Interaction effects of GIT1 and DRD4 gene variants on continuous performance test variables in patients with ADHD.
ABSTRACT: The G protein-coupled receptor kinase interacting protein 1 gene (GIT1) has been proposed to be a risk gene for attention deficit hyperactivity disorder (ADHD), and it regulates the endocytosis of G protein-coupled receptors like dopamine receptors. The purpose of this study was to investigate the interaction effects of GIT1 and dopamine receptor D4 (DRD4) gene variants on variables of the continuous performance test (CPT).This study recruited 255 ADHD patients and 98 healthy controls (HC) who underwent CPT and genetic analyses. The genotypes were classified into two groups (the C/C and C/T genotype groups for GIT1, 4R homozygotes and others for DRD4) and the genotype × genotype effects were examined using hierarchical multivariable linear regression analyses.There were significant GIT1 × DRD4 effects for commission errors on the CPT in the ADHD group (p = .006). In contrast, there were no significant GIT1 × DRD4 effects on any CPT variables in the HC.The present findings demonstrated that there were significant interaction effects of the GIT1 and DRD4 gene variants on impulsivity in ADHD. Replication studies with larger sample sizes that include patients from various ethnic backgrounds are warranted to confirm these findings.
Project description:BACKGROUND:Lead is known to be associated with attention-deficit/hyperactivity disorder (ADHD) even at low concentrations. We aimed to evaluate neurocognitive functions associated with lead in the blood and the interactions between lead and dopaminergic or noradrenergic pathway-related genotypes in youths with ADHD. METHODS:A total of 259 youths with ADHD and 96 healthy controls (aged 5-18?years) enrolled in this study. The Korean Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version was conducted for psychiatric diagnostic evaluation. Blood lead levels were measured, and their interaction with dopaminergic or noradrenergic genotypes for ADHD; namely, the dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and alpha-2A-adrenergic receptor (ADRA2A) genotypes were investigated. All participants were assessed using the ADHD Rating Scale-IV (ADHD-RS). Participants also completed the continuous performance test (CPT) and Stroop Color-Word Test (SCWT). Analysis of covariance was used for comparison of blood lead levels between ADHD and control groups. A multivariable linear regression model was used to evaluate the associations of blood lead levels with the results of ADHD-RS, CPT, and SCWT; adjusted for intelligence quotient (IQ), age, and sex. A path analysis model was used to identify the mediating effects of neurocognitive functions on the effects of blood lead on ADHD symptoms. To evaluate the effect of the interaction between blood lead and genes on neuropsychological functions, hierarchical regression analyses were performed. RESULTS:There was a significant difference in blood lead levels between the ADHD and control groups (1.4?±?0.5 vs. 1.3?±?0.5??g/dL, p?=?.005). Blood lead levels showed a positive correlation with scores on omission errors(r?=?.158, p?=?.003) and response time variability (r?=?.136, p?=?.010) of CPT. In the multivariable linear regression model, blood lead levels were associated with omission errors (B?=?3.748, p?=?.045). Regarding the effects of lead on ADHD symptoms, hyperactivity-impulsivity was mediated by omission errors. An interaction effect was detected between ADRA2A DraI genotype and lead levels on omission errors (B?=?5.066, p?=?.041). CONCLUSIONS:Our results indicate that neurocognitive functions at least partly mediate the association between blood lead levels and ADHD symptoms, and that neurocognitive functions are affected by the interaction between blood lead levels and noradrenergic genotype.
Project description:The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (GxE) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children.Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6-17 years.There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for GxE interactions.Despite the large sample size, no GxE interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in rater-specific behaviors.
Project description:OBJECTIVE:Sleep problems is the most common side effect of methylphenidate (MPH) treatment in ADHD youth and carry potential to negatively impact long-term self-regulatory functioning. This study aimed to examine whether applying machine learning approaches to pre-treatment demographic, clinical questionnaire, environmental, neuropsychological, genetic, and neuroimaging features can predict sleep side effects following MPH administration. METHOD:The present study included 83 ADHD subjects as a training dataset. The participants were enrolled in an 8-week, open-label trial of MPH. The Barkley Stimulant Side Effects Rating Scale was used to determine the presence/absence of sleep problems at the 2nd week of treatment. Prediction of sleep side effects were performed with step-wise addition of variables measured at baseline: demographics (age, gender, IQ, height/weight) and clinical variables (ADHD Rating Scale-IV (ADHD-RS) and Disruptive Behavior Disorder rating scale) at stage 1, neuropsychological test (continuous performance test (CPT), Stroop color word test) and genetic/environmental variables (dopamine and norepinephrine receptor gene (DAT1, DRD4, ADRA2A, and SLC6A2) polymorphisms, blood lead, and urine cotinine level) at stage 2, and structural connectivities of frontostriatal circuits at stage 3. Three different machine learning algorithms ((Logistic Ridge Regression (LR), support vector machine (SVM), J48) were used for data analysis. Robustness of classifier model was validated in the independent dataset of 36 ADHD subjects. RESULTS:Classification accuracy of LR was 95.5% (area under receiver operating characteristic curve (AUC) 0.99), followed by SVM (91.0%, AUC 0.85) and J48 (90.0%, AUC 0.87) at stage 3 for predicting sleep problems. The inattention symptoms of ADHD-RS, CPT response time variability, the DAT1, ADRA2A DraI, and SLC6A2 A-3081T polymorphisms, and the structural connectivities between frontal and striatal brain regions were identified as the most differentiating subset of features. Validation analysis achieved accuracy of 86.1% (AUC 0.92) at stage 3 with J48. CONCLUSIONS:Our results provide preliminary support to the combination of multimodal classifier, in particular, neuroimaging features, as an informative method that can assist in predicting MPH side effects in ADHD.
Project description:Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD. Use of a multiplex family design (i.e., samples of families that included multiple affected members) may facilitate identification of additional gene variants of interest and advance understanding of gene-environment interplay in regard to parenting. Thirty multiplex families consisting of 114 individuals (66 youth, 48 parents) completed a multi-stage, multi-informant diagnostic and neurocognitive assessment, measures of parenting, and provided saliva samples for DNA analyses. Sanger sequencing of the DRD4 gene yielded 16 rare variants; a polygenic risk score was computed for both parents and youth. Generalized estimating equations (GEE) examined the predictive effects of parental ADHD symptoms, parental neurocognitive functioning, and poor parenting dimensions on youth ADHD as well as moderation of these effects by parental and youth DRD4 variants. Findings indicated that parental DRD4 variants moderated the impact of parental ADHD and neurocognitive functioning on youth ADHD symptoms. Youth DRD4 variants moderated the impact of parental inconsistent discipline on child ADHD. In all cases, stronger associations were observed for those individuals with more risk variants. These exploratory findings highlight the potential utility of a multiplex family design for examining the interplay between parent and child characteristics in predicting youth outcomes.
Project description:Attention-deficit hyperactivity disorder (ADHD) is a common childhood neurobehavioral disorder characterized by inattention, poor impulse control, and motor restlessness. Risk factors include familial stressors, anxiety disorders, learning disabilities, abnormal brain development, heritability, and dopamine polymorphisms. Children with an orofacial clefting (OFC) history are at increased risk of familial stressors, anxiety disorders, learning disabilities, and abnormal brain development. Given this overlap, we present a conceptual model proposing that children with OFC may be more likely to exhibit ADHD symptoms than children without and explore this relationship using pilot data.This cross-sectional pilot study included 29 children with OFC or a first-degree relative with OFC recruited through a cleft research registry.The Disruptive Behavior Disorder Scale was used to collect data on children's ADHD symptoms. Saliva or whole blood samples were collected from children and parents for DNA analyses. ADHD-associated dopamine polymorphisms within the DRD4, DRD2, and DAT1 genes were genotyped. We tested for associations between presence of OFC and dopamine polymorphisms. Mixed-effects models tested whether children with OFC and dopamine polymorphisms had more ADHD symptoms.The DRD4 4-repeat allele was associated with increased inattentive ADHD symptoms (p = .03). Having the DRD2 Taq1A1 allele and OFC predicted fewer (p = .02) inattentive ADHD symptoms. Children with OFC were significantly less likely to have the DAT1 10-repeat allele (p = .04).Results indicate that further investigation among a larger sample of children with OFC is warranted, particularly for relationships with inattentive ADHD.
Project description:The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/"long" allele was identified as an ADHD risk factor in European-Caucasian populations (d?=?1.31, 95%CI: 1.17-1.47, Z?=?4.70/d?=?1.36, 95%CI: 1.20-1.55, Z?=?4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/"short" allele was a protective factor in European-Caucasian and South American populations (d?=?0.83, 95%CI: 0.75-0.92, Z?=?3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d?=?1.20, 95%CI: 0.71-1.69, Z?=?4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48?bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression downregulation was found in ADHD specific brain regions (Putamen, Z score?=?-3.02, P?=?0.00252). Overall, our results suggest that DRD4 48?bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.
Project description:BACKGROUND: We reviewed systematically the results of genetic studies investigating associations between putative susceptibility genes for attention-deficit hyperactivity disorder (ADHD) and neuropsychological traits relevant for this disorder. METHODS: We identified papers for review through the PubMed database. RESULTS: Twenty-nine studies examined 10 genes (DRD4, DAT1, COMT, DBH, MAOA, DRD5, ADRA2A, GRIN2A, BDNF and TPH2) in relation to neuropsychological traits relevant for ADHD. For DRD4, the continuous performance test (CPT) and derived tasks were the most used tests. Association of high reaction time variability with the 7-repeat allele absence appears to be the most consistent result and seems to be specific to ADHD. Speed of processing, set-shifting and cognitive impulsiveness were less frequently investigated but seem to be altered in the 7-repeat allele carriers. No effect of genotype was found on response inhibition (the stop and go/no-go tasks). For DAT1, 4 studies provide conflicting results in relation to omission and commission errors from CPT and derived tasks. High reaction time variability seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity. The other genes have attracted fewer studies, and the reported findings need to be replicated. LIMITATIONS: Although we aimed to perform a formal meta-analysis, this was not possible because the number of studies using the same neurocognitive endophenotypes was limited. We referred only minimally to the various theoretical frameworks in this field of research; more detail would have been beyond the scope of our systematic review. Finally, sample sizes in most of the studies we reviewed were small. Thus, some negative findings could be attributed to a lack of statistical power, and positive results should be considered preliminary until they are replicated in extended samples. CONCLUSION: Several methodological issues, including measurement errors, developmental changes in cognitive abilities, sex, psychostimulant effects and presence of comorbid conditions, represent confounding factors and may explain conflicting results.
Project description:G-protein coupled receptor kinase-interacting protein (GIT) proteins include an N-terminal Arf GTPase-activating protein domain, and a C terminus that binds proteins regulating adhesion and motility. Given their ability to form large molecular assemblies, the GIT1 protein must be tightly regulated. However, the mechanisms regulating GIT1 functions are poorly characterized. We found that carboxy-terminal-truncated fragments of GIT1 bind their partners with higher efficiency compared with the full-length GIT1. We have explored the hypothesis that GIT1 is regulated by an intramolecular mechanism, and we identified two distinct intramolecular interactions between the N and C terminus of GIT1. The release of these interactions increases binding of GIT1 to paxillin and liprin-alpha, and it correlates with effects on cell spreading. Analysis of cells plated on fibronectin has shown that different deletion mutants of GIT1 either enhance or inhibit spreading, depending on their subcellular localization. Moreover, although the association between betaPIX and GIT1 is insufficient to activate GIT1 binding to paxillin, binding of a PAK1 fragment including the betaPIX-binding domain enhances paxillin binding to betaPIX/GIT1, indicating that p21-activated kinase can activate the binding of paxillin to GIT1 by a kinase-independent mechanism. The release of the identified intramolecular interaction seems to be an important mechanism for the regulation of GIT1 functions.
Project description:Choice impulsivity has been linked to dopamine function and is consistently observed in attention deficit/hyperactivity disorder (ADHD) as a preference for smaller-immediate over larger-delayed rewards using choice-delay paradigms. More sophisticated delay discounting paradigms have yielded inconsistent results. Context and sample characteristics may have contributed to these variations. In this study we examine the effect of type (real vs hypothetical) and magnitude of reward as well as of variation in dopamine genes on choice impulsivity. We selected 36 male adolescents with ADHD-combined subtype (ADHD-CT) and 32 controls (mean age=15.42, SD=2.05) to form four roughly equally sized subgroups on the basis of DAT1(10/6) haplotype dosage (2 copies and <2 copies). Participants, who were also genotyped for the COMT(val158met) and DRD4(48bp-VNTR) polymorphisms, performed a hypothetical and a real-time discounting task and provided self-ratings of trait impulsivity. The ADHD-CT group discounted rewards more steeply than controls only in the hypothetical task, with delay, but not reward magnitude, influencing choices. They also rated themselves as more impulsive compared with controls. DAT1(10/6) dosage and the COMT(Val158Met) genotype predicted trait impulsivity and discounting rates in the hypothetical task, but not in the real-time task. Our results directly link variation in genes putatively influencing dopamine signaling in the prefrontal cortex (COMT(Val158Met)) and the striatum (DAT1(10/6)) with discounting rates in a hypothetical task (but not a real-time task) and self-ratings of trait impulsivity in ADHD-CT and healthy controls. The lack of magnitude effects in the hypothetical task suggests that discounting in this task may be influenced by different processes in ADHD-CT than in healthy controls.