DHD is a neurodevelopmental psychiatric disorder that affects around 5% of children and adolescents and 2.5% of adults worldwide 1. ADHD is often persistent and markedly impairing, with increased risk of harmful outcomes, such as injuries 2 , traffic accidents 3 , increased healthcare utilization 4,5 , substance abuse 6 , criminality 7 , unemployment 8 , divorce 4 , suicide 9 , AIDS risk behaviors 8 and premature mortality 10. Epidemiologic and clinical studies implicate genetic and environmental risk factors that affect the structure and functional capacity of brain networks involved in behavior and cognition 1 in the etiology of ADHD. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder Ditte Demontis

Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

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

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

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