Qiujin Qian

Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism.

Attention deficit hyperactivity disorder (ADHD) is the most common childhood‐onset behavioral disorder. Boys are more often affected than girls. Family, twin, and adoption studies have supported a strong genetic basis. Some studies show that a catechol‐O‐methyltransferase (COMT) polymorphism affecting enzyme activity was associated with personality characteristics and diseases, such as novelty‐seeking personality, substance abuse, and heroin addiction, whose features are similar to ADHD or are associated with ADHD. These findings suggest that the COMT gene may be a candidate gene for ADHD. TDT, HHRR, and case‐control association studies were conducted within a sample of 202 nuclear ADHD families, 340 ADHD cases, and 226 controls in the Han Chinese population. Diagnoses and ADHD subtypes were ascertained according to DSM‐IV criteria using American Clinical Diagnostic Interviewing Scales. The HHRR analysis suggested that the low enzyme‐activity COMT Met allele was preferentially transmitted to ADHD boys (160 trios, χ2 = 3.858, P = 0.05, df = 1) but not girls. This association is particularly pronounced among male ADHD probands without any comorbidity (50 trios, HHRR: χ2 = 5.128, P = 0.024, df = 1; TDT: χ2 = 4.558, P = 0.033, df = 1), especially the ADHD‐I subtype (32 trios, HHRR: χ2 = 5.792, P = 0.016, df = 1; TDT: χ2 = 5.333, P = 0.021, df = 1). The case‐control study revealed that the Val allele was more frequent in females meeting ICD‐10 or DSM‐IV criteria for ADHD than in female controls (86 and 79.5%, respectively, χ2 = 4.059, P = 0.044, df = 1). Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions.

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.

A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset behavioral disorder with a definite genetic component. The search for genes predisposing to ADHD has focused on genes involved in the regulation of monoamine systems. In this study, we emphasized genes that underlie various aspects of dopamine, norepinephrine and serotonin neurotransmissions and performed a comprehensive association analysis by screening with 245 single-nucleotide polymorphisms (SNPs) of 23 candidate genes in a sample of Chinese Han descent. A total of 182 DSM-IV ADHD children and 184 healthy controls were genotyped and analyzed with an average density of one SNP every 6.1 kb. Both single-SNP and multi-marker haplotype analyses were implemented to exploit association signal for ADHD and its diagnostic subtypes. Empirical P-values were derived on the basis of 5000 permutations to evaluate gene-wide statistical significance. MAOA yielded highly suggestive evidence of association (empirical P<0.01, OR=1.94) with ADHD. For inattentive ADHD, MAOA, DDC and SYP showed suggestive evidence of association (empirical P<0.05). ADRA2C achieved suggestive significance (empirical P<0.05) for ADHD combined type. Additionally, for six genes (SNAP25, NET1, DBH, CHRNA4, DRD3 and SYT1) we detected one or more SNPs with nominal P-values⩽0.05. This study has identified several genes as promising susceptibility loci for ADHD. Replication efforts and further investigations remain necessary to provide definite proof of association.

Family-based and case-control association studies of DRD4 and DAT1 polymorphisms in Chinese attention deficit hyperactivity disorder patients suggest long repeats contribute to genetic risk for the disorder.

Molecular genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated the variable number of tandem repeat (VNTR) polymorphisms of two candidate genes, the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1). We sought to determine if these genes were relevant to the etiology of ADHD in China by using both family‐based (N = 202 nuclear ADHD families) and case‐control (N = 340 ADHD cases, and 226 controls) association study designs. Diagnoses and subtypes were ascertained according to Clinical Diagnostic Interview Scales (CDIS) using DSM‐IV criteria. The repeat numbers at the DRD4 VNTR ranged from 2 to 6 repeats in the Han Chinese controls, with the most common being the 4‐repeat (77%) and 2‐repeat (19.4%) alleles. Neither the 7‐repeat allele nor longer repeats were found. For the DAT1 VNTR, the repeat numbers ranged from 6 to 7 repeats and 9 to 11 repeats. The 10‐repeat allele was the most frequent (90.7%). The long‐repeat alleles of DRD4 (ranging from 4 to 6 repeats) and DAT1 (ranging from 11 to 12 repeats), were present more frequently in ADHD probands than controls (P < 0.05), although there was no significant allelic association when the alleles were analyzed separately from each other and there findings were not supported by within family tests of association. An exploratory stratification by gender suggests that long‐repeat alleles of DRD4 and DAT1 may increase the risk for ADHD in Han Chinese children.

Possible association of the alpha-2A adrenergic receptor gene (ADRA2A) with symptoms of attention-deficit/hyperactivity disorder

A dysfunction of the central noradrenergic system has long been suggested to be involved in attention‐deficit/hyperactivity disorder (ADHD). Pharmacological evidence from animal studies and clinical practice has identified the alpha‐2A adrenergic receptor gene (ADRA2A) as a candidate gene in ADHD. Some findings from Caucasian populations seem to support a role for this gene in ADHD. The current study first examined the association of the ADRA2A MspI and DraI polymorphisms with ADHD in the Han Chinese population, which differs quite substantially from the Caucasian population in the frequencies of alleles at these polymorphisms. No biased transmission of alleles of either polymorphism was observed using transmission disequilibrium test (TDT) analysis in a sample of 268 nuclear families with an ADHD proband; however, haplotype analysis only identified a trend toward over‐transmission of the M/C haplotype to probands with the combined subtype of ADHD (χ2 = 3.233, P = 0.072). The mm genotype of the MspI polymorphism was also marginally related (P = 0.051) to lower ADHD symptom scores in a sample of 559 Chinese children with ADHD, which is inconsistent with data from Caucasian samples. Our results provide weak evidence for a possible role of ADRA2A in ADHD symptom expression.

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.

Evaluation of potential gene–gene interactions for attention deficit hyperactivity disorder in the Han Chinese population

Several lines of evidence suggest that attention‐deficit/hyperactivity disorder (ADHD) is a polygenic disorder produced by the interaction of several genes with minor effects. To explore potential gene–gene interactions among candidate genes for ADHD, we studied the dopamine D2 receptor (DRD2), dopamine D4 receptor (DRD4), dopamine transporter (DAT1), and catechol‐O‐methyltransferase (COMT) genes in the Han Chinese population. A sample of 340 children with ADHD was diagnosed according to the DSM‐IV criteria. We also recruited 226 unrelated controls. Identified polymorphisms included a 48‐base‐pair‐repeat in Exon 3 of DRD4, a 40‐base‐pair‐repeat in the 3′ untranslated region of DAT1, a restriction‐fragment‐length polymorphism at codon 158 of COMT, and a −241A > G transition in the promoter of DRD2. Associations of polymorphisms with ADHD and its subtypes were examined by comparing allele frequencies between probands and controls. Binary logistic regression analysis was used to examine the potential gene–gene interactions. Binary logistic regression analysis with the sample of refined phenotypes showed that male gender and long‐repeat genotypes of DRD4 and DAT1 were independent risk factors for ADHD. We found no evidence for gene–gene interactions among the candidate genes studied. The present study suggests that dopamine candidate genes are associated with increased vulnerability to ADHD in the Han Chinese population. Copyright

Attention Deficit Hyperactivity Disorder comorbid oppositional defiant disorder and its predominately inattentive type: evidence for an association with COMT but not MAOA in a Chinese sample

BackgroundThere are three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). The most common comorbid disorder in ADHD is ODD. DSM-IV describes three ADHD subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C). Prior work suggests that specific candidate genes are associated with specific subtypes of ADHD in China. Our previous association studies between ADHD and functional polymorphisms of COMT and MAOA, consistently showed the low transcriptional activity alleles were preferentially transmitted to ADHD-IA boys. Thus, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the ODD phenotype among Chinese ADHD boys.Methods171 Chinese boys between 6 and 17.5 years old (mean = 10.3, SD = 2.6) with complete COMT val158met and MAOA-uVNTR genotyping information were studied. We used logistic regression with genotypes as independent variables and the binary phenotype as the dependent variable. We used p < 0.05 as the level of nominal statistical significance. Bonferroni correction procedures were used to adjust for multiple comparisons.ResultsOur results highlight the potential etiologic role of COMT in the ADHD with comorbid ODD and its predominately inattentive type in male Chinese subjects. ADHD with comorbid ODD was associated with homozygosity of the high-activity Val allele, while the predominantly inattentive ADHD subtype was associated with the low-activity Met allele. We found no evidence of association between the MAOA-uVNTR variant and ADHD with comorbid ODD or the ADHD-IA subtype.ConclusionOur study of attention deficit hyperactivity disorder comorbid oppositional defiant disorder and its predominately inattentive type highlights the potential etiologic role of COMT for ADHD children in China. But we failed to observe an interaction between COMT and MAOA, which suggests that epistasis between COMT and MAOA genes does not influence the phenotype of ADHD-IA with comorbid ODD in a clinical sample of Chinese male subjects. To confirm our findings further studies with a larger number of subjects and healthy controls are needed.

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.

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.