Robert D. Oades

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder : association signals in DRD4, DAT1 and 16 other genes

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, starting in early childhood and persisting into adulthood in the majority of cases. Family and twin studies have demonstrated the importance of genetic factors and candidate gene association studies have identified several loci that exert small but significant effects on ADHD. To provide further clarification of reported associations and identify novel associated genes, we examined 1038 single-nucleotide polymorphisms (SNPs) spanning 51 candidate genes involved in the regulation of neurotransmitter pathways, particularly dopamine, norepinephrine and serotonin pathways, in addition to circadian rhythm genes. Analysis used within family tests of association in a sample of 776 DSM-IV ADHD combined type cases ascertained for the International Multi-centre ADHD Gene project. We found nominal significance with one or more SNPs in 18 genes, including the two most replicated findings in the literature: DRD4 and DAT1. Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA and PNMT. Further studies will be needed to confirm or refute the observed associations and their generalisability to other samples.

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

OBJECTIVE Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. METHOD We used data from four projects: a) the Childrens Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. RESULTS No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. CONCLUSIONS Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorders heritability.

The role of noradrenaline in tuning and dopamine in switching between signals in the CNS.

Neuronal catecholaminergic activity modulates central nervous function. Specifically noradrenaline can exert a tuning or biassing function whereby the signal to noise ratio is altered. Dopamine activity may promote switching between inputs and outputs of information to specific brain regions. It has been ten years since evidence for a tuning function was advanced for noradrenaline and in the last 5 years the switching hypothesis for dopamine has been tentatively put forward. Recent studies are reviewed to show that while catecholamine activity contributes to neural interactions in separate brain regions that give rise to the organization of different functions, their working principles may be common between species and independent of the nucleus of origin. Behavioral examples are discussed and an attempt is made to integrate this with evidence from intracellular recording studies. It is suggested that the tuning principle in noradrenergic systems is particularly important for the formation of associations and neural plasticity (interference control) and that the switching principle of dopaminergic systems modulates the timing, time-sharing and initiation of responses (program-control).

Genome-Wide Association Scan of Quantitative Traits for Attention Deficit Hyperactivity Disorder Identifies Novel Associations and Confirms Candidate Gene Associations

Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband‐parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome‐wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P‐values with a magnitude less than 10−5, are discussed in this manuscript. Seventeen of these candidate genes had association P‐values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P‐values lower than 0.01 and multiple association P‐values at a magnitude of 10−5 in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD.

Genome-wide association scan of attention deficit hyperactivity disorder

Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family‐based TDT data. None of the SNP association tests achieved genome‐wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family‐based association, and suggest that variable missing genotype rates may be the source of this bias.

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Emotional lability in children and adolescents with attention deficit hyperactivity disorder (ADHD): Clinical correlates and familial prevalence.

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, chi(2)-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.

Response variability in Attention-Deficit/Hyperactivity Disorder: A neuronal and glial energetics hypothesis

1. AbstractBackgroundCurrent concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD.The hypothesisWe propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing).Testing the hypothesisMulti-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca2+), as well as astrocyte function (α1, α2 and β-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin).Implications of the hypothesisThe hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype – namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well.

The development of food search behavior by rats: the effects of hippocampal damage and haloperidol.

Food deprived rats were required to locate four pellets of food located in 4 of 16 holes in an enclosed arena. Three groups of animals were studied in 11 testing sessions: rats with bilateral hippocampal damage; rats with bilateral neocortical damage; and an unoperated group. Half of each group received haloperidol and half received saline injection 20 min before Sessions 4 through 10. No injections were given on the first three sessions or on the final, 11th session. Animals with hippocampal lesions visited more nonfood holes than control animals and did not develop consistent sequences of food-hole visits. The administration of haloperidol reduced the number of consistent sequences of food seeking behaviors by intact animals without significantly affecting the efficiency of performance as measured by the number of nonfood holes visited. Haloperidol reduced the number of visits to nonfood holes of animals with hippocampal lesions.

Delay and reward choice in ADHD: an experimental test of the role of delay aversion

Children with attention deficit/hyperactivity disorder (ADHD) choose smaller sooner (SS) over larger later (LL) rewards more than controls. Here we assess the contributions of impulsive drive for immediate rewards (IDIR) and delay aversion (DAv) to this pattern. We also explore the characteristics of, and the degree of familiality in, ADHD SS responders. We had 360 ADHD probands; 349 siblings and 112 controls (aged between 6 to 17 years) chose between SS (1 point after 2 s) and LL reward (2 points after 30 s) outcomes on the Maudsley Index of Delay Aversion (Kuntsi, Oosterlaan, & Stevenson, 2001): Under one condition SS choice led to less overall trial delay under another it did not. ADHD participants chose SS more than controls under both conditions. This effect was larger when SS choice reduced trial delay. ADHD SS responders were younger, had lower IQ, more conduct disorder and had siblings who were more likely to be SS responders themselves. The results support a dual component model in which both IDIR and DAv contribute to SS choice in ADHD. SS choice may be a marker of an ADHD motivational subtype.