One-year follow-up of the effectiveness and mediators of cognitive behavioural therapy among adults with attention-deficit/hyperactivity disorder: secondary outcomes of a randomised controlled trial.

BACKGROUND: The long-term effectiveness of cognitive behavioural therapy (CBT) in medicated attention-deficit/hyperactivity disorder (ADHD) adults with residual symptoms needs to be verified across multiple dimensions, especially with respect to maladaptive cognitions and psychological quality of life (QoL). An exploration of the mechanisms underlying the additive benefits of CBT on QoL in clinical samples may be helpful for a better understanding of the CBT conceptual model and how CBT works in medicated ADHD. METHODS: We conducted a secondary analysis of a randomised controlled trial including 98 medicated ADHD adults with residual symptoms who were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M)-only group. Outcomes included ADHD-core symptoms (ADHD Rating Scale), depression symptoms (Self-rating Depression Scale), maladaptive cognitions (Automatic Thoughts Questionnaire and Dysfunctional Attitude Scale), and psychological QoL (World Health Organization Quality of Life-Brief Version-psychological domain). Mixed linear models (MLMs) were used to analyse the long-term effectiveness at one-year follow-up, and structural equation modeling (SEM) was performed to explore the potential mechanisms of CBT on psychological QoL. RESULTS: ADHD patients in the CBT + M group outperformed the M-only group in reduction of ADHD core symptoms (d = 0.491), depression symptoms (d = 0.570), a trend of reduction of maladaptive cognitions (d = 0.387 and 0.395, respectively), and improvement of psychological QoL (d = - 0.433). The changes in above dimensions correlated with each other (r = 0.201 ~ 0.636). The influence of CBT on QoL was mediated through the following four pathways: 1) changes in ADHD core symptoms; 2) changes in depressive symptoms; 3) changes in depressive symptoms and then maladaptive cognitions; and 4) changes firstly in depressive symptoms, maladaptive cognitions, and then ADHD core symptoms. CONCLUSIONS: The long-term effectiveness of CBT in medicated ADHD adults with residual symptoms was further confirmed. The CBT conceptual model was verified in clinical samples, which would be helpful for a deeper understanding of how CBT works for a better psychological QoL outcome. TRIAL REGISTRATION: ChiCTR1900021705 (2019-03-05).

Bidirectional associations between maladaptive cognitions and emotional symptoms, and their mediating role on the quality of life in adults with ADHD: a mediation model.

Background/objectives: Adults with attention-deficit/hyperactivity disorder (ADHD) have more maladaptive cognitions, emotional problems and a poorer quality of life (QoL). A verification of the psychological model in clinical samples is needed for a better understanding of the mechanisms of ADHD diagnosis on QoL via maladaptive cognitions, emotional symptoms, and their interactions. Methods: 299 ADHD participants and 122 healthy controls were recruited. ADHD core symptoms, maladaptive cognitions, emotional symptoms and psychological QoL were rated. Pearson's correlation and structural equation modeling were analyzed to explore the relationship and influence of ADHD diagnosis on QoL. Results: More maladaptive cognitions, emotional symptoms, and poorer QoL were found in the ADHD group, and the dysfunctional attitudes were on par between ADHD with or without medication (p = 0.368). Moderate to strong correlations were found between emotional symptoms, maladaptive cognitions and QoL, and ADHD core symptoms presented correlations among the above scores (r = 0.157 ~ 0.416, p < 0.01) in ADHD participants. The influence of ADHD diagnosis on QoL was mediated through maladaptive cognitions, emotional symptoms, and their bidirectional interactions (p < 0.05), especially those with stable medication. Conclusion: Our study is the first to verify the psychological model in adults with ADHD in China. The findings determined the direct influence of ADHD diagnosis on QoL and the indirect influence through maladaptive cognitions, emotional symptoms, and their interactions, emphasizing the importance of interventions for emotional symptoms and maladaptive cognitions for ADHD patients both with or without medication for a better QoL outcome.

Efficacy of cognitive behavioural therapy in medicated adults with attention-deficit/hyperactivity disorder in multiple dimensions: a randomised controlled trial.

The study aimed to evaluate the efficacy of group cognitive behavioural therapy (CBT) in medicated adults with attention-deficit/hyperactivity disorder (ADHD) with a multidimensional evaluation and follow-up to week 36. Ninety-eight adult ADHD were randomly allocated to the CBT combined with medication (CBT + M) group or the medication (M) only group. The primary endpoint was the ADHD-Rating Scale (ADHD-RS). Secondary endpoints included emotional symptoms, self-esteem, automatic thoughts, quality of life (QoL), and executive function (EF). The outcome measures were obtained at baseline (T1), after the 12-week CBT treatment (T2), and at two follow-up time points (week 24, T3, and week 36, T4). Compared to the M-only group, the patients in the CBT + M group showed an overall significantly greater reduction from baseline in ADHD core symptoms (ADHD-RS total score at T3, and inattention subscale at T2 and T3), depression and anxiety symptoms (T2-T4), state anxiety (T2 and T3) and trait anxiety (T2), automatic thoughts questionnaire at T3, and QoL (physical domain, psychological domain, and social domain, most significant at T3 and weakened at T4). These findings further confirmed the efficacy of CBT on multiple dimensions and verified improvements in automatic thinking in adult ADHD. The superiority of the combination treatment mainly manifested in reduced inattention, emotional symptoms, and maladaptive thoughts and improved QoL. Trial registration number ChiCTR1900021705 (March-05-2019).

Cortical Morphometric Abnormality and Its Association with Working Memory in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents. The present study investigated the cortical morphology features and their relationship with working memory (WM). METHODS: In the present study, a total of 36 medication naïve children with ADHD (aged from 8 to 15 years) and 36 age- and gendermatched healthy control (HC) children were included. The digit span test was used to evaluate WM. The magnetic resonance imaging (MRI) was used to examine the characteristics of cortical morphology. Firstly, we compared the cortical morphology features between two groups to identify the potential structural alterations of cortical volume, surface, thickness, and curvature in children with ADHD. Then, the correlation between the brain structural abnormalities and WM was further explored in children with ADHD. RESULTS: Compared with the HC children, the children with ADHD showed reduced cortical volumes in the left lateral superior temporal gyrus (STG) (p=6.67×10-6) and left anterior cingulate cortex (ACC) (p=3.88×10-4). In addition, the cortical volume of left lateral STG was positively correlated with WM (r=0.36, p=0.029). CONCLUSION: Though preliminary, these findings suggest that the reduced cortical volumes of left lateral STG may contribute to the pathogenesis of ADHD and correlate with WM in children with ADHD.

Adult ADHD, executive function, depressive/anxiety symptoms, and quality of life: A serial two-mediator model.

BACKGROUND: Adult attention-deficit/hyperactivity disorder (ADHD) is associated with impaired executive function (EF), depressive/anxiety symptoms, and poor quality of life (QoL). In this study, we aimed to investigate correlations among these variables and to build a simple or serial mediation model for exploring the mechanisms between adult ADHD and QoL. METHODS: This was a cross-sectional study. The sample included 223 participants with ADHD and 54 healthy volunteers. Participants were required to complete the following scales: ADHD Rating Scale (ADHD-RS), Brief Version of the World Health Organization Quality of Life Scale (WHOQOL-BREF), Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A), Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS). Correlations among EF, depressive/anxiety symptoms and QoL were analyzed using Pearson correlation. The simple and serial mediation models were analyzed using PROCESS (version 3.3). RESULTS: The correlations between EF and QoL, depressive/anxiety symptoms and QoL, and depressive/anxiety symptoms and EF were statistically significant. In ADHD adults with comorbidities, the correlation coefficients were between -0.19 and -0.47, -0.20 and -0.62, 0.28 and 0.50, respectively. In simple mediation models, EF and depressive/anxiety symptoms were significant mediators respectively between ADHD and QoL, respectively. In a serial two-mediator model, ADHD could affect QoL indirectly via EF and then via depressive/anxiety symptoms significantly. LIMITATIONS: The average age was young, the degree of education was high, and only self-reported scales were relied on. CONCLUSIONS: There is a mutual effect between EF and emotional symptoms. This was the first study to build a serial two-mediator model between ADHD and QoL, suggesting the importance of EF and depressive/anxiety symptoms.

A potential association of RNF219-AS1 with ADHD: Evidence from categorical analysis of clinical phenotypes and from quantitative exploration of executive function and white matter microstructure endophenotypes.

AIMS: Attention-deficit/hyperactivity disorder (ADHD) is a neuropsychiatric disorder of substantial heritability, yet emerging evidence suggests that key risk variants might reside in the noncoding regions of the genome. Our study explored the association of lncRNAs (long noncoding RNAs) with ADHD as represented at three different phenotypic levels guided by the Research Domain Criteria (RDoC) framework: (i) ADHD caseness and symptom dimension, (ii) executive functions as functional endophenotype, and (iii) potential genetic influence on white matter architecture as brain structural endophenotype. METHODS: Genotype data of 107 tag single nucleotide polymorphisms (SNP) from 10 candidate lncRNAs were analyzed in 1040 children with ADHD and 630 controls of Chinese Han descent. Executive functions including inhibition and set-shifting were assessed by STROOP and trail making tests, respectively. Imaging genetic analyses were performed in a subgroup of 33 children with ADHD and 55 controls using fractional anisotropy (FA). RESULTS: One SNP rs3908461 polymorphism in RNF219-AS1 was found to be significantly associated with ADHD caseness: with C-allele detected as the risk genotype in the allelic model (P = 8.607E-05) and dominant genotypic model (P = 9.628E-05). Nominal genotypic effects on inhibition (p = 0.020) and set-shifting (p = 0.046) were detected. While no direct effect on ADHD core symptoms was detected, mediation analysis suggested that SNP rs3908461 potentially exerted an indirect effect through inhibition function [B = 0.21 (SE = 0.12), 95% CI = 0.02-0.49]. Imaging genetic analyses detected significant associations between rs3908461 genotypes and FA values in corpus callosum, left superior longitudinal fasciculus, left posterior limb of internal capsule, left posterior thalamic radiate (include optic radiation), and the left anterior corona radiate (P FWE corrected  < 0.05). CONCLUSION: Our present study examined the potential roles of lncRNA in genetic etiological of ADHD and provided preliminary evidence in support of the potential RNF219-AS1 involvement in the pathophysiology of ADHD in line with the RDoC framework.

Cognitive behavioural therapy in groups for medicated adults with attention deficit hyperactivity disorder: protocol for a randomised controlled trial.

INTRODUCTION: Cognitive behavioural therapy (CBT) is an evidence-based treatment for adults with attention deficit hyperactivity disorder (ADHD). However, it is still inconsistent whether a combination of CBT would have additive effects in medicated ADHD in adulthood. And if CBT would have additional effects, what kind and which dimension would CBT play a part? This study estimates the efficacy of CBT in stable medicated adult ADHD, using long-term outcomes and multidimensional evaluations. METHODS AND ANALYSIS: It is a two-armed, randomised controlled trial on the superiority of the efficacy of 12 weeks of CBT on medicated adult ADHD. We compare the short-term and long-term outcomes between CBT combined with medication (CBT+M) group and the medication-only (M) group, including ADHD core symptoms, emotional symptoms, executive function, self-esteem, life quality and brain function using functional near-infrared spectroscopy data. Participants are outpatients of the Peking University Sixth Hospital and those recruited online, diagnosed as adult ADHD and with stable medication treatment. We estimate ADHD core symptoms and combined symptoms at baseline (T1) and week 12 (T2), week 24 (T3), week 36 (T4) and week 48 (T5). ETHICS AND DISSEMINATION: This trial has been approved by the Ethics and Clinical Research Committees of Peking University Sixth Hospital and will be performed under the Declaration of Helsinki with the Medical Research Involving Human Subjects Act (WMO). The results will be disseminated in a peer-reviewed journal and a conference presentation. TRIAL REGISTRATION NUMBER: ChiCTR (ChiCTR1900021705).

Alterations of cerebral perfusion and functional brain connectivity in medication-naïve male adults with attention-deficit/hyperactivity disorder.

AIMS: Functional brain abnormalities, including altered cerebral perfusion and functional connectivities, have been illustrated in adults with attention-deficit/hyperactivity disorder (aADHD). The present study attempted to explore the alterations of cerebral blood flow (CBF) and resting-state functional connectivity (RSFC) simultaneously to understand the neural mechanisms for adults with ADHD comprehensively. METHODS: Resting-state arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) data were acquired for 69 male aADHD and 69 matched healthy controls (HCs). The altered CBFs associated with aADHD were explored based on both categorical (aADHD vs HCs) and dimensional (correlation with aADHD core symptoms) perspectives. Then, the seed-based RSFC analyses were developed for the regions showing significant alterations of CBF. RESULTS: Significantly decreased CBF in the large-scale resting-state networks regions (eg, ventral attentional network, somatomotor network, limbic network) and subcortical regions was indicated in aADHD compared with HCs. The correlation analyses indicated that the hypoperfusion in left putamen/global pallidum and left amygdala/hippocampus was correlated with ADHD inattentive and total symptoms, respectively. Further, weaker negative functional connectivity between left amygdala and bilateral supplementary motor area, bilateral superior frontal gyrus, and left medial frontal gyrus was found in adults with ADHD. CONCLUSION: The present findings suggested alterations of both cerebral perfusion and functional connectivity for the left amygdala in aADHD. The combination of CBF and RSFCs may help to interpret the neuropathogenesis of ADHD more comprehensively.

The Characteristics and Age Effects of Emotional Lability in ADHD Children With and Without Oppositional Defiant Disorder.

Objective: This study evaluated the concurrent validity of emotional lability (EL) in children with ADHD. Method: A total of 2,015 children with ADHD and 745 typically developed controls (TDCs) were assessed and compared on EL. Results: ADHD participants expressed higher EL scores than TDCs, not influenced by gender or IQ. Higher levels of EL symptoms were found in children with comorbid oppositional defiant disorder (ODD) and with ADHD-combined subtype. Receiver operating characteristic (ROC) analyses showed a strong screening efficacy of EL symptoms on ADHD. The effect of developmental age on EL showed a desisting pattern in TDCs, as opposed to a persisting pattern in ADHD (not influenced by ODD comorbid status). ODD symptoms in ADHD showed an ascending pattern. Conclusion: EL can potentially serve as a sentinel index for the presence of ADHD, especially when the ADHD presentation is atypical. ODD may embody a developmental entity distinct from EL.

A comparison of efficacy between cognitive behavioral therapy (CBT) and CBT combined with medication in adults with attention-deficit/hyperactivity disorder (ADHD).

The study aimed to explore whether cognitive behavioral therapy (CBT) combined with medication is superior to CBT alone in core symptoms, emotional symptoms, self-esteem as well as social and cognitive functions of adult attention-deficit/hyperactivity disorder (ADHD) patients. Samples from a previous RCT study and outpatient participants were all included. A total of 124 patients received 12 weeks of manualized CBT sessions, either with (n = 57) or without (n = 67) medication. Efficacy variables were evaluated at baseline and each week. Mixed linear models (MLM) were used to compare differences between the two groups in all of the above domains. Within-group comparisons showed that both groups had robust improvements in core ADHD symptoms, emotional symptoms and social functional outcomes. The CBT + M group presented more domains of improvement in executive functions than the CBT group. However, comparisons between groups didn't indicate the superiority of CBT + M in core symptoms, emotional symptoms and self-esteem. Instead, the CBT group showed a greater improvement in the physical domain of the WHOQOL-BREF than the CBT + M group. This study further indicated that CBT is an effective treatment for adults with ADHD. A combination of CBT and medication presented broader improvements in executive functions, but not in clinical symptoms, than CBT alone.

Interaction Between Season of Birth and COMT Val158Met (rs4680) in ADHD in a Large Sample of Chinese Han Participants.

OBJECTIVE: To investigate the interaction between catechol-O-methyltransferase gene (COMT) Val108/158Met (rs4680) and season of birth (SOB) on ADHD and its symptoms. METHOD: We conducted transmission disequilibrium tests (TDTs) in 976 trios, then further performed the above analyses in subgroups according to SOB. Quantitative analyses were performed for ADHD symptoms evaluated by ADHD Rating Scale-IV in 1,530 ADHD cases. RESULTS: Overall, there was no association between COMT and ADHD. After stratification, we found an increased transmission of the Val allele in the trios born in spring, while a decreased transmission was observed in the autumn months. We also observed a significant interaction between Val108/158Met and SOB on ADHD symptoms. Among those born in spring, Met carriers had milder ADHD symptoms compared with Val homozygotes, whereas opposite association was found in those born in autumn. CONCLUSION: Our study provided evidence for the modifying effect of SOB on the association between COMT and ADHD along with its symptoms.

Cognitive Function of Children and Adolescents with Attention Deficit Hyperactivity Disorder and Learning Difficulties: A Developmental Perspective.

BACKGROUND: The cognitive function of children with either attention deficit hyperactivity disorder (ADHD) or learning disabilities (LDs) is known to be impaired. However, little is known about the cognitive function of children with comorbid ADHD and LD. The present study aimed to explore the cognitive function of children and adolescents with ADHD and learning difficulties in comparison with children with ADHD and healthy controls in different age groups in a large Chinese sample. METHODS: Totally, 1043 participants with ADHD and learning difficulties (the ADHD + learning difficulties group), 870 with pure ADHD (the pure ADHD group), and 496 healthy controls were recruited. To investigate the difference in cognitive impairment using a developmental approach, all participants were divided into three age groups (6-8, 9-11, and 12-14 years old). Measurements were the Chinese-Wechsler Intelligence Scale for Children, the Stroop Color-Word Test, the Trail-Making Test, and the Behavior Rating Inventory of Executive Function-Parents (BRIEF). Multivariate analysis of variance was used. RESULTS: The results showed that after controlling for the effect of ADHD symptoms, the ADHD + learning difficulties group was still significantly worse than the pure ADHD group, which was, in turn, worse than the control group on full intelligence quotient (98.66 ± 13.87 vs. 105.17 ± 14.36 vs. 112.93 ± 13.87, P < 0.001). The same relationship was also evident for shift function (shifting time of the Trail-Making Test, 122.50 [62.00, 194.25] s vs. 122.00 [73.00, 201.50] s vs. 66.00 [45.00, 108.00] s, P< 0.001) and everyday life executive function (BRIEF total score, 145.71 ± 19.35 vs. 138.96 ± 18.00 vs. 122.71 ± 20.45, P < 0.001) after controlling for the effect of the severity of ADHD symptoms, intelligence quotient, age, and gender. As for the age groups, the differences among groups became nonsignificant in the 12-14 years old group for inhibition (meaning interference of the Stroop Color-Word Test, 18.00 [13.00, 25.00] s vs. 17.00 [15.00, 26.00] s vs. 17.00 [10.50, 20.00] s , P = 0.704) and shift function (shifting time of the Trail-Making Test, 62.00 [43.00, 97.00] s vs. 53.00 [38.00, 81.00] s vs. 101.00 [88.00, 114.00] s, P = 0.778). CONCLUSIONS: Children and adolescents with ADHD and learning difficulties have more severe cognitive impairment than pure ADHD patients even after controlling for the effect of ADHD symptoms. However, the differences in impairment in inhibition and shift function are no longer significant when these individuals were 12-14 years old.

Childhood predictors of persistent ADHD in early adulthood: Results from the first follow-up study in China.

It is known that childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood. Previous studies have demonstrated that gender, ADHD symptoms, functional impairment severity, medication treatment, IQ, comorbid with oppositional defiant disorder, conduct disorder and follow-up periods were associated with ADHD persistence in longitudinal samples of western population. In this study, we attempted to widely investigate the predictors particularly in a Chinese Han ADHD cohort. 399 children who met DSM-IV ADHD criteria were followed up into early adulthood. Ordinal logistic regression combined with survival analysis were conducted to examine the association of retrospectively reported childhood factors with adult ADHD persistence based on both categorical indicators and quantitative traits. 46.37% of the participants still met ADHD criteria in adulthood. Logistic models and survival analyses indicated that ADHD combined type appeared as a significant risk factor for ADHD persistence while superior IQ played a protective role even after controlling for the other potential confounders. When quantitative traits were applied, a number of hyperactivity/impulsivity symptoms and IQ still made significant contributions. In conclusion, our results indicated the syndromic continuity of ADHD. Further, a number of hyperactivity/impulsivity symptoms were a risk factor while higher IQ was protective for ADHD persistence.

Interactions between MAOA and SYP polymorphisms were associated with symptoms of attention-deficit/hyperactivity disorder in Chinese Han subjects.

As candidate genes of attention--deficit/hyperactivity disorder (ADHD), monoamine oxidase A (MAOA), and synaptophysin (SYP) are both on the X chromosome, and have been suggested to be associated with the predominantly inattentive subtype (ADHD-I). The present study is to investigate the potential gene-gene interaction (G × G) between rs5905859 of MAOA and rs5906754 of SYP for ADHD in Chinese Han subjects. For family-based association study, 177 female trios were included. For case-control study, 1,462 probands and 807 normal controls were recruited. The ADHD Rating Scale-IV (ADHD-RS-IV) was used to evaluate ADHD symptoms. Pedigree-based generalized multifactor dimensionality reduction (PGMDR) for female ADHD trios indicated significant gene interaction effect of rs5905859 and rs5906754. Generalized multifactor dimensionality reduction (GMDR) indicated potential gene-gene interplay on ADHD RS-IV scores in female ADHD-I. No associations were observed in male subjects in case-control analysis. In conclusion, our findings suggested that the interaction of MAOA and SYP may be involved in the genetic mechanism of ADHD-I subtype and predict ADHD symptoms.

The developmental trajectories of executive function of children and adolescents with Attention Deficit Hyperactivity Disorder.

This study examined the developmental trajectories of executive function (EF) of children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD) in Han Chinese. Five hundred and fifteen children and adolescents with ADHD and 249 healthy controls took part in this study. All of them were administered four EF tests capturing inhibition, working memory, shifting and planning components. The participants were further divided into four age groups, 7-8, 9-10, 11-12, and 13-15 years old, respectively, for developmental trajectories comparison. The performance of the typical developing children and adolescents aged 7-15 were reported to get stable at age 11-12 for inhibition, working memory and planning, and kept developing till age 13-15 for shifting. For inhibition and shifting, participants with ADHD displayed similar performance to the healthy controls who were 2 years younger whereas they did poorer than the healthy controls of their same age. And at age 13-15, such poorer performance disappeared for inhibition but maintained for shifting. No significant differences were found between participants with and without ADHD in working memory and planning across all age groups. The current findings suggested, compared with healthy controls, Han Chinese children and adolescents with ADHD displayed delayed developmental trajectories on inhibition and shifting, whereas they showed similar trend of development on working memory and planning.

BAIAP2 exhibits association to childhood ADHD especially predominantly inattentive subtype in Chinese Han subjects.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder with a high heritability. Much evidence of hemisphere asymmetry has been found for ADHD probands from behavioral level, electrophysiological level and brain morphology. One previous research has reported possible association between BAIAP2, which is asymmetrically expressed in the two cerebral hemispheres, with ADHD in European population. The present study aimed to investigate the association between BAIAP2 and ADHD in Chinese Han subjects. METHODS: A total of 1,397 ADHD trios comprised of one ADHD proband and their parents were included for family-based association tests. Independent 569 ADHD cases and 957 normal controls were included for case-control studies. Diagnosis was performed according to the DSM-IV criteria. Nine single nucleotide polymorphisms (SNPs) of BAIAP2 were chosen and performed genotyping for both family-based and case-control association studies. RESULTS: Transmission disequilibrium tests (TDTs) for family-based association studies showed significant association between the CA haplotype comprised by rs3934492 and rs9901648 with predominantly inattentive type (ADHD-I). For case-control study, chi-square tests provided evidence for the contribution of SNP rs4969239, rs3934492 and rs4969385 to ADHD and its two clinical subtypes, ADHD-I and ADHD-C. However, only the associations for ADHD and ADHD-I retained significant after corrections for multiplicity or logistic regression analyses adjusting the potential confounding effect of gender and age. CONCLUSIONS: These above results indicated the possible involvement of BAIAP2 in the etiology of ADHD, especially ADHD-I.

Association analyses of MAOA in Chinese Han subjects with attention-deficit/hyperactivity disorder: family-based association test, case-control study, and quantitative traits of impulsivity.

Monoamine oxidase A (MAOA) plays a critical role in the metabolism of monoamine neurotransmitters including serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Genetic studies have found an association between MAOA and attention-deficit/hyperactivity disorder (ADHD), especially impulsivity. However, there has been inconsistency among studies which may be due to the complexity and heterogeneity of ADHD, including its sexual dimorphism and the presence of several subtypes. We conducted transmission disequilibrium tests (TDTs) in 1,253 trios and found no association between five single nucleotide polymorphisms (SNPs) of MAOA with ADHD in general or in the predominantly inattentive (ADHD-I) or combined types (ADHD-C), but with the predominantly hyperactive/impulsivity type (ADHD-HI). The association with MAOA was restricted to males, especially males with ADHD-HI. Logistic regression analyses of data from 1,824 cases and 957 controls did not indicate any association. We used analysis of covariance to analyze the association between MAOA genotype with the "inhibit" factor of the Behavior Rating Inventory of Executive Function (BRIEF) in 640 probands and performance on the Stroop test in 810 probands. Probands homozygous for risk alleles found in the TDT test had higher "inhibit" scores on the BRIEF scale which represents more severe impulsivity; this results also was restricted to males. No association was found with Stroop test performance. In conclusion, our results provide some evidence that MAOA may be associated with the ADHD-HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD. However, the results were strongly influenced by gender.

Dopamine ß-hydroxylase gene associates with stroop color-word task performance in Han Chinese children with attention deficit/hyperactivity disorder.

The cognitive deficits observed in attention deficit/hyperactivity disorder (ADHD) are candidate endophenotypes for genetic association studies. Dopamine ß-hydroxylase (DßH) converts dopamine to norepinephrine, and its activity is under strong genetic control. Prior studies suggest association between ADHD and DBH gene. The present study examined associations between a putative functional single nucleotide polymorphism (SNP) at DBH with performance on the Stroop task in patients with ADHD and in healthy control subjects. A total of 812 Han Chinese youths with DSM-IV ADHD and 233 unaffected controls were included in the study. Comprehensive phenotype data were collected, including performance on a series of Stroop interference tests examining inhibition of response to interfering stimuli. DBH SNP -1021C/T was genotyped using the 5'-exonuclease (TaqMan®) method. Compared to unaffected controls, children with ADHD performed significantly worse in all categories of the Stroop test. In ADHD cases, DBH genotype at -1021C/T significantly associates with reaction times of incongruent color word parts but not the interference times, with TT genotype performing significantly better in both reaction time and interference time than other two genotype groups. DBH genotype did not associate with cognitive performance in unaffected controls or in the combined group. DBH genotype at -1021C/T associates with differences in performance on the Stroop task in children with ADHD.

Gene-gene interaction between COMT and MAOA potentially predicts the intelligence of attention-deficit hyperactivity disorder boys in China.

The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism (Val158Met) affecting the activity of the enzyme, and the monoamine oxidase A (MAOA) gene contains a VNTR polymorphism (MAOA-uVNTR) that affects the transcription of the gene. COMT and MAOA each contribute to the enzymatic degradation of dopamine and noradrenaline. Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities, including intelligence, is modulated by dopamine. Since our previous association studies between attention deficit hyperactivity disorder (ADHD) and these two functional polymorphisms consistently showed the low activity alleles were preferentially transmitted to inattentive ADHD boys, the goal of the present study was to test the hypothesis that the interaction between COMT Val158Met and MAOA-uVNTR may affect the intelligence in a clinical sample of Chinese male ADHD subjects (n = 264). We found that the COMT x MAOA interaction significantly predicted full scale (FSIQ) and performance (PIQ) IQ scores (P = 0.039, 0.011); the MAOA-uVNTR significantly predicted FSIQ, PIQ and verbal IQ (VIQ) (P = 0.009, 0.019, 0.038); COMT Val158Met independently had no effect on any of the IQ scores. Only the COMT x MAOA interaction for PIQ remained significant after a Bonferroni correction. Among all combined genotypes, the valval-3R genotype predicted higher intelligence, (average 106.7 +/- 1.6, 95% C.I. 103.7-109.8 for FSIQ), and the valval-4R predicted lower intelligence (average 98.0 +/- 2.3, 95% C.I. 93.5-102.6 for FSIQ). These results suggest that there is an inverted U-shaped relationship between intelligence and dopaminergic activity in our sample. Our finding that gene-gene interaction between COMT and MAOA predicts the intelligence of ADHD boys in China is intriguing but requires replication in other samples.

[Association study of intelligence of attention deficit hyperactivity disorder children in China].

OBJECTIVE: To investigate the association of 5-HT(2A) receptor gene (HTR2A)-1438A/G, Catechol-O-methyltransferase (COMT) gene Val158Met, Monoamine oxidase A ( MAOA ) gene 30 bp-VNTR(MAOA-uVNTR)polymorphisms, and the educational attainment level of the parents with the intelligence of attention deficit hyperactivity disorder (ADHD) in China. METHODS: A total of 485 DSM-IV ADHD children of Chinese Han descent were included, both complete IQ evaluation, HTR2A-1438A/G, COMT gene Val158Met, and MAOA-uVNTR genotyping results were obtained. The quantitative traits of psychometric IQ were calculated by using the Chinese Wechsler Intelligence Scale for Children (C-WISC). The multifactor linear regression analysis was used to test the associated factors on intelligence. RESULTS: Analyses revealed that ADHD children with low enzymatic activity (3R for males, 3R3R for females) of MAOA-uVNTR performed better on Full Scale IQ (FIQ) than did patients with high enzymatic activity (4R for males, 3R4R/4R4R for females) [(102.6+/-12.4) vs (100.3+/-11.7), P=0.078]. The patients with high-enzymatic activity (ValVal) of COMT gene Val158Met performed significantly better on FIQ than did patients with mid-low enzymatic activity (ValMet and MetMet)[(103.5+/-13.6) vs (100.5+/-11.5), P=0.036]. ADHD children with GG genotype of HTR2A-1438A/G performed significantly better on some aspects of C-WISC test (Full Scale IQ and Verbal Scale IQ) than did children with GA and AA genotypes [FIQ :(106.9+/-10.7) vs (100.7+/-12.3) vs (101.7+/-12.9), P=0.003; VIQ: (110.1+/-10.6) vs (103.5+/-12.1) vs (105.1+/-13.2), P=0.001]. The educational attainment level of the parents was associated with all the aspects of C-WISC test (Full Scale IQ, Verbal Scale IQ, and Performance Scale IQ). The multiple linear regression analysis showed that the genotype of HTR2A-1438A/G had significant correlation with FIQ, VIQ and PIQ; while the educational attainment level of the mother had significant correlation with FIQ and VIQ. CONCLUSION: The HTR2A-1438A/G polymorphism and the educational attainment level of the mother were associated with the intelligence of ADHD children in China.