Nanda Lambregts-Rommelse

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.

High loading of polygenic risk for ADHD in children with comorbid aggression

Objective Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. Conclusions Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Does an attention bias to appetitive and aversive words modulate interference control in youth with ADHD

ABSTRACT Interference control refers to the ability to selectively attend to certain information while ignoring distracting information. This ability can vary as a function of distractor relevance. Distractors that are particularly relevant to an individual may attract more attention than less relevant distractors. This is referred to as attention bias. Weak interference control and altered reward sensitivity are both important features of attention deficit hyperactivity disorder (ADHD). However, interference control is typically studied in isolation. This study integrates both. Youths (aged 9 to 17 years) with ADHD (n = 37, 25 boys) and typically-developing controls (n = 38, 20 boys) completed a Stroop task using appetitive words and matched neutral words to assess whether appetitive distractors diminished interference control more in youths with ADHD than controls. In order to test for specificity, aversive words were also included. As expected, appetitive words disrupted interference control but this effect was not stronger for youths with ADHD than the controls. Aversive words, on the other hand, facilitated interference control. Dimensional analyses revealed that this facilitation effect increased substantially as a function of ADHD symptom severity. Possible mechanisms for this effect include up-regulation of interference control as a function of induced negative mood, or as a function of increased effort. In conclusion, appetitive words do not lead to worse interference control in youths with ADHD compared with controls. Interference control was modulated in a valence-specific manner, concurrent with mood-induced effects on cognitive control.

Editorial focused issue 'The role of nutrition in child and adolescent onset mental disorders'

the plasticity of the brain at this early age; structural and/ or functional damage may persist after repletion [1]. The central effect of nutrient deficiency or supplementation is dependent on the requirement of the central nervous system for a nutrient in specific metabolic pathways and structural components. A specific nutrient may promote normal brain development at one time point and be toxic at another. Furthermore, different concentrations of nutrients may be required during development. Concentrations of several nutrients are tightly regulated (e.g., iron) with aberrant brain development ensuing from both a deficiency and an excess. Important nutrients during late fetal and early neonatal life include protein, zinc, iron, copper, choline, and polyunsaturated fatty acids (PUFA; 1). Prenatal exposure to an ‘unhealthy diet’ has been associated with ADHD symptoms, further linked to altered epigenetic modification of blood-derived DNA [2]. The study by Daraki et al. in this issue [3] illustrates how low maternal serum vitamin D concentrations during the first trimester were related to behavioral difficulties, especially ADHDlike symptoms, at preschool age in the child. As vitamin D amounts of the developing fetus are dependent on maternal stores, maternal vitamin D deficiency is of great concern for its consequences in the offspring. Maternal vitamin D performs a number of biological functions that are fundamental to early brain development [4], including proliferation and differentiation of brain cells [5], regulation of axonal growth [6], calcium signaling within the brain, and neurotrophic and neuroprotective actions [6]. These results may suggest that appropriate supplementation of vitamin D during pregnancy may reduce the incidence of behavioral difficulties and ADHD-like symptoms later in life in the offspring. The systematic review by Föcker et al. in this issue [7] illustrates that based on the results from 25 cross-sectional studies and 8 longitudinal studies, vitamin D seems to play a Childhood neurodevelopmental and psychiatric disorders are known to be complex conditions of multifactorial aetiology, involving both genetic and environmental determinants. There is a rapidly growing awareness that mental symptoms and psychiatric disorders are linked to nutrition. This focused issue of European Child+Adolescent Psychiatry will present a state-of-the-art overview of the topic of nutrition and child and adolescent psychiatric disorders, with the aim of moving this highly promising field forward by formulating a research agenda and to inform clinicians regarding the currently available therapeutic and preventive options. Food intake affects brain development and function in all age groups, starting from the phase in utero in terms of cognitive processes, mood, and brain performance. Accordingly, nutritional deficiencies can result in a vast array of age-dependent clinical symptoms, which affect the function of the central nervous system. Nutritional insults can have a particularly strong effect on the developing brain between weeks 24 and 42 of gestation, during which several neurologic processes, including synapse formation and myelination build upon one another [1]. A remarkable plasticity is a core feature of the young brain, thus potentially allowing for substantial repair after appropriate nutrient repletion. However, vulnerability to nutritional insults seemingly outweighs