Showing papers by "James J. McGough published in 2015"

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Treatment of Children With Attention-Deficit/Hyperactivity Disorder (ADHD) and Irritability: Results From the Multimodal Treatment Study of Children With ADHD (MTA)

Abstract: Objective: Clinically impairing irritability affects 25% to 45% of children with attention-deficit/hyperactivity disorder (ADHD); yet, we know little about what interventions are effective in treating children with ADHD and co-occurring irritability. We used data from the Multimodal Treatment Study of Children With ADHD (MTA) to address 3 aims: to establish whether irritability in children with ADHD can be distinguished from other symptoms of oppositional defiant disorder (ODD); to examine whether ADHD treatment is effective in treating irritability; and to examine how irritability influences ADHD treatment outcomes. Method: Secondary analyses of data from the MTA included multivariate analyses, and intent-to-treat randomeffects regression models were used. Results: Irritability was separable from other ODD symptoms. For treating irritability, systematic stimulant treatment was superior to behavioral management but not to routine community care; a combination of stimulants and behavioral treatment was superior to community care and to behavioral treatment alone, but not to medication alone. Irritability did not moderate the impact of treatment on parent- and teacher-reported ADHD symptoms in any of the 4 treatment groups. Conclusion: Treatments targeting ADHD symptoms are helpful for improving irritability in children with ADHD. Moreover, irritability does not appear to influence the response to treatment of ADHD. Clinical trial registration information—Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://www. clinicaltrials.gov; NCT00000388.

Pharmacotherapy of the Preschool ADHD Treatment Study (PATS) Children Growing Up.

Abstract: Objective To describe the long-term psychopharmacological treatment of children first diagnosed with attention-deficit/hyperactivity disorder (ADHD) as preschoolers. Method In a systematic, prospective, naturalistic follow-up, 206 (68.0%) of the 303 children who participated in the Preschool ADHD Treatment Study (PATS) were reassessed 3 years (mean age 7.4 years) and 179 (59.1%) were reassessed 6 years (mean age 10.4 years) after completion of the controlled study. Pharmacotherapy and clinical data were obtained from the parents. Pharmacotherapy was defined as use of a specific class of medication for at least 50% of the days in the previous 6 months. Results At year 3, a total of 34.0% of the participants were on no pharmacotherapy, 41.3% were on stimulant monotherapy, 9.2% were on atomoxetine alone or with a stimulant, 8.3% were on an antipsychotic usually together with a stimulant, and the remaining 7.2% were on other pharmacotherapy; overall, 65.0% were on an indicated ADHD medication. At year 6, a total of 26.8% of the participants were on no pharmacotherapy, 40.2% were on stimulant monotherapy, 4.5% were on atomoxetine alone or with a stimulant, 13.4% were on an antipsychotic, and 15.1% were on other pharmacotherapy; overall, 70.9% were on an indicated ADHD medication. Antipsychotic treatment was associated with more comorbidity, in particular disruptive behavior disorders and pervasive development disorders, and a lower level of functioning. Conclusion In this study, the long-term pharmacotherapy of preschoolers with ADHD was heterogeneous. Although stimulant medication continued to be used by most children, about 1 child in 4 was off medication, and about 1 in 10 was on an antipsychotic.

A parietal biomarker for ADHD liability : As predicted by the distributed effects perspective model of ADHD

Abstract: Background: We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations, and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent Distributed Effects Model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD. Method: The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities (i.e., ADHD risk factors). Results: Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of rightward parietal asymmetry were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs. Conclusion: Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability.

Neuropsychological and dimensional behavioral trait profiles in Costa Rican ADHD sib pairs: Potential intermediate phenotypes for genetic studies.

Abstract: Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity.