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Difficulty with sustaining attention to a task is a hallmark of ADHD. It would be useful to know which measures of sustained attention best predict a diagnosis of ADHD. Participants were 129 children with a diagnosis of ADHD and 129 matched controls who completed the fixed Sustained Attention to Response Task (SART). The number of commission and omission errors, standard deviation of response time (SDRT), tau, fast and slow frequency variability, d-prime, and mu were able to successfully classify children with and without ADHD. The mean response time, criterion, and sigma were not able to classify participants. The best classifiers were d-prime (0.75 Area Under the Receiver Operated Characteristic), tau (.74), SDRT (0.74), omission errors (0.72), commission errors (0.71), and SFAUS (0.70). This list of the best classifier measures derived from the SART may prove useful for the planning of future studies. [ABSTRACT FROM AUTHOR]

Objectives. Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. Methods. We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. Results. A SNP within the 3′ untranslated region of DBH rs129882 showed a significant association with ADHD (χ2 = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. Conclusions. These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD. [ABSTRACT FROM AUTHOR]

The Test of Everyday Attention for Children (TEA-Ch) is a reliable neuropsychological assessment of attention control in children. Methylphenidate (MPH) is an effective treatment to improve attentional difficulties in children with attention deficit/hyperactivity disorder (ADHD). Previous studies investigating the effects of MPH on attention performance of children with ADHD have produced mixed results and prior MPH usage may have confounded these results. No previous study has tested the effects of MPH on the entire TEA-Ch battery. This study investigated the effects of MPH on attention performance using the entire TEA-Ch in 51 medication-naïve children with ADHD compared with 35 nonmedicated typically developing children. All children were tested at baseline and after 6 weeks: The children with ADHD were medication-naïve at baseline, received MPH for 6 weeks and were tested whilst on medication at the second testing session. A beneficial effect of MPH administration was found on at least one subtest of each of the three forms of attention (selective, sustained, and attentional control) assessed by the TEA-Ch, independent of practice effects. MPH aided performance on the TEA-Ch tasks that were inherently nonarousing and that might require top-down control of attention. It is recommended that the TEA-Ch measures—Sky Search Count (selective attention),Score! (sustained attention), Creature Counting Time Taken for older children (attentional control), and Same Worlds (attentional control) be prioritized for use in future pharmacological studies using MPH. [ABSTRACT FROM PUBLISHER]

Background: There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.Aims: To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.Method: We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.Results: Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 10(-4), R(2) = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 × 10(-6), R(2) = 0.59%).Conclusions: This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries. [ABSTRACT FROM AUTHOR]

Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD samples from Ireland and Australia. Although suggestive evidence of association (nominal p ≤ 0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ = 9.39, p-corrected = 0.019, OR = 1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ = 7.79, p-corrected = 0.042 OR = 2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association. [ABSTRACT FROM AUTHOR]

Background: Emotional lability (EL) is commonly seen in patients with attention-deficit/hyperactivity disorder (ADHD). The reasons for this association remain currently unknown. To address this question, we examined the relationship between ADHD and EL symptoms, and performance on a range of neuropsychological tasks to clarify whether EL symptoms are predicted by particular cognitive and/or motivational dysfunctions and whether these associations are mediated by the presence of ADHD symptoms. Methods: A large multi-site sample of 424 carefully diagnosed ADHD cases and 564 unaffected siblings and controls aged 6-18 years performed a broad neuropsychological test battery, including a Go/No-Go Task, a warned four-choice Reaction Time task, the Maudsley Index of Childhood Delay Aversion and Digit span backwards. Neuropsychological variables were aggregated as indices of processing speed, response variability, executive functions, choice impulsivity and the influence of energetic and/or motivational factors. EL and ADHD symptoms were regressed on each neuropsychological variable in separate analyses controlling for age, gender and IQ, and, in subsequent regression analyses, for ADHD and EL symptoms respectively. Results: Neuropsychological variables significantly predicted ADHD and EL symptoms with moderate-to-low regression coefficients. However, the association between neuropsychological parameters on EL disappeared entirely when the effect of ADHD symptoms was taken into account, revealing that the association between the neuropsychological performance measures and EL is completely mediated statistically by variations in ADHD symptoms. Conversely, neuropsychological effects on ADHD symptoms remained after EL symptom severity was taken into account. Conclusions: The neuropsychological parameters examined, herein, predict ADHD more strongly than EL. They cannot explain EL symptoms beyond what is already accounted for by ADHD symptom severity. The association between EL and ADHD cannot be explained by these cognitive or motivational deficits. Alternative mechanisms, including overlapping genetic influences (pleiotropic effects) and/or alternative neuropsychological processes need to be considered. [ABSTRACT FROM AUTHOR]

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed disorder of school-age children. Although genetic and brain-imaging studies suggest a contribution of altered dopamine (DA) signaling in ADHD, evidence of signaling perturbations contributing to risk is largely circumstantial. The presynaptic, cocaine- and amphetamine (AMPH)-sensitive DA transporter (DAT) constrains DA availability at presynaptic and postsynaptic receptors following vesicular release and is targeted by the most commonly prescribed ADHD therapeutics. Using polymorphism discovery approaches with an ADHD cohort, we identified a hDAT (human DAT) coding variant, R615C, located in the distal C terminus of the transporter, a region previously implicated in constitutive and regulated transporter trafficking. Here, we demonstrate that, whereas wild-type DAT proteins traffic in a highly regulated manner, DAT 615C proteins recycle constitutively and demonstrate insensitivity to the endocytic effects of AMPH and PKC (protein kinase C) activation. The disrupted regulation of DAT 615C parallels a redistribution of the transporter variant away from GM1 ganglioside- and flotillin1-enriched membranes, and is accompanied by altered CaMKII (calcium/calmodulin-dependent protein kinase II) and flotillin-1 interactions. Using C-terminal peptides derived from wild-type DAT and the R615C variant, we establish that the DAT 615C C terminus can act dominantly to preclude AMPHregulation of wild-type DAT. Mutagenesis of DATC-terminal sequences suggests that phosphorylation of T613 may be important in sorting DAT between constitutive and regulated pathways. Together, our studies support a coupling of DAT microdomain localization with transporter regulation and provide evidence of perturbed DAT activity and DA signaling as a risk determinant for ADHD. [ABSTRACT FROM AUTHOR]

Objective: To examine the factor structure of attention-deficit/hyperactivity disorder (ADHD) in a clinical sample of 1,373 children and adolescents with ADHD and their 1,772 unselected siblings recruited from different countries across a large age range. Hierarchical and correlated factor analytic models were compared separately in the ADHD and sibling samples, across three different instruments and across parent and teacher informants. Specific consideration was given to factorial invariance analyses across different ages and different countries in the ADHD sample. Method: A sample of children and adolescents between 5 and 17 years of age with ADHD and their unselected siblings was assessed. Participants were recruited from seven European countries and Israel. ADHD symptom data came from a clinical interview with parents Parental Account of Childhood Symptoms and questionnaires from parents and teachers (Conners Parent and Teacher). Results: A hierarchical general factor model with two specific factors best represented the structure of ADHD in both the ADHD and unselected sibling groups, and across informants and instruments. The model was robust and invariant with regard to age differences in the ADHD sample. The model was not strongly invariant across different national groups in the ADHD sample, likely reflecting severity differences across the different centers and not any substantial difference in the clinical presentation of ADHD. Conclusions: The results replicate previous studies of a model with a unitary ADHD component and separable specific traits of inattention and hyperactivity/impulsivity. The unique contribution of this study was finding support for this model across a large developmental and multinational/multicultural sample and its invariance across ages. [ABSTRACT FROM AUTHOR]

Objectives. Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity. Methods. Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q). Results. Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs. Conclusions. Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary. [ABSTRACT FROM AUTHOR]

A number of genes with function related to synaptic neurochemistry have been genetically associated with attention deficit/hyperactivity disorder. However, susceptibility to the development of common psychiatric disorders by single variants acting alone, can so far only explain a small proportion of the heritability of the phenotype. It has been postulated that the unexplained 'dark heritability' may at least in part be due to epistatic effects, which may account for the small observed marginal associations, and the difficulties with replication of positive findings. We undertook a comprehensive exploration of pair-wise interactions between genetic variants in 24 candidate genic regions involved in monoaminergic catabolism, anabolism, release, re-uptake and signal transmission in a sample of 177 parent-affected child trios using a case-only design and a case-pseudocontrol design using conditional logistic regression. Marker-pairs thresholded on interaction odds ratio (OR) and P-value are presented. We detected a number of interaction ORs >4.0, including an interesting correlation between markers in the ADRA1B and DBH genes in affected individuals, and several further interesting but smaller effects. These effects are no larger than you would expect by chance under the assumption of independence of all pair-wise relations; however, independence is unlikely. Furthermore, the size of these effects is of interest and attempts to replicate these results in other samples are anticipated. [ABSTRACT FROM AUTHOR]

Background: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures. Methods: Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures. Results: Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores. Conclusions: When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity. [ABSTRACT FROM AUTHOR]

Background: The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with the combined type of attention deficit/hyperactivity disorder (ADHD-CT) and 1446 'unselected' siblings. The aim was to analyse the IMAGE sample with respect to demographic features (gender, age, family status, and recruiting centres) and psychopathological characteristics (diagnostic subtype, symptom frequencies, age at symptom detection, and comorbidities). A particular focus was on the effects of the study design and the diagnostic procedure on the homogeneity of the sample in terms of symptom-based behavioural data, and potential consequences for further analyses based on these data. Methods: Diagnosis was based on the Parental Account of Childhood Symptoms (PACS) interview and the DSM-IV items of the Conners' teacher questionnaire. Demographics of the full sample and the homogeneity of a subsample (all probands) were analysed by using robust statistical procedures which were adjusted for unequal sample sizes and skewed distributions. These procedures included multi-way analyses based on trimmed means and winsorised variances as well as bootstrapping. Results: Age and proband/sibling ratios differed between participating centres. There was no significant difference in the distribution of gender between centres. There was a significant interaction between age and centre for number of inattentive, but not number of hyperactive symptoms. Higher ADHD symptom frequencies were reported by parents than teachers. The diagnostic symptoms differed from each other in their frequencies. The face-to-face interview was more sensitive than the questionnaire. The differentiation between ADHD-CT probands and unaffected siblings was mainly due to differences in hyperactive/impulsive symptoms. Conclusions: Despite a symptom-based standardized inclusion procedure according to DSM-IV criteria with defined symptom thresholds, centres may differ markedly in probands' ADHD symptom frequencies. Both the diagnostic procedure and the multi-centre design influence the behavioural characteristics of a sample and, thus, may bias statistical analyses, particularly in genetic or neurobehavioral studies. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated whether if one or more familial factors influence slow and variable reaction times, impaired response inhibition, and choice impulsivity related to attention-deficit/hyperactivity disorder (ADHD). The study included 1,265 people, aged six to 18 years, from Belgium, Germany, Ireland, Israel, Spain, Switzerland and Great Britain. Study authors concluded that two familial pathways to cognitive impairments is presents in ADHD.

Background: The goal of this study was to investigate the occurrence, severity and clinical correlates of emotional lability (EL) in children with attention deficit/hyperactivity disorder (ADHD), and to examine factors contributing to EL and familiality of EL in youth with ADHD. Methods: One thousand, one hundred and eighty-six children with ADHD combined type and 1827 siblings (aged 6–18 years) were assessed for symptoms of EL, ADHD, associated psychopathology and comorbid psychiatric disorders with a structured diagnostic interview (PACS) as well as parent and teacher ratings of psychopathology (SDQ; CPRS-R:L; CTRS-R:L). Analyses of variance, regression analyses, χ2-tests or loglinear models were applied. Results: Mean age and gender-standardized ratings of EL in children with ADHD were >1.5 SD above the mean in normative samples. Severe EL (>75th percentile) was associated with more severe ADHD core symptoms, primarily hyperactive-impulsive symptoms, and more comorbid oppositional defiant, affective and substance use disorders. Age, hyperactive-impulsive, oppositional, and emotional symptoms accounted for 30% of EL variance; hyperactive-impulsive symptoms did not account for EL variance when coexisting oppositional and emotional problems were taken into account, but oppositional symptoms explained 12% of EL variance specifically. Severity of EL in probands increased the severity of EL in siblings, but not the prevalence rates of ADHD or ODD. EL and ADHD does not co-segregate within families. Conclusion: EL is a frequent clinical problem in children with ADHD. It is associated with increased severity of ADHD core symptoms, particularly hyperactivity-impulsivity, and more symptoms of comorbid psychopathology, primarily symptoms of oppositional defiant disorder (ODD), but also affective symptoms, and substance abuse. EL in ADHD seems to be more closely related to ODD than to ADHD core symptoms, and is only partly explainable by the severity of ADHD core symptoms and associated psychopathology. Although EL symptoms are transmitted within families, EL in children with ADHD does not increase the risk of ADHD and ODD in their siblings. [ABSTRACT FROM AUTHOR]

The article discusses the study on predicting spatial inattention in children with attention-deficit/hyperactivity disorder (ADHD) through dopaminergic haplotype. In this study, a case control design was used for the subjects comprised of 115 children with ADHD who underwent two versions of spatial orientation task. It concludes that 10/3 dopamine transporter gene (DAT1) haplotype, a replicated genetic risk factor for ADHD can explain heterogeneity in selective attention in ADHD.

Background: An important theory of attention suggests that there are three separate networks that execute discrete cognitive functions. The ‘alerting’ network acquires and maintains an alert state, the ‘orienting’ network selects information from sensory input and the ‘conflict’ network resolves conflict that arises between potential responses. This theory holds promise for dissociating discrete patterns of cognitive impairment in disorders where attentional deficits may often be subtle, such as in attention deficit hyperactivity disorder (ADHD). Methods: The Attentional Network Test (ANT), a behavioural assay of the functional integrity of attention networks, was used to examine the performance of 73 children with ADHD and 73 controls. Results: Performance on the ANT clearly differentiated the children with and without ADHD in terms of mean and standard deviation (SD) of reaction time (RT), the number of incorrect responses made and the number of omission errors made. The ADHD group demonstrated deficits in the conflict network in terms of slower RT and a higher number of incorrect responses. The ADHD group showed deficits in the alerting network in terms of the number of omission errors made. There was no demonstration of a deficit in the orienting network in ADHD on this task. Conclusions: The children with ADHD demonstrated deficits in the alerting and conflict attention networks but normal functioning of the orienting network. [ABSTRACT FROM AUTHOR]

Background: 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 (G×E) 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. Methods: 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. Results: 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 G×E interactions. Conclusion: Despite the large sample size, no G×E 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. [ABSTRACT FROM AUTHOR]

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (3′ untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 3′-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.Neuropsychopharmacology (2008) 33, 2536–2545; doi:10.1038/sj.npp.1301637; published online 28 November 2007 [ABSTRACT FROM AUTHOR]

Objective: The primary purpose of this study was to confirm the association of a specific haplotype of the dopamine transporter gene and attention deficit hyperactivity disorder (ADHD), which could be one source of the heterogeneity seen across published studies. Method: The authors previously reported the association of ADHD with a subgroup of chromosomes containing specific alleles of two variable-number tandem repeat polymorphisms within the 3′ untranslated region and intron 8 of the dopamine transporter gene. They now report on this association in a sample of ADHD combined-type probands. Results: The original observations were confirmed, with an overall odds ratio of 1.4 across samples. Conclusions: These data challenge results of meta-analyses suggesting that dopamine transporter variation does not have an effect on the risk for ADHD, and they indicate that further investigation of functional variation in the gene is required. [ABSTRACT FROM AUTHOR]

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3′ variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.Neuropsychopharmacology (2005) 30, 2290–2297. doi:10.1038/sj.npp.1300839; published online 3 August 2005 [ABSTRACT FROM AUTHOR]

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT1, DRD4, DBH, and DRD5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT1 (480bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD5 (148bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD1, DRD2 (Taq I), DRD3, DRD4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses. [Copyright &y& Elsevier]

Attention-deficit hyperactivity disorder (ADHD) varies in its clinical presentation and course. Susceptibility gene variants for ADHD and associated antisocial behaviour are being identified with emerging evidence of gene-environment interaction. Genes and environmental factors that influence the origins of disorder are not necessarily the same as those that contribute to its course and outcome. [ABSTRACT FROM AUTHOR]

Objective: A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs. Method: The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD. Results: No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS. Conclusions: Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways. [ABSTRACT FROM AUTHOR]

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between time reproduction, performance variability, and sustained attention deficits in children with attention-deficit/hyperactivity disorder (ADHD) combined (ADHD-C) and inattentive (ADHD-l) subtypes, relative to matched controls. Method: Participants (age range 7.1-1 4.1 years) performed a time reproduction task. A subset of the ADHD group was also tested on the Sustained Attention to Response Test. Absolute discrepancy, accuracy coefficient, and intraindividual variability scores on the time reproduction task were compared across the three groups (ADHD-C: N = 20; ADHD-l: N = 19; controls: N = 44) and correlated with the Sustained Attention to Response Test. Results: First, significantly better performance was observed in matched controls than in children with ADHD on the time reproduction task. Second, there was a significant difference between the two ADHD subtypes in the variability of the size of errors made at high time intervals (36-60 seconds). Third, intraindividual performance variability in the direction (over-versus under-estimations) of time reproductions correlated with sustained attention performance. Conclusions: Children with ADHD varied more in the size and direction of their time reproduction errors than control children. Those with ADHD-C demonstrated more intraindividual variability than did those with ADHD-I in the size of their errors. The data provide support for a relationship between sustained attention and time reproduction. This relationship has previously been inferred from common right-lateralized neural circuitry that is thought to subserve these processes. [ABSTRACT FROM AUTHOR]

Abstract: Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Parent-of-origin effect and risk for attention-deficit/hyperactivity disorder: Balancing the evidence against bias and chance findings," by Ridha Joober and Sarojini Sengupta in the present issue of the journal.

Objective: Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. Method: The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neuro-transmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Results: Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms (pempirical = .007) but not with inattentive symptoms (pempirical = .73). Analysis of parent-rated Conners hyperactive/ impulsive symptom scores validated this result (pempirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, pempirical = .0004; serotonin, pempirical = .0149; neuritic outgrowth, pempirical = .0452). Conclusion: The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to identify biological risk factors involved in this disorder. [ABSTRACT FROM AUTHOR]

Background: Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in attention-deficit/hyperactivity disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion would be associated with serotonin-regulating genes. Methods: Impulsive drive for immediate reward and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) with a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter serotonin-transporter-linked polymorphic region polymorphism and a DAT1 (SLC6A3) 40-base pair variable number tandem repeat located in the 3′-untranslated region of the gene. Results: There was no effect of dopamine transporter (DAT)1 on IDIR. As predicted, serotonin-transporter-linked polymorphic region s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G single nucleotide polymorphism and were independent of age, IQ, and oppositional defiant disorder symptoms. Conclusions: The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented. [ABSTRACT FROM AUTHOR]

Abstract: The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as well as problems with response inhibition. In the present study we used fMRI to investigate the role of dopaminergic genetic variation on executive functioning by comparing how activation associated with successful and unsuccessful inhibitions differs based on DAT1-genotype and ADHD-diagnosis in adolescents performing a go/nogo task. The results identify regional specificity concerning which functional differences can be attributed to the possession of the high risk DAT1 genotype, the clinical condition or an interaction between the two. During response inhibition, individuals with two copies of the 10-repeat allele showed increased activation in frontal, medial, and parietal regions, which may indicate that inhibition is more effortful for this group. Conversely, this group displayed a reduced error response in the parahippocampal gyrus, suggestive of reduced learning from errors. There were also a number of frontal, parietal, medial and occipital regions, where the relationship between genotype and fMRI-activation differed between the ADHD group and the typically developing adolescents. Finally, the ADHD group displayed decreased activation in parietal and (pre)frontal regions during response inhibition, and in frontal and medial brain regions on error trials. [Copyright &y& Elsevier]

The article discusses a study which aims to identify the genetic variants that influence the trait of attention-deficit/hyperactivity disorder (ADHD), the most common childhood onset psychiatric condition, that has shown to be highly heritable. The study used case-control analyses of 896 cases and found no genome-wide significant associations. The study found that candidate gene findings that suggest the effects of ADHD risk variants are very small.

Background: Limited success has been achieved through previous attention-deficit/hyperactivity disorder (ADHD) linkage scans, which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci (QTL). Methods: A set of 1094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative single nucleotide polymorphism (SNP) panel. Two quantitative traits measuring the children''s symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score. Results: A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p < .04. Setting-specific suggestive linkage signals were also found: logarithm of odds (LOD) = 2.2 at 9p23 for home trait and LOD = 2.6 at 11q21 for school trait. Conclusions: These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia. [Copyright &y& Elsevier]

Abstract: Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to dopamine signaling is suggested in ADHD that may be ameliorated by methylphenidate (MPH). This study investigated the effects of MPH administration on the variability in RT and error performance on a sustained attention task of a group of 31 medication naïve children with ADHD, compared with 22 non-ADHD, non-medicated, control children. All children performed the fixed-sequence sustained attention to response task (SART) at two time-points: at baseline and after six weeks. The children with ADHD were tested when medication naive at baseline and after six weeks of treatment with MPH and whilst on medication. The medication naïve children with ADHD performed the SART with greater errors of commission and omission when compared with the control group. They demonstrated greater standard deviation of RT and fast moment-to-moment variability. They did not differ significantly from the control group in terms of slow variability in RT. MPH administration resulted in reduced and normalised levels of commission errors and fast, moment-to-moment variability in RT. MPH did not affect the rate of omission errors, standard deviation of RT or slow frequency variability in RT. MPH administration may have a specific effect on those performance components that reflect sustained attention and top–down control rather than arousal. [Copyright &y& Elsevier]

Background: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. Methods: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. Results: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. Conclusions: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association. [Copyright &y& Elsevier]

Abstract: Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1–9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA. [Copyright &y& Elsevier]

Abstract: Response time (RT) variability is a common finding in ADHD research. RT variability may reflect frontal cortex function and may be related to deficits in sustained attention. The existence of a sustained attention deficit in ADHD has been debated, largely because of inconsistent evidence of time-on-task effects. A fixed-sequence Sustained Attention to Response Task (SART) was given to 29 control, 39 unimpaired and 24 impaired-ADHD children (impairment defined by the number of commission errors). The response time data were analysed using the Fast Fourier Transform, to define the fast-frequency and slow-frequency contributions to overall response variability. The impaired-ADHD group progressively slowed in RT over the course of the 5.5min task, as reflected in this group''s greater slow-frequency variability. The fast-frequency trial-to-trial variability was also significantly greater, but did not differentially worsen over the course of the task. The higher error rates of the impaired-ADHD group did not become differentially greater over the length of the task. The progressive slowing in mean RT over the course of the task may relate to a deficit in arousal in the impaired-ADHD group. The consistently poor performance in fast-frequency variability and error rates may be due to difficulties in sustained attention that fluctuate on a trial-to-trial basis. [Copyright &y& Elsevier]

Background: Dopamine beta hydroxylase (DβH) catalyzes the conversion of dopamine to noradrenaline. Attention-deficit/hyperactivity disorder (ADHD) has been associated with the A2 allele of a Taq I polymorphism of the DBH gene. Since catecholamines regulate visual attention, we examined whether participants with ADHD were impaired on a task requiring temporal attention and how DBH genotype influenced temporal attention in ADHD. Methods: Thirty-seven children and adolescents with ADHD and 52 matched, normal control subjects participated. Participants were presented with two visual stimuli, separated in time by either 50, 100, or 200 milliseconds, and were asked to judge the temporal order of their onset. Genotypes for the Taq 1 polymorphism were available for 33 of the ADHD participants. Results: Attention-deficit/hyperactivity disorder participants were more error prone than control subjects, particularly when stimuli were presented close together in time (i.e., at the 50 milliseconds asynchrony). Moreover, ADHD individuals homozygous for the A2 allele performed more poorly than those without this allele, and this difference was accentuated at the 50 milliseconds asynchrony. Conclusions: Attention-deficit/hyperactivity disorder participants have an impaired rate of perceptual processing for rapidly presented visual events. Deficits in the temporal resolution of visual attention in ADHD are associated with the A2 allele of the Taq I DBH polymorphism or another variant with which it is in linkage disequilibrium. [Copyright &y& Elsevier]

Family, twin, and adoption studies have demonstrated a significant genetic contribution to the etiology of attention-deficit/hyperactivity disorder (ADHD). Pharmacological, neuroimaging, and animal-model findings suggest imbalances in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in ADHD. We have examined monoaminergic candidate genes for possible genetic association with ADHD in the Irish population, focusing particularly on genes of the dopaminergic and serotonergic systems. We have observed that several of these genes are associated with ADHD, including DAT1, DBH, DRD4, DRD5, and 5HT1B. Here, we present what appears to be a systematic overtransmission of paternal alleles at candidate genes associated with ADHD. For the nine genes included in the analysis, the overall odds ratio for paternal transmission was 2, compared with 1.3 for maternal transmission (paternal vs. maternal χ2 = 9.6; P = .0019). Transmission to females, from either parent, was significantly stronger than to males. Possible reasons for this preferential transmission include imprinting and ascertainment bias, although results of further analyses show that the latter is unlikely. [ABSTRACT FROM AUTHOR]

Abstract: ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n =22) in relation to dopamine transporter genotype (DAT1) and also controls (n =20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the “high-risk” 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD. [Copyright &y& Elsevier]

Abstract: Genetic associations for Attention Deficit Hyperactivity Disorder (ADHD), a common highly heritable childhood behavioural disorder, require replication in order to establish whether they are true positive findings. The current study aims to replicate recent association findings from the International Multi-centre ADHD Genetics (IMAGE) project in one of the most studied genes related to ADHD, the dopamine transporter (DAT1) gene. In a family-based sample of 450 ADHD probands, three Single Nucleotide Polymorphism (SNP) markers have been genotyped using TaqMan assays. Transmission Disequilibrium Test analysis demonstrates that one of three SNP markers (rs11564750) in the 5′ promoter region of the gene is significantly associated with ADHD (P =0.02). This provides further evidence that in addition to the well-known and investigated 3′UTR polymorphism associated with ADHD, there is potentially a further association signal emanating from the 5′ promoter region of the gene. Further replication and functional studies are now required to fully understand the consequence of polymorphisms present at both the 5′ and 3′ ends of the DAT1 gene and their role in ADHD pathophysiology. [Copyright &y& Elsevier]

Attention Deficit/Hyperactivity Disorder (ADHD) is the most prevalent mental disorder of childhood. Genetic influences are recognised as a major predisposing factor for ADHD with heritability estimated between 75–90% which is comparable to that of major psychiatric mental illnesses, such as autism and schizophrenia. Identifying the individual DNA variations that confer risk to ADHD has been a major scientific challenge over the last 20 years. In this investigation, we conducted a Genome-Wide Association Study (GWAS) involving 480 ADHD-DSM-IV diagnosed samples compared to 1207 ethnically notched controls. Genotyping was conducted using Psych-Chip platform (Illumina, 2015). This array has been developed by Illumina in tandem with the Psychiatric Genomics Consortium for the purpose of large-scale genetic studies in psychiatry. The Psych-Chip contains a GWAS backbone of 588,628 markers enriched with 50,000 single nucleotide polymorphisms (SNPs) which have been implicated in psychiatric conditions and/or neurodevelopmental disorders. Quality control of the genotypic data was conducted as described in Anderson et al. [2010]. Although no significant SNP association was observed at the GWAS level (5.0 E−8, several SNPs exhibited strong trends toward association. For example, association with rs6659350 which was mapped 22.8 kbp upstream of the Tenascin-R gene (TNR), was tantalizingly close to GWAS significance (p=8.49E−08). In addition, rs2410116 (mapped 300.2kbp upstream of DLC1 Rho GTPase Activating Protein (DLC1)) also showed a strong trend toward association with ADHD (p= 2.3E−07). Further, seven other SNPs (rs10006479, rs7007897, rs10835019, rs17772064, rs11788670, rs415300, rs2295135) showed strong trends (p-values ranged between 1.01E−05 and 2.98E−06). Although our sample has limited power to detect reliable genome wide association with ADHD, it represents a contribution of never before analysed (predominantly Australian) samples to the international GWAS effort. Although our analysis shows promising trends towards association, ultimately these results will need to be verified in the context of current international ADHD GWAS consortia. [ABSTRACT FROM AUTHOR]