Haimei Li

Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome-wide association study of both common and rare variants

Attention‐deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case–control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM‐IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome‐wide association analyses were performed using PLINK. SNP‐heritability and SNP‐genetic correlations with ADHD in Caucasians were estimated with genome‐wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein–Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome‐wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP‐heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP‐genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHDs etiology.

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.

Comparative study of OROS-MPH and atomoxetine on executive function improvement in ADHD: a randomized controlled trial

This study aimed to compare the effects of osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine (ATX) on executive function in children and adolescents with attention deficit hyperactivity disorder (ADHD) by a randomized controlled trial. Subjects who met DSM-IV ADHD criteria were randomized to receive either OROS-MPH or ATX treatment. The doses were titrated to achieve optimal response and then maintained for 4-6 wk. A battery of executive function tests and the Behavior Rating Inventory of Executive Function (BRIEF) were administered to subjects who completed the dose titration (OROS-MPH, n=85; ATX, n=57) at the pre- and post-treatment periods. Forty-six children without ADHD were recruited as controls. Both OROS-MPH and ATX significantly improved scores in the Rey Complex Figure Test (RCFT), digit span, and Stroop color-word task. The scores in RCFT and the reverse digit span were not significantly different from the control group at post-treatment assessment (OROS-MPH=ATX=control, p>0.05), whereas the word interference time of the Stroop test was still more than that of the control group (OROS-MPH=ATX>control, p>0.05). OROS-MPH also significantly improved the total correct response in the verbal fluency test to normal level, and the shifting time in the trail-making test to subnormal level. The current findings suggest both OROS-MPH and ATX improved executive function generally in children and adolescents with ADHD, and could return working memory back to normative performance level.

Synaptosome-related (SNARE) genes and their interactions contribute to the susceptibility and working memory of attention-deficit/hyperactivity disorder in males

BACKGROUNDS N-ethylmaleimide-sensitive attachment protein receptor (SNARE) complex involved in neurotransmission via exocytosis was implicated in attention-deficit/hyperactivity disorder (ADHD). The present study investigated the influence of SNARE related genes and their interaction on ADHD susceptibility and their cognitive functions. METHODS We genotyped eight single nucleotide polymorphisms (SNP) of Syntaxin 1A (STX1A), vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 kDa (SNAP25) and conducted case-control studies in 1404 male ADHD and 617 male controls. Quantitative analyses were performed for genotypes and performance on the Rey-Osterrieth complex figure test (RCFT), digit span test and Stroop test in 383 ADHD males. In addition, we explored gene-gene interactions by generalized multifactor dimensionality reduction (GMDR) followed with logistic regression and analyses of covariance for verifying. RESULTS Genotypic distribution of rs875342 of STX1A was significantly different between ADHD and controls. The SNPs, rs363039 of SNAP25 and rs1150 of VAMP2, were significantly associated with RCFT scores, while rs875342 of STX1A with digit span. We found genetic interaction models between these three genes and ADHD susceptibility as well as working memory function evaluated by RCFT. CONCLUSION SNARE complex genes and their interactions may play a significant role in susceptibility and working memory of ADHD.

Sex-specific association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and plasma BDNF with attention-deficit/ hyperactivity disorder in a drug-naïve Han Chinese sample

A functional polymorphism of the brain derived neurotrophic factor gene (BDNF) (Val66Met) has been suggested to be involved in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). It also has an impact on peripheral BDNF levels in psychiatric disorders. This study examined the association of Val66Met with plasma BDNF level of ADHD in Han Chinese children (170 medication - naïve ADHD patients and 155 unaffected controls, aged 6-16 years). The Val allele was showed a higher frequency in females with ADHD (n=84) than controls (P=0.029) from the case-control association study. The analysis of covariance (ANCOVA) indicated that the mean plasma BDNF levels of ADHD patients were significantly higher than that of controls (P=0.001). We performed both total sample and sex stratified analyses to investigate the effect of Val66Met genotype on the plasma BDNF levels, but only a trend of association was found in females with ADHD (n=84), with a tendency of lower plasma BDNF level in Val allele carriers than Met/Met genotype carriers (P=0.071). Our results suggested a sex-specific association between BDNF and ADHD. Furthermore, there was a possible sex-specific relationship between the BDNF Val66Met genotype and plasma BDNF levels. However, further studies are required to elucidate the role of BDNF in ADHD.

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

BackgroundAttention-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.MethodsA 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.ResultsTransmission 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.ConclusionsThese above results indicated the possible involvement of BAIAP2 in the etiology of ADHD, especially ADHD-I.

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.

Dopamine β-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 β‐hydroxylase (DβH) 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.

Association of Y-linked variants with impulsivity and aggression in boys with attention-deficit/hyperactivity disorder of Chinese Han descent

Y chromosome plays important role in brain function and may help to explain the sex difference in attention-deficit/hyperactivity disorder (ADHD). A total of 857 boys with ADHD and 574 male controls were genotyped for 14 Y-linked markers. Analyses for both dichotomous phenotype and quantitative traits and the interaction effects with MAOA were performed. The results indicated significant association of four markers (M88, M95, M175, and M119) with inhibition function and aggression in boys with ADHD. Positive interaction effects with MAOA were also detected. In conclusion, some Y-linked variants may be associated with the impulsivity and aggression in boys with ADHD.

The divergent impact of COMT Val158Met on executive function in children with and without attention-deficit/hyperactivity disorder

Children with attention‐deficit/hyperactivity disorder (ADHD) usually display deficits in executive function (EF), which are primarily mediated by prefrontal cortex (PFC). The functional polymorphism of catechol‐O‐methyltransferase (COMT), Val158Met (rs4680), leads to observed polymorphic differences in the degradation of dopamine within PFC. This study aimed to explore the effect of rs4680 on EF using case–control design. In addition, considering the dynamic development of EF, we also attempted to investigate whether this genetic influence changes during development or not. A total of 597 ADHD children and 154 unaffected controls were recruited. The EF was evaluated using Rey–Osterrieth complex figure test (RCFT), trail making test (TMT) and Stroop color and word test for working memory, shifting and inhibition. Association between genotype and EF was analyzed using analysis of covariance (ancova). The results showed significant interaction effect of genotype and ADHD diagnosis on RCFT performance (P < 0.001). However, the associated genotypes between ADHD and controls were divergent. In ADHD, the Met carriers performed better than the Val homozygotes on detail immediate [(10.38 ± 6.90) vs. (9.33 ± 6.92), P = 0.007] and detail delay [(9.96 ± 6.86) vs. (8.86 ± 6.89), P = 0.004], while Val homozygotes showed better performance compared with Met carrier controls [for detail immediate (14.55 ± 6.18) vs. (11.10 ± 6.45), P<0.001; for detail delay (14.31 ± 5.96) vs. (11.31 ± 6.96), P = 0.001]. We did not find significant interaction between genetic variant and development. COMT Val158Met (rs4680) may have divergent effect on working memory in ADHD children compared with healthy controls.