specific changes in DAT expression, compared to "classical" MIX-HET subjects: greater DAT availability may elevate threshold for dopamine action. Further behavioral and epigenetic characterizations of MAT-HETs, together with deeper characterization of maternal roles, could help to explore parent-of-origin mechanisms for such a peculiar phenotype.
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Its etiology is not clearly understood yet, but neurobiological, genetic and environmental factors are shown to play a role. The relationship between ADHD and miRNAs has been studied quite recently, and few studies have been conducted up to now. In this study, peripheral blood expression levels of miR-5692b, miR-let-7d, miR-124-3p, miR-4447 and miR-107 of 30 children and adolescents with combined type ADHD were compared to 30 healthy controls to understand the roles of these miRNAs in the ADHD etiopathogenesis. Compared to controls, levels of miR-5692b (p = 0.006) were found higher and levels of miR-let-7d (p = 0.017) were found lower in the ADHD group. There was no significant difference in terms of miR-124-3p, miR-4447, and miR-107 levels between the groups. In conclusion, our findings support other studies suggesting the importance of miRNAs in the pathogenesis of ADHD. Regarding the regulatory role of miRNAs in gene regulation, their contribution to etiopathogenesis and heterogeneity of ADHD should be investigated further.
The article presents the overview of foreign and Russian behavioral disorder studies (e.g ADHD) in children and teens. Four approaches to the diagnosis and correction of ADHD in children and adolescents are identified: Anglo-Saxon (biomedical), French (socio-psychological), Russian (medical-psychological and neuropsychological), Asian (educational). Prospects on the etiopathogenetic mechanisms of the occurrence of behavioral disorders and their correction (medication, neuropsychological, psychotherapeutic, etc.) indicated.
It is well known that dopaminergic genes affect the development of attention deficit hyperactivity disorder (ADHD) in various populations. Many studies have shown that variable number tandem repeats (VNTRs) located within the 3′-untranslated region of DAT1 and in exon 3 of DRD4 are associated with ADHD development; however, these results were inconsistent. Therefore, we investigated the genetic association between two VNTRs and ADHD in Korean children. We determined the VNTRs using PCR. We examined genotype and allele frequency differences between the experimental and control groups, along with the odds ratios, using Chi square and exact tests. We observed a significant association between the children with ADHD and the control group in the 10R/10R genotype of DAT1 VNTRs (p = 0.025). In addition, the 11R allele of DAT1 VNTRs showed a higher frequency in the control group than in the ADHD group (p = 0.023). Also, the short repeat (without 11R) and long repeat alleles (including 11R) were associated with ADHD (p < 0.05). The analysis of DRD4 VNTRs revealed that the 2R allele is associated with ADHD (p = 0.025). A significant result was also observed in long and short repeats (p < 0.05). Additionally, ADHD subtypes showed that the DRD4 VNTRs are associated with combined and hyperactive-impulsive subtype groups (p < 0.05). Therefore, our results suggest that DAT1 VNTRs and DRD4 VNTRs play a role in the genetic etiology of ADHD in Korean children.
Geneticists use olfactory conditioning in Drosophila to identify learning genes; however, little is known about how these genes are integrated into short-term memory (STM) pathways. Here, we investigated the hypothesis that the STM evidence base is weak. We performed systematic review and meta-analysis of the field. Using metrics to quantify variation between discovery articles and follow-up studies, we found that seven genes were both highly replicated, and highly reproducible. However, ~80% of STM genes have never been replicated. While only a few studies investigated interactions, the reviewed genes could account for >1000% memory. This large summed effect size could indicate irreproducibility, many shared pathways, or that current assay protocols lack the specificity needed to identify core plasticity genes. Mechanistic theories of memory will require the convergence of evidence from system, circuit, cellular, molecular, and genetic experiments; systematic data synthesis is an essential tool for integrated neuroscience.
Attention deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder which affects children and adults. ADHD is one of the psychiatric disorders with the strongest genetic basis according to familial, twin and SNP‐based epidemiological studies. In this review, we provide an update of recent insights in the genetic basis of ADHD. We discuss recent progress from genome‐wide association studies (GWAS) looking at common variants as well as rare copy number variations (CNVs). New analysis of gene groups, so‐called functional ontologies, provide some insight into the gene networks afflicted, pointing to the role of neurodevelopmentally expressed gene‐networks. Bioinformatic methods such as functional enrichment analysis and protein–protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Additionally, CNVs seem to map on important pathways implicated in synaptic signalling and neurodevelopment. While some candidate gene associations of e.g. neurotransmitter receptors and signalling have been replicated, they do not seem to explain significant variance in recent GWAS. We discuss insights from recent case‐control SNP‐GWAS which gave whole‐genome significant SNPs in ADHD.
Although the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) were originally intended for children [1, 2], the criteria are the same for adults and can be reliably used to diagnose individuals who are currently experiencing symptoms of the disorder and have a history of these symptoms since early childhood [3, 4]. It is also necessary to document impairment in professional, academic, and personal settings and that the symptoms are due primarily to ADHD and not to another psychiatric condition or other environmental or personal circumstances. Rating scales can be quite helpful for documenting symptoms (ADHD symptom scales) or for more structured evaluations which can be used in fully establishing the diagnosis. A further utility of ADHD adult symptom scales can be in monitoring the response to treatment. There are several diagnostic interviews and symptom rating scales that can be used in the clinical evaluation of adults for ADHD (Tables 18.1 and 18.2), which are generally economical and effective in obtaining a large amount of data quickly, including symptom severity and response to treatment. Many of these measures include adult-specific prompts and probes designed to assess the impact and severity of ADHD symptoms using a semi-structured interview, which is particularly advantageous for clinicians who have limited experience in working with adult ADHD patients. There are also measures that assess ADHD-related impairments in executive function (EF), emotional regulation (ER), occupational, and quality-of-life domains.
Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val. We developed DAT Val559 knock-in mice, as a construct valid model of dopaminergic alterations that drive multiple clinical phenotypes, and here evaluate the impact of lifelong expression of the variant on impulsivity and motivation, utilizing the 5- choice serial reaction time task (5-CSRTT) and Go/NoGo as well as tests of time estimation (peak interval analysis), reward salience (sucrose preference), and motivation (progressive ratio test). Our findings indicate that the DAT Val559 variant induces impulsivity behaviors that are dependent upon the reward context, with increased impulsive action observed when mice are required to delay responding for a reward, whereas mice are able to withhold responding if there is a probability of reward for a correct rejection. Utilizing peak interval and progressive ratio tests, we provide evidence that impulsivity is likely driven by an enhanced motivational phenotype that also may drive faster task acquisition in operant tasks. These data provide critical validation that DAT, and more generally, DA signaling perturbations can drive impulsivity that can manifest in specific contexts and not others, and may rely on motivational alterations which may also drive increased maladaptive reward seeking.
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder of which three basic symptoms are lack of attention, over-activity that is improper to the age and impulsivity, all of which appear in childhood. Its incidence is %5-12 in children and %4.4 in adults throughout the world. ADHD provides a basis for important problems for both patient, family and society and thus it is important to diagnose the disorder early and understand the factors that create predisposition to the disorder. ADHD is a multifactorial disorder with an etiology of genetic and environmental com-ponents. The importance of genetic factors first implied by Cantwell and Morrison is supported by many studies ever since. All these studies showed that inheritance rate of ADHD is as high as %76. The aim of this article is to explain ADHD genetics in categorization of twin studies, adoption studies, family studies, segregation analyzes and molecular genetic researches and to review the genetic component of ADHD.
This chapter discusses the so-called “main” effects of environments and genes on the manifestation of conduct problems. It makes an inquiry into environmental and genetic risk factors that, when considered in isolation at least seemingly are associated with heightened likelihood for antisocial behaviors. The chapter focuses on the dichotomy of environmental and genetic influences in an effort to raise important questions about the relationships between risky environments and risky genes. It presents data from both schools of thought on the causes of crime — one focused on the role of individual differences and the other focused on structural and contextual variables that predispose an individual to violence. The chapter also primarily focuses on individual differences raising from the coaction of environments and genes. It attempts to summarize this overview with a few statements of relevance to practitioners working with individuals who have demonstrated antisocial behavior and with the lay public.
Introduction
Several studies showed that DAT1 polymorphism closed related with ADHD although the results were not consistently found. Studies in China, South Korea, Japan revealed that 10-repeat allele gave a risk for ADHD. Based on that understanding, this study tried to identify whether the similar polymorphism of DAT1 was also apparent in Indonesian children with ADHD.
Method
This was a case – control study. Case was 50 Indonesian origin children with ADHD and without any other mental disorders and metal retardation. Control is Indonesian origin children without ADHD, other mental disorders and mental retardation. ADHD diagnosis was taken after doing the psychiatric interview and observation based on the DSM-IV TR diagnostic criteria for ADHD at the Child and Adolescent Psychiatry Out-patient Clinic, Dr. Cipto Mangunkusumo National Referral Hospital – Faculty of Medicine Universitas Indonesia. DNA isolation, DNA purity and concentration were measured. PCR was done by using a primer based on Homo sapiens solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3), RefSeq Gene on chromosome 5 with accession number NG_015885.1. To identify the serial of repeated allele, we used the sequencing technique.
Results
There were 47 children with ADHD and 48 children without ADHD that involved in the final analysis. The mean of age amongst ADHD group was 9.18 (2.42) and 8.10 (2.46) years old in non-ADHD group. The 10-repeated allele of DAT1 was the highest proportion in both.
Conclusion
This finding was apparently similar with other studies on DAT1 polymorphism across Asian.
Background: Mothers' positive emotions expressed about their children with attention deficit/hyperactivity disorder (ADHD) are associated with a reduced likelihood of comorbid conduct problems (CP). We examined whether this association with CP, and one with emotional problems (EMO), is moderated by variants within three genes, previously reported to be associated with ADHD and to moderate the impact of environmental risks on conduct and/or emotional problems; the dopamine transporter gene (SLC6A3/DAT1), the dopamine D4 receptor gene (DRD4) and the serotonin transporter gene (SLC6A4/5HTT). Methods: Seven hundred and twenty-eight males between the ages of 5 and 17 with a DSM-IV research diagnosis of combined type ADHD were included in these analyses. Parents and teachers rated children's conduct and emotional problems. Positive maternal expressed emotion (PMEE) was coded by independent observers on comments made during a clinical assessment with the mother based on current or recent medication-free periods. Results: Sensitivity to the effects of PMEE on CP was moderated by variants of the DAT1 and 5HTT genes. Only children who did not carry the DAT1 10R/10R or the 5HTT l/l genotypes showed altered levels of CP when exposed to PMEE. The effect was most marked where the child with ADHD had both these genotypes. For EMO, sensitivity to PMEE was found only with those who carried the DAT1 9R/9R. There was no effect of DRD4 on CP or EMO. Conclusion: The gene–environment interactions observed suggested that genetic make-up can alter the degree of sensitivity an ADHD patients has to their family environment. Further research should focus on distinguishing general sensitivity genotypes from those conferring risk or protective qualities
Objectives: The dopamine (DAT) and norepinephrine (NET) transporters, encoded by SLC6A3 and SLC6A2 genes, regulate neurotransmitters controlling motor activity, attention, mood swings, and stress induced anxiety, thus becoming targets for therapeutic intervention. We explored contribution of SLC6A3 (rs40184, rs2652511) and SLC6A2 (rs3785143, rs11568324) variants in Attention-deficit hyperactivity disorder associated traits.
Methods: Nuclear families with ADHD probands (N = 200) and ethnically matched controls (N = 180) were recruited based on the DSM-IV-TR. Behavioral traits were assessed by the Conners' Parent Rating Scale-revised. Genomic DNA obtained from peripheral blood leukocytes was subjected to PCR based amplification of target sites followed by restriction fragment length polymorphism and sequencing based analysis. Statistical analysis was performed by population as well as family-based methods.
Results: The control population showed significant difference in allelic and genotypic frequencies for rs40184, rs2652511 and rs11568324 in comparison to other Asian populations. Family-based analysis exhibited preferential transmission of rs3785143 and rs11568324 “C” alleles (P = 0.009 & 0.05). Gene variants showed association with behavioral problems and co-morbid disorders. Multifactor Dimensionality Reduction analysis revealed independent as well as synergistic effects of studied sites and phenotypic traits.
Conclusion: Data obtained for the first time evidenced association of dopamine and norepinephrine transporter gene variants with phenotypic traits and co-morbidity of Indian ADHD probands.
For decades, the nosology of mental illness has been based largely upon the descriptions in the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM). A recent challenge to the DSM approach to psychiatric nosology from the National Institute on Mental Health (USA) defines Research Domain Criteria (RDoC) as an alternative. For RDoC, psychiatric illnesses are not defined as discrete categories, but instead as specific behavioral dysfunctions irrespective of DSM diagnostic categories. This approach was driven by two primary weaknesses noted in the DSM: (1) the same symptoms occur in very different disease states; and (2) DSM criteria lack grounding in the underlying biological causes of mental illness. RDoC intends to ground psychiatric nosology in those underlying mechanisms. This review addresses the suitability of RDoC vs. DSM from the view of modeling mental illness in animals. A consideration of all types of psychiatric dysfunction is beyond the scope of this review, which will focus on models of conditions associated with frontostriatal dysfunction.
Context:
Fatigue is a common problem in oncology patients. Less is known about decrements in energy levels and the mechanisms that underlie both fatigue and energy.
Objectives:
In patients with breast cancer, variations in neurotransmitter genes between Lower and Higher Fatigue latent classes and between the Higher and Lower Energy latent classes were evaluated.
Methods:
Patients completed assessments prior to and monthly for 6 months following surgery. Growth mixture modeling was used to identify distinct latent classes for fatigue severity and energy levels. Thirty candidate genes involved in various aspects of neurotransmission were evaluated.
Results:
Eleven single nucleotide polymorphisms (SNPs) or haplotypes (i.e., ADRB2 rs1042718, BDNF rs6265, COMT rs9332377, CYP3A4 rs4646437, GALR1 rs949060, GCH1 rs3783642, NOS1 rs9658498, NOS1 rs2293052, NPY1R Haplotype A04, SLC6A2 rs17841327 and 5HTTLPR + rs25531 in SLC6A4) were associated with latent class membership for fatigue. Seven SNPs or haplotypes (i.e., NOS1 rs471871, SLC6A1 rs2675163, SLC6A1 Haplotype D01, SLC6A2 rs36027, SLC6A3 rs37022, SLC6A4 rs2020942, and TAC1 rs2072100) were associated with latent class membership for energy. Three of thirteen genes (i.e., NOS1, SLC6A2, SLC6A4) were associated with latent class membership for both fatigue and energy.
Conclusions:
Molecular findings support the hypothesis that fatigue and energy are distinct, yet related symptoms. Results suggest that a large number of neurotransmitters play a role in the development and maintenance of fatigue and energy levels in breast cancer patients.
Reward-based motivations to eat seem to overpower homeostatic drives in some individuals. Binge eating represents an extreme phenotype of hedonic overeating, is a significant risk factor for substantial weight gain over time, and a defining symptom of both binge eating disorder (BED) and bulimia nervosa. Experts believe the action of the neurotransmitter dopamine on the brain’s “common reward pathway” is primarily accountable for hedonic motivations for food intake. The genetically determined action and availability of dopamine on this pathway appear to determine individual variations in the tendency to overeat and vulnerability to binge eating disorders and obesity. Some experts speculate dysfunctional dopamine availability predisposes individuals to binge eating based on the Reward Deficiency Syndrome theory of addictive behaviors; whereas, contrasting views propose an elevated dopamine signal also places individuals at risk for binge eating due to a stronger appetitive motivation and response to food cues and eating. Dopamine availability is polygenic and determined by several factors, one of which is the density of dopamine transporter (DAT) – which regulates the strength and duration of the dopamine signal by transporting it back into the presynaptic neuron. The gene encoding the DAT protein has been of particular interest in studies on addictions and eating behavior, as it contains a functional VNTR polymorphism. Variations of the DAT gene (DAT1) VNTR are associated with differences in DAT-binding site density, and therefore, levels of dopamine availability. This chapter reviews the literature on the role of the DAT1 in obesity and binge eating disorders.
The USA and the Russian Federation have been competing with each other for what appears to be a rather dubious leadership in having the highest number of prisoners per 100,000 people (Walmsley 2008), with the USA being a clear first (756 in 2008), and Russia—the leader of a cluster (629 in 2008) formed primarily by developing nations (e.g., Rwanda—604, St. Kitts and Nevis—588, Cuba—531, U.S. Virgin Islands—512, with the rest of the countries falling below and far below 500; 59% of the countries had less than 150 prisoners per 100,000 people). This trend is replicated in the juvenile justice systems as well, with USA and Russia detaining and/or incarcerating the largest number of juveniles per capita in the world.
Introduction New diagnostic criteria for attention-deficit hyperactivity disorder (ADHD) have been introduced in the latest edition of the Diagnostic and Statistical Manual for Mental Disorders (fifth edition, DSM-5) that was published in May 2013 [1]. Various changes to DSM-IV were suggested by the committee chosen to revise the criteria which then led to exploration of various large-scale existing datasets to test out the results and discover the implications of many of these proposals. (Note – the author did not serve on this committee but did consult with it and provide datasets to it.) Many of the proposals for change were founded on a number of criticisms that were previously leveled at the extant DSM-IV diagnostic criteria [2–5]. Rather than just discuss the various changes that have occurred in the DSM-5 criteria for ADHD, this chapter places those changes in the context of the larger issues and criticisms they were intended to address. It also discusses several additional issues apparently not planned to be addressed as of this time, yet deserved to be acknowledged and possibly even corrected by clinicians utilizing DSM-5 criteria. At the outset, it should be understood that the problems with DSM-IV and the need for their correction in no way invalidate those criteria for use in the diagnosis of ADHD in children and adults. Since DSM-III [6], efforts have increased to make the criteria more empirically based, in part, using available scientific evidence as well as testing the proposed criteria in field trials [7, 8]. From a scientific standpoint, existing knowledge (criteria in this case) is always imperfect but can be further refined and made more accurate as a representation of material reality or a truth claim. This occurs through a Darwinian process of testing the existing information against reality and using the feedback (criticism) received in return from such testing to revise the knowledge base.
Introduction Neuroimaging of attention-deficit hyperactivity disorder (ADHD) involves the application of increasingly sophisticated approaches to an intermittently moving target. The first imaging studies, which are reviewed elsewhere [1], used computed-axial tomography even before the diagnosis of attention deficit disorders with or without hyperactivity had been formulated in 1980 and did not detect differences when applied quantitatively [2]. The second generation of imaging studies harnessing positron emission tomography methods first detected substantial differences between individuals with ADHD and healthy controls [3], but the use of injected radioligands meant that this approach was mostly limited to studies of adults [1] with rare exceptions [4]. The widespread availability of high-resolution three-dimensional magnetic resonance imaging (MRI) by the early 1990s revolutionized ADHD structural imaging, as the technique could be applied to children and adolescents without entailing risks greater than those encountered in daily life. The designation as a minimal risk procedure was particularly important for the inclusion of healthy children as comparison subjects and for the conduct of longitudinal studies. The resulting profusion of investigations has become too voluminous to even enumerate. For example a PubMed search on March 16, 2013 with the abbreviated search terms MRI and ADHD returned 846 results.
Attention-Deficit Hyperactivity Disorder (ADHD) is a chronic neurobehavioral disorder characterized by persistent and often acute distractibility, hyperactivity, and impulsivity. It is a condition usually associated with children but in recent years the diagnosis of ADHD in adults has risen significantly. ADHD often coexists with a wide array of other psychiatric illnesses, including depression and bipolar disorder, thus complicating its assessment and management. In Attention-Deficit Hyperactivity Disorder in Adults and Children, a team of world renowned experts bring together the recent research in this area and cover the history, diagnosis, epidemiology, comorbidity, neuroimaging, and a full spectrum of clinical options for the management of ADHD. The wide ranging, detailed coverage in this text will be of interest to psychiatrists, psychologists, social workers, coaches, physicians, or anyone who wants to develop a deeper understanding of the etiology, characteristics, developmental process, diagnostics, and range of treatment modalities.
SIR—The dopamine transporter gene (DAT1 SCL6A3) is an important candidate for mediating susceptibility to attention-deficit hyperactivity disorder (ADHD), given its relevance for related behaviors, and its blockade by effective stimulant drugs. To date, most studies examined a 40 bp variable number tandem repeat (VNTR) in the 3'-untranslated region of the gene. Along with recurrent reports of preferential transmission of the 10-repeat (480 bp) allele, there are some negative reports, and a meta-analysis of 11 studies with a total of 824 informative meioses yielded a nonsignificant pooled odds ratio estimate of 1.27 (95% CI 0.99–1.63, 0.06).1A previous study that did not detect significant association with the VNTR found a haplotype consisting of the 10-repeat allele and two 3' biallelic sites significantly associated with ADHD.2 A recent study replicated association of the VNTR with ADHD, with stronger associations observed for 3' microsatellite marker haplotypes that include the 10-repeat allele.3 If the VNTR is a marker for an adjacent functional DAT1 variant, a linkage disequilibrium (LD) association approach may increase the sensitivity for locating association with the phenotype, and may help explain part of the variance in previous reports that examined the VNTR as a single marker. In the present study, we examined an exon 15 haplotype located in the 3'-untranslated region, consisting of the VNTR and an upstream G2319A substitution in LD,4 in a sample of ADHD triads, confirming association with the VNTR, and stronger association with the haplotype. The sample was previously described and consisted of 76 nuclear ADHD families.5 Of these, 68 trios were informative for the VNTR site, 50 trios were informative for the A2319G site, and a total of 64 trios were informative for the haplotype analysis. The extended transmission disequilibrium test6 was used to determine allelic association with individual markers, and HAPMAX (http://www.uwcm.ac.uk/uwcm/mg/download) was used for the multimarker haplotype relative risk (HRR) analysis. The DAT1 VNTR alleles showed marginally significant biased transmission to affected children (2 for genotype-wise TDT=9.08, df=3, P=0.028); preferential transmission was also observed for the 2319 G allele (2=3.97, df=1, P=0.046) (Table 1). The two sites demonstrated strong LD (D' coefficient=1.000). Multimarker HRR analysis showed a globally significant biased transmission of haplotypes (2=14.56, df=5, P=0.0124).
Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
We have screened a human substantia nigra cDNA library with probes derived from the rat dopamine transporter. A 3.5-kilobase cDNA clone was isolated and its corresponding gene was located on the distal end of chromosome 5 (5p15.3). This human clone codes for a 620-amino acid protein with a calculated molecular weight of 68,517. Hydropathicity analysis suggests the presence of 12 putative transmembrane domains, a characteristic feature of sodium-dependent neurotransmitter carriers. The rat and the human dopamine transporters are 92% homologous. When permanently expressed in mouse fibroblast Ltk- cells, the human clone is able to induce a saturable, time- and sodium-dependent, dopamine uptake. This transport is blocked by psychostimulant drugs (cocaine, l- and d-amphetamine, and phenyclidine), neurotoxins (6-hydroxydopamine and N-methyl-4-phenylpyridine (MPP))+), neurotransmitters (epinephrine, norepinephrine, gamma-aminobutyric acid, and serotonin), antidepressants (amitriptyline, bupropion, desipramine, mazindol, nomifensine, and nortriptyline), and various uptake inhibitors (mazindol, GBR 12783, GBR 12909, and amfonelic acid). The rank orders of the Ki values of these substances at the human and the rat dopamine transporters are highly correlated (r = 0.998). The cloning of DNA human dopamine transporter gene has allowed establishment of a cell line stably expressing the human dopamine transporter and, for the first time, an extensive characterization of its pharmacology. Furthermore, these newly developed tools will help in the study of the regulation of dopamine transport in humans and in the clarification of the potential role of the dopamine transporter in a variety of disease states.
Antibodies specific for the dopamine transporter (DAT) was developed and characterized by immunoblot analysis, immunoprecipitation, and immunocytochemistry, and used for immunolocalization of transporter protein in rat brain at the light microscopic level. Antibodies targeting the N-terminus, the second extracellular loop, and the C-terminus were generated from fusion proteins containing amino acid sequences from these respective regions. Immunoblot analysis demonstrated that N-terminus and loop antibodies were specific for expressed cloned DAT, recognized transporter protein in rat and human striatal membranes, and were sensitive to preabsorption with excess homologous fusion protein. Immunoprecipitation studies demonstrated that anti-DAT antisera recognized solubilized, radiolabeled DAT protein in a concentration-dependent manner. DAT immunocytochemistry with these antibodies were also sensitive to preabsorption with fusion protein and to lesions of dopaminergic mesostriatal and mesocorticolimbic pathways. Regional distribution of DAT coincided with established dopaminergic innervation of several regions, including ventral mesencephalon, medial forebrain bundle, and dorsal and ventral striatum. However, certain mismatches between immunocytochemical distributions of DAT and tyrosine hydroxylase were apparent, indicating that dopaminergic systems are heterogeneous and may use independent mechanisms for the regulation of dopamine levels in brain. The generation of specific DAT antibodies will permit further characterization of the cellular and subcellular localization of DAT protein, and of dopaminergic circuits in neurological and psychiatric disorders.
Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not revealed a consistent Mendelian mode of transmission. The response of ADHD patients to medications that inhibit the dopamine transporter, including methylphenidate, amphetamine, pemoline, and bupropion, led us to consider the dopamine transporter as a primary candidate gene for ADHD. To avoid effects of population stratification and to avoid the problem of classification of relatives with other psychiatric disorders as affected or unaffected, we used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the dopamine transporter locus (DAT1) and DSM-III-R-diagnosed ADHD (N = 49) and undifferentiated attention-deficit disorder (UADD) (N = 8) in trios composed of father, mother, and affected offspring. HHRR analysis revealed significant association between ADHD/UADD and the 480-bp DAT1 allele (chi 2 7.51, 1 df, P = .006). When cases of UADD were dropped from the analysis, similar results were found (Chi 2 7.29, 1 df, P = .007). If these findings are replicated, molecular analysis of the dopamine transporter gene may identify mutations that increase susceptibility to ADHD/UADD. Biochemical analysis of such mutations may lead to development of more effective therapeutic interventions.
Disruption of the mouse dopamine transporter gene results in spontaneous hyperlocomotion despite major adaptive changes, such as decreases in neurotransmitter and receptor levels. In homozygote mice, dopamine persists at least 100 times longer in the extracellular space, explaining the biochemical basis of the hyperdopaminergic phenotype and demonstrating the critical role of the transporter in regulating neurotransmission. The dopamine transporter is an obligatory target of cocaine and amphetamine, as these psychostimulants have no effect on locomotor activity or dopamine release and uptake in mice lacking the transporter.
Attention deficit hyperactivity disorder (ADHD) is a common condition of childhood the symptoms of which include inattention, excessive motor activity, inpulsivity and distractibility. It is strongly familial and twin and adoption studies suggest that the familiality is due, at least in part, to shared genes. Gillis et al found concordance rates in ADHD for MZ and DZ twins of 81% and 29% respectively. Stimulant drugs (eg, methylphenidate) are effective in the treatment of ADHD and inhibit the dopamine transporter. This has led to the development of a hypodopaminergic hypothesis for the disease. Cook et al examined a 3' variable number of tandem repeat (VNTR) polymorphism at the dopamine transporter gene (DAT1) in a sample of 49 ADHD patients and their parents, using the haplotype relative risk (HRR) method. They found a significant association (chi 2 = 7.29, 1 d.f., P = 0.007) between ADHD and the 480-bp DAT1 VNTR allele. The authors stressed the importance of independent replication and we have achieved this in a study of 40 probands and their parents, using the same robust HRR method. As in the study of Cook et al we found that the 480-bp allele was preferentially transmitted to ADHD probands (chi 2 = 6.07, 1 d.f., P = 0.014).
Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses.
Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews.
Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision.
In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias.
A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
Attention deficit hyperactivity disorder (ADHD) is a common disorder of childhood characterized by inattention, excessive motor activity, impulsivity, and distractibility. It is associated with serious disability in children, adolescents and adults. The etiology of the disorder is unknown, but it has a strong genetic component. Pharmacological and biochemical studies have suggested that dopaminergic and noradrenergic systems are involved. Using a sample of affected children and their parents we have found preferential transmission of alleles at polymorphisms at the dopamine transporter (DAT1), RR=1.2 (1.05-1.37), P=0.006, re-confirming and extending our previous findings for DAT1 (new sample one-tailed P=0.039); dopamine-beta-hydroxylase (DBH), RR=1.31 (1.09-1.56), P=0.0027; and the dopamine D5 receptor (DRD5), RR=1.67 (1.29-2.15), P=0.00005. Transmission of the 'associated' alleles at DAT1 and DBH is stronger in familial cases, RR(DAT1)=1.29 (1.04-1.59), RR(DBH)=1.49 (1.10-2.00), but for DRD5, transmission is stronger in non-familial cases, RR=1.59 (1.05-2.42). TDT analysis of complete trios supports the HHRR analysis, with P<0.05, for DAT1 P<0.005 and DBH and P<0.01 for DRD5. Attributable fractions for DAT1, DBH and DRD5 are calculated at 0.08, 0.12 and 0.20 respectively.
Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system.
This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum).
Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups.
These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.
The role in spatial divided and sustained attention of D1 and D2-like dopamine (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was investigated in a five-choice serial reaction time task. Rats were trained to detect brief flashes of light (0.5–0.25 sec) presented randomly in a spatial array of five apertures. When performance stabilized, animals received bilateral microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats were divided into two groups, with low (<75% correct) and high (>75%) baseline levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no significant effect on any task variable. SCH 23390 (0.3 μg) selectively impaired the accuracy of attentional performance in rats in the high baseline condition. By contrast, SKF 38393 (0.06 μg) enhanced the accuracy of attentional performance in the low baseline condition, a lower dose (0.03 μg) also increasing the speed of making correct responses. Finally, the beneficial effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0 μg).
The results provide apparently the first demonstration of enhanced cognitive function after local administration of a D1 receptor agonist to the mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in modulating attentional function.
The role of the 3' untranslated region in posttranscriptional regulation of mRNA expression is being elucidated. Here we describe diseases arising from anomalies in this region, that affect the expression of one or more genes.
Stimulant drugs are widely used in the treatment of ADHD in children and adults. Hundreds of studies over the past 60 years have demonstrated their effectiveness in improving attention span, increasing impulse control, and reducing hyperactivity and restlessness. Despite widespread interest in these compounds, however, their mechanisms of action in the central nervous system have remained poorly understood. Recent advances in the basic and clinical neurosciences now afford the possibility of elucidating these mechanisms. The current volume is the first to bring this expanding knowledge to bear on the central question of why and how stimulants exert their therapeutic effects. The result is a careful, comprehensive, and insightful integration of material by well-known scientists that significantly advances our understanding of stimulant effects and charts a course for future research. Part I presents a comprehensive description of the clinical features of ADHD and the clinical repsonse to stimulants. Part II details the cortical and subcortical neuroanatomy and functional neurophysiology of dopamine and norepinephrine systems with respect to the regulation of attention, arousal, activity, and impulse control on the basis of animal studies. Part III is devoted to clinical research, including recent studies of neuroimaging, genetics, pharmacodynamic and pharmacokinetic properties of stimulants, effects on cognitive functions, neurophysiological effects in humans with and without ADHD and in non-human primates, and comparison of stimulants and non-stimulants in the treatment of ADHD. Part IV is a masterful synthesis that presents alternative models of stimulant drug action and generates key hypotheses for continued research. The volume will be of keen interest to researchers and clinicians in psychiatry, psychology, and neurology, neuroscientists studying stimulants, and those persuing development of new drugs to treat ADHD.
Dopamine transporter (DAT) levels vary in normal subjects and deviate from the normal range in pathological states. We investigated mechanisms by which the DAT gene may influence DAT protein expression. As the 3′-untranslated region (3′-UTR) of the DAT gene varies with regard to length and single nucleotide polymorphisms (SNPs), we addressed whether the 3′-UTR of sequence-defined DAT alleles can differentially affect the level of reporter gene expression in vitro. We first established that within individual rhesus monkeys, two alleles of the DAT gene were expressed in the substantia nigra. We then transfected HEK-293 cells with HSV-TK- and SV40-driven luciferase expression vectors harboring downstream DAT 3′-UTR segments of alleles containing polymorphisms of length (human: 9 or 10 repeat units) or SNPs within alleles of fixed length (human: Dral-sensitive (Dral+) vs Dral-insensitive (Dral-) 10-repeat alleles; rhesus monkey: Bst11071-sensitive (Bst+) vs Bst11071-insensitive (Bst-) 12-repeat alleles). Vectors containing the 3′-UTR segment of a human DAT allele containing nine tandem repeat units resulted in significantly higher levels of luciferase production than analogous vectors containing 10 tandem repeat units. Depending on the promoter used, vectors containing the human or monkey 3′-UTR segments that differed on the basis of an SNP resulted in increases or decreases in luciferase gene expression. This report provides experimental evidence that variability in the length or the sequence of the 3′-UTR of the DAT gene may influence levels of DAT protein in the brain.
The regulation of dopamine and other monoamines has been implicated in both the aetiology of hyperactivity and the well-characterised response of hyperactivity to stimulants such as methylphendidate. More recently, deletion of Snap-25, DAT1, and DRD3 in mice has each been shown to cause markerd overactivity (responsive to amphetamine in the case of Snap-25). Studies in human samples with childhood ADHD suggest that genetic variation of DRD4 and DAT1 may both influence susceptibility to ADHD, although neither of these two associations are yet confirmed. We have collected a sample of 100 DSM-IV ADHD probands and matched controls. Association analysis of polymorphisms within DRD4, DAT1, DRD3, TH, SERT, NET1, and COMT, as well as mutation screening of Snap-25, has been performed. Data have been analysed in clinical groups of DSM-IV ADHD mixed type, categorised in several ways: (1) unselected for comorbid conditions or drug response, (2) no significant comorbid conditions, unselected for drug response (± conduct disorder), (3) no signficant comorbid disorders, methylphendidate responders only. To date, we have detected no significant associations with polymorphisms within these genes. In particular, our data do not lend support to the previously reported association with the 480 bp repeat allele of DAT1 [71%, 71%, 73%, and 73% in (1),(2),(3), and controls, respectively] , or the reported association with the 7-repeat allele of DRD4 [13%, 12%, 11%, and 13% in (1), (2), (3), and controls, respectively].
Adis Comment
All the drugs appearing in the Adis Profile Summary table have been selected based on information contained in R&D InsightTM, a proprietary product of Adis International. As the emphasis of Drugs in R&D is on the clinical potential of new drugs, selection of agents for a full profile is based on the extensiveness of available data. Information on all drugs in clinical development, as identified from R&D InsightTM, is included in the summary table. Information and/or profiles of agents in preclinical development may be included as appropriate.
Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993–998, Gill et al., Molecular Psychiatry 1997;2:311–313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121–124; Smalley et al., 1998;3:427–430; Swanson et al., Molecular Psychiatry 1998;3:38–41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37–42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.
This study utilized a sample of 313 eight- to sixteen-year-old same-sex twin pairs (183 monozygotic, 130 dizygotic) to assess the etiology of comorbidity between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD). RD was assessed by a discriminant function score based on the Peabody Individual Achievement Test, a standardized measure of academic achievement. The DSM-III version of the Diagnostic Interview for Children and Adolescents was used to assess symptoms of ADHD, and separate factor scores were computed for inattention and hyperactivity/impulsivity (hyp/imp). Individuals with RD were significantly more likely than individuals without RD to exhibit elevations on both symptom dimensions, but the difference was larger for inattention than hyp/imp. Behavior genetic analyses indicated that the bivariate heritability of RD and inattention was significant (h2g(RD/Inatt) = 0.39), whereas the bivariate heritability of RD and hyp/imp was minimal and nonsignificant (h2g(RD/Hyp) = 0.05). Approximately 95% of the phenotypic covariance between RD and symptoms of inattention was attributable to common genetic influences, whereas only 21% of the phenotypic overlap between RD and hyp/imp was due to the same genetic factors. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:293–301, 2000. © 2000 Wiley-Liss, Inc.
Involvement of the dopaminergic system has been suggested in patients suffering from attention deficit hyperactivity disorder (ADHD) since the symptoms can be successfully treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). This study reports the findings on the status of the DAT in adults with ADHD before and after commencement of treatment with methylphenidate, as measured using [99mTc]TRODAT-1. Seventeen patients (seven males, ten females, aged 21-64 years, mean 38 years) were examined before and after the initiation of methylphenidate treatment (3ǹ mg/day). All subjects were injected with 800 MBq [99mTc]TRODAT-1 and imaged 3 h p.i. Single-photon emission tomography (SPET) scans were acquired using a triple-headed gamma camera. For semiquantitative evaluation of the DAT, transverse slices corrected for attenuation were used to calculate specific binding in the striatum, with the cerebellum used as background [(STR-BKG)/BKG]. Data were compared with an age-matched control group. It was found that untreated patients presented with a significantly increased specific binding of [99mTc]TRODAT-1 to the DAT as compared with normal controls [(STR-BKG)/BKG: 1.43ǂ.18 vs 1.22ǂ.06, P<0.001]. Under treatment with methylphenidate, specific binding decreased significantly in all patients [(STR-BKG)/BKG: 1.00ǂ.14, P<0.001]. Our findings suggest that the number of DAT binding sites is higher in drug-naive patients suffering from ADHD than in normal controls. The decrease in available DAT binding sites under treatment with methylphenidate correlates well with the improvement in clinical symptoms. The data of this study help to elucidate the complex dysregulation of the dopaminergic neurotransmitter system in patients suffering from ADHD and the effect of treatment with psychoactive drugs.
Ten previously untreated adults with attention deficit hyperactivity disorder (ADHD) were investigated before and after 4 weeks of treatment with a dose of 3×5 mg methylphenidate/d by single photon emission computed tomography (SPECT) with [Tc–99m]TRODAT-1, the first Tc-99m labelled SPECT ligand specifically binding to the dopamine transporter (DAT). For semiquantitative evaluation of the DAT, specific binding ([STR–BKG]/BKG) was calculated in the striatum (STR) with the cerebellum used as background (BKG). The patients with ADHD presented with increased specific binding of Tc-99m-TRODAT-1 to the DAT as compared with age and sex matched controls ([STR–BKG]/BKG 1.43±0.18 vs. 1.22±0.05, P<0.001). After treatment with methylphenidate specific binding decreased in all patients ([STR–BKG]/BKG 1.02±0.23, P<0.001). Thus, for the first time it could be demonstrated using SPECT that methylphenidate lowers increased striatal DAT availability in adults suffering from ADHD.
Dopamine transporter density was measured in vivo in six adult patients with attention deficit hyperactivity disorder. We have shown a 70% increase in age-corrected dopamine transporter density in patients with attention hyperactivity disorder compared with healthy controls.
Conceptual and technological advances in cognitive neuroscience and molecular genetics have the potential to identify the pathogenesis of psychiatric disorders. This article reviews the application of these technologies to the scientific study of attention deficit hyperactivity disorder. It begins with a summary of shifts in conceptualization and scientific study of this common condition. This is followed by a critical review of findings from recent cognitive, neuroimaging, and genetic studies. The available data do not yet permit an integration across these different levels of enquiry, but implicate problems in response inhibition, dysfunction of frontostriatal networks, and genetic factors in the pathogenesis of this complex behavioral phenotype. The review closes with suggestions for future interdisciplinary research.
The human dopamine transporter (DAT1) gene is localized to chromosome 5p15.3 by in situ hybridization and PCR amplification of rodent somatic cell hybrid DNA. Analysis of a 40-bp repeat in the 3' untranslated region of the message revealed variable numbers of the repeat ranging from 3 to 11 copies. These results will aid in the investigation of a role for this gene in genetic disorders of the dopaminergic system in humans.
Clinical, animal and neuroanatomical studies of differential isomer and dosage effects of CNS stimulant medications on behaviour are reviewed. Wender's hypothesis that an underlying biochemical abnormality and a disorder of reinforcement was the primary deficit in "MBD" children is restated in terms of a disorder of polysynaptic dopaminergic circuits, between prefrontal and striate centres. Wender's notion of a disorder of reinforcement is broadened to include a disorder of planning and correction of behaviour, including capacity for cortical control of automatic instinctual motor programmes. The dopamine hypothesis of Attention Deficit Hyperactivity Disorder (ADHD) is examined from the point of view of differential dose effects of CNS stimulant medications, and theories of neural control. Clinical, animal and neuropharmacological studies are reviewed. Implications of the findings for understanding clinical and side effects in ADHD children of stimulants are discussed.
We compare two statistical methods for combining event rates from several studies. Both methods treat each study as a separate stratum. The Peto-modified Mantel-Haenszel (Peto) method estimates a combined odds ratio assuming homogeneity across strata and provides a test for heterogeneity. The DerSimonian and Laird modified Cochran method (D&L) produces a weighted average of rate differences, where the weights allow for among-study variability. We analyse 22 meta-analyses from ten reports by both methods. The pooled estimates are divided by their standard errors to produce a Z-statistic. A t-test comparing Z-statistics from all 22 studies suggests that the D&L method tends to be more conservative [d(Peto - D&L) = 0.29, t = 2.53, p = 0.02]. For a subset of 14 non-heterogeneous studies, the difference is smaller and non-significant (d = 0.09, t = 0.72, p = 0.49). The results from the methods correlate well (r = 0.66 for all 22 studies, r = 0.95 for 14 non-heterogeneous studies). Thus, the presence of heterogeneity influences our conclusion. We discuss the statistical and scientific implications of these findings.
The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice. Histological analyses suggested that there are no major changes in general anatomy of the mutant mouse brains, but indicated that the expression of dynorphin is greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice do not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibit locomotor hyperactivity. These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity.
Studies of association between candidate genes and disease can be designed to use cases with disease, and in place of nonrelated controls, their parents. The advantage of this design is the elimination of spurious differences due to ethnic differences between cases and nonrelated controls. However, several statistical methods of analysis have been proposed in the literature, and the choice of analysis is not always clear. We review some of the statistical methods currently developed and present two new statistical methods aimed at specific genetic hypotheses of dominance and recessivity of the candidate gene. These new methods can be more powerful than other current methods, as demonstrated by simulations. The basis of these new statistical methods is a likelihood approach. The advantage of the likelihood framework is that regression models can be developed to assess genotype-environment interactions, as well as the relative contribution that alleles at the candidate-gene locus make to the relative risk (RR) of disease. This latter development allows testing of (1) whether interactions between alleles exist, on the scale of log RR, and (2) whether alleles originating from the mother or father of a case impart different risks, i.e., genomic imprinting.
Synthesis of research findings has long been a part of reviewing and summarizing a field of study. Public health decisions are made on the available evidence. We summarize the approaches to research synthesis that draw on the best available evidence and the use of quantitative summaries through meta-analysis. We focus on observational studies. Heterogeneity offers the potential to observe a relation across study populations and circumstances. We emphasize the benefits of heterogeneity in overviews and the need to explore and describe the sources of heterogeneity. Random effects approaches to combining data are recommended, and the use of regression approaches is emphasized. Excluding studies with extreme results may bias a research synthesis and underestimate the true variance of the results, thus contributing to misleading inference. Thorough searching is the best guard against publication bias. We conclude with guidelines for combining epidemiological studies.
Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine beta-hydroxylase (D beta H), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and substractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order attention deficit hyperactivity disorder (ADHD), stuttering oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.
To investigate heritability and continuum versus categorical approaches to attention-deficit hyperactivity disorder (ADHD), using a large-scale twin sample.
A cohort of 1,938 families with twins and siblings aged 4 to 12 years, recruited from the Australian National Health and Medical Research Council Twin Registry, was assessed for ADHD using a DSM-III-R-based maternal rating scale. Probandwise concordance rates and correlations in monozygotic and dizygotic twins and siblings were calculated, and heritability was examined using the De Fries and Fulker regression technique.
There was a narrow (additive) heritability of 0.75 to 0.91 which was robust across familial relationships (twin, sibling, and twin-sibling) and across definitions of ADHD as part of a continuum or as a disorder with various symptom cutoffs. There was no evidence for nonadditive genetic variation or for shared family environmental effects.
These findings suggest that ADHD is best viewed as the extreme of a behavior that varies genetically throughout the entire population rather than as a disorder with discrete determinants. This has implications for the classification of ADHD and for the identification of genes for this behavior, as well as implications for diagnosis and treatment.
The objective of this report is to provide a new methodology for evaluating the performance of meta-analysis (MA) in corroborating results of large trials (LT) and to identify factors that could explain lack of similarity in the results. We used two criteria to judge the degree of similarity between a MA and the LT: (a) the ratio of the relative risk of the MA to the relative risk of the LT; and (b) the 95% confidence interval about this ratio. Furthermore, this degree of similarity was cross-tabulated with the presence or not of evidence of selective inclusion of positive studies (e.g., publication bias) as judged from "funnel plots" and statistical indicators. Depending on which of our two criteria was used, we found that between 20% and 53% of the 30 MAs studied have high or very high degree of similarity with the LT. We also found strong evidence that factors influencing asymmetrical funnel plots of MA, such as publication bias, may play an important role in this degree of similarity. There was a sizeable proportion of meta-analyses that did not agree with large trial results. We recommend that funnel plots be used as a tool for identifying which MAs can mislead. However, the statistical indicators at hand are unlikely to be of use in many area of medicine considering the regrettably small number of randomized controlled trials per topic available.
The magnitude of genetic and environmental factors and the influence of contrast effects on attention-deficit hyperactivity disorder (ADHD) symptomatology were examined on a sample of 900 twin pairs, aged 7-13, participating in the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). In addition, the genetic and environmental correlations between ADHD and oppositional-defiant disorder/conduct disorder (ODD/CD) symptomatology were estimated. A series of structural models was applied to maternal ratings from a telephone survey, designed to screen for the three dimensions of ADHD symptomatology (hyperactivity, impulsivity, and inattention) and ODD/CD symptomatology. Model-fitting results suggested that ADHD symptomatology is highly heritable and influenced mostly by additive genetic, specific environmental, and contrast effects. However, this analysis could not exclude with statistical significance additional effects from dominance. The results of the best-fitting bivariate model suggested that the genetic correlation between the two traits is 50% and replicated previous findings of a common genetic factor influencing the comorbidity of ADHD and ODD/CD symptomatologies.
VNTR (variable number of tandem repeat) markers, also called single-copy minisatellites, were originally isolated from human DNA as highly informative restriction fragment length polymorphisms for mapping purposes. Evidence has lately emerged that some VNTR sequences play significant roles in the regulation of transcription, and that some may also influence the translational efficiency or stability of mRNA, or modify the activity of proteins by altering their structure. Some apparent associations of VNTR sequences with personality traits or with susceptibility to diseases have strengthened the likelihood that these tandemly-repeated genomic elements are of physiological and biological importance. In this review, we summarize recent progress in efforts to clarify mechanisms involving VNTR sequences.
The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain.
Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [11C]methylphenidate administered through an orogastric tube.
At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of dopamine transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the dopamine transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration.
Oral methylphenidate is very effective in blocking dopamine transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the dopamine transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.
Attention-deficit hyperactivity disorder (ADHD) is an early-onset, clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. Family, twin, adoption, segregation analysis, and molecular genetic studies show that is has a substantial genetic component. Although their results are still tentative, molecular genetic studies suggest that three genes may increase the susceptibility to ADHD: the D4 dopamine receptor gene, the dopamine transporter gene, and the D2 dopamine receptor gene. Studies of environmental adversity have implicated pregnancy and delivery complications, marital distress, family dysfunction, and low social class. The pattern of neuropsychological deficits found in ADHD children implicate executive functions and working memory; this pattern is similar to what has been found among adults with frontal lobe damage, which suggests that the frontal cortex or regions projecting to the frontal cortex are dysfunctional in at least some ADHD children. Moreover, neuroimaging studies implicate frontosubcortical pathways in ADHD. Notably, these pathways are rich in catecholamines, which have been implicated in ADHD by the mechanism of action of stimulants--the class of drugs that effectively treats many ADHD children. Yet human studies of the catecholamine hypothesis of ADHD have produced conflicting results, perhaps due to the insensitivity of peripheral measures.
Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.
The dopamine transporter (DAT) is the primary mechanism for dopamine clearance from the synapse in midbrain dopaminergic neurons, and the target of psychostimulant and neurotoxic drugs such as cocaine, amphetamine, and MPTP. Consequently, the gene for DAT (SLC6A3) has been the focus of many population-based case-control association studies using a 40-bp VNTR in the 3'-untranslated region. Results have differed depending on the population studied, suggesting allele frequency effects are involved. For this reason, a global survey of allele frequencies for this VNTR polymorphism was performed.
Individuals (n = 1528) from 30 populations around the world were typed for this VNTR using PCR and agarose gel electrophoresis.
As with previous studies, the ten-repeat allele is most common, except for a Middle Eastern population in which the nine-repeat allele is most frequent. Frequencies of the nine- and ten-repeat alleles vary widely even among European populations.
Many previous association studies have used "white" or "black" U.S. populations. However, many different ethnic groups have contributed to these populations. The large variation in allele frequencies observed in this study emphasizes the inadequacy of most past studies using the case-control design and the importance of matching patient and control populations in future association studies.
Recent studies using positron emission tomography (PET) have established the relationship between an intravenous dose of cocaine and the percentage occupancy of the dopamine transporter in humans, and have documented the requirement of more than 50% occupancy for perception of the "high". The present experiments were conducted to examine dose-occupancy and dose-effect relationships in mice for cocaine and also for methylphenidate, a dopamine uptake blocker used in pediatric psychiatry.
Percentage occupancies of the dopamine transporter by cocaine and methylphenidate were estimated after intravenous injection in mice from the displacement of in vivo binding of [(3)H]cocaine from the striatum. Locomotor activity was measured in a photocell apparatus.
The relationship between drug doses (milligrams of hydrochloride salt per kilogram body weight) and percentage occupancy of the dopamine transporter was indistinguishable for cocaine and methylphenidate, and corresponded to about 50% occupancy at 0.25 mg/kg and about 80% at 1 mg/kg. This was similar to the relationship between drug dose and transporter occupancy, previously measured in human and baboons using [(11)C]cocaine or [(11)C]d-threo-methylphenidate and PET. Methylphenidate increased locomotor activity in the mice substantially more than cocaine at the same dose and the same degree of dopamine-transporter receptor occupancy.
The range of dopamine-transporter occupancy required for behavioral activation in the mice was thus similar to that previously reported for experience of a cocaine- or methylphenidate-induced "high" in human subjects. Our results are consistent with other studies in which both cocaine and methylphenidate were evaluated in animal behavioral assays and were found to have very similar psychopharmacological properties.
In vivo availability of striatal dopamine transporter (DAT) protein has been reported to be reduced among alcoholics, and allelic variation of the DAT gene (SLC6A3) has been associated with severity of alcohol withdrawal. We examined the VNTR polymorphism of the 3' untranslated region of SLC6A3 and DAT protein availability in 14 abstinent alcoholics and 11 control subjects. Single photon emission computed tomography (SPECT) and plasma levels of the radioligand [I-123]beta-CIT were used to quantify DAT protein availability. Individuals with the 9-repeat/10-repeat genotype had a mean 22% reduction of DAT protein availability in putamen compared with 10-repeat homozygous individuals (t = 2.14, df = 23, p < .05). Consistent with earlier studies, alcoholism, per se, was not significantly associated with either DAT availability or DAT genotype. These findings suggest that the VNTR polymorphism of the DAT gene effects translation of the DAT protein. This effect may explain a variety of clinical associations that have been reported with this polymorphism.
We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. We then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.
A polymorphism with a variable number of tandem repeats (VNTR) found in the 3' untranslated region of the human dopamine transporter gene (DAT1) was scored in unrelated individuals drawn from 10 geographically widely dispersed populations in order to assess this marker's usefulness in human population genetics. The populations that were analyzed in this study included 4 indigenous groups of Siberia, natives of North and South America, as well as Caucasian and Oceanic groups, most of which represented small-scale societies. A total of 5 DAT1 alleles were seen overall, but only in one Siberian population, the Altai-Kizhi, were all 5 present, and in the Native Americans of Colombia the locus was monomorphic. The most common allele, DAT1*10, ranged in frequency from 52% in Greeks to 100% in South Americans. The high frequency of the DAT1*10 allele (approximately 90%) among Mongoloid groups of north and east Asia distinguishes them from most Caucasian groups. The presence of the rare DAT1*7 allele in relatively high frequency (approximately 5%) among all Siberian groups suggests a close affinity with north Asian groups, especially Mongolians. The presence of the even rarer DAT1*13 allele in one Siberian population, the Altai-Kizhi, reflects this group's long historical contact with Mongolians. The results demonstrated that the DAT1 VNTR polymorphism is useful in investigating population relationships, and that rare alleles at this locus may be particularly valuable in understanding the extent of genetic affinity between neighboring groups and in situations where admixture is suspected. However, because of both the association and linkage of this VNTR locus with attention-deficit hyperactivity disorder (ADHD) in children, and its highly restricted polymorphism (usually 3 alleles) in most human groups, the possibility of selection constraints on the DAT1 gene cannot be ignored.