SummaryThe genetic architecture of autism spectrum disorder involves the interplay of common and rare variation and their impact on hundreds of genes. Using exome sequencing, analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, and a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic, transcriptional, and chromatin remodeling pathways. These include voltage-gated ion channels regulating propagation of action potentials, pacemaking, and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodelers, prominently histone post-translational modifications involving lysine methylation/demethylation.

BACKGROUND Neuroimaging studies show structural alterations in several brain regions in children and adults with attention-deficit/hyperactivity disorder (ADHD). Through the formation of the worldwide ENIGMA ADHD Working Group, we addressed weaknesses of prior imaging studies and meta-analyses in sample size and methodological heterogeneity. METHODS Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites (age range: 4–63 years; 66% males). Individual sites analyzed magnetic resonance imaging brain scans with harmonized protocols. Case-control differences in subcortical structures and intracranial volume (ICV) were assessed through mega-and meta-analysis. FINDINGS The volumes of the accumbens (Cohen’s d=−0.15), amygdala (d=−0.19), caudate (d=−0.11), hippocampus (d=−0.11), putamen (d=−0.14), and ICV (d=−0.10) were found to be smaller in cases relative to controls. Effect sizes were highest in children, case-control differences were not present in adults. Explorative lifespan modeling suggested a delay of maturation and a delay of degeneration. Psychostimulant medication use or presence of comorbid psychiatric disorders did not influence results, nor did symptom scores correlate with brain volume. INTERPRETATION Using the largest data set to date, we extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. We add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD, and provide unprecedented precision in effect size estimates. Lifespan analyses suggest that, in the absence of well-powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of life provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING National Institutes of Health

Empathy allows emotional psychological inference about other person's mental states and feelings in social contexts. We aimed at specifying the common and differential neural mechanisms of “self”- and “other”-related attribution of emotional states using event-related functional magnetic resonance imaging. Subjects viewed faces expressing emotions with direct or averted gaze and either focused on their own emotional response to each face (self-task) or evaluated the emotional state expressed by the face (other-task). The common network activated by both tasks included the left lateral orbito-frontal and medial prefrontal cortices (MPFC), bilateral inferior frontal cortices, superior temporal sulci and temporal poles, as well as the right cerebellum. In a subset of these regions, neural activity was significantly correlated with empathic abilities. The self- (relative to the other-) task differentially activated the MPFC, the posterior cingulate cortex (PCC)/precuneus, and the temporo-parietal junction bilaterally. Empathy-related processing of emotional facial expressions recruited brain areas involved in mirror neuron and theory-of-mind (ToM) mechanisms. The differential engagement of the MPFC, the PCC/precuneus, and temporo-parietal regions in the self-task indicates that these structures act as key players in the evaluation of one's own emotional state during empathic face-to-face interaction. Activation of mirror neurons in a task relying on empathic abilities without explicit task-related motor components supports the view that mirror neurons are not only involved in motor cognition but also in emotional interpersonal cognition. An interplay between ToM and mirror neuron mechanisms may hold for the maintenance of a self-other distinction during empathic interpersonal face-to-face interactions.