Genetic Markers of ADHD-Related Variations in Intracranial Volume

• Published in: The American journal of psychiatry Vol. 176; no. 3; pp. 228 - 238
• Main Authors: Klein, Marieke, Walters, Raymond K, Demontis, Ditte, Stein, Jason L, Hibar, Derrek P, Adams, Hieab H, Bralten, Janita, Roth Mota, Nina, Schachar, Russell, Sonuga-Barke, Edmund, Mattheisen, Manuel, Neale, Benjamin M, Thompson, Paul M, Medland, Sarah E, Børglum, Anders D, Faraone, Stephen V, Arias-Vasquez, Alejandro, Franke, Barbara
• Format: Journal Article
• Language: English
• Published: United States American Psychiatric Association 01.03.2019
• Subjects: Amygdala - pathology; Attention Deficit Disorder with Hyperactivity - etiology; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - pathology; Attention deficit hyperactivity disorder; Brain - pathology; Case-Control Studies; Caudate Nucleus - pathology; Etiology; Genetic markers; Genetic Markers - genetics; Genome-Wide Association Study; Hippocampus - pathology; Humans; Linkage Disequilibrium - genetics; Medicin och hälsovetenskap; Neurodevelopmental disorders; Nucleus Accumbens - pathology; Organ Size - genetics; Polymorphism, Single Nucleotide - genetics; Putamen - pathology; Quantitative Trait Loci - genetics; Systematic review; ADHD; Genetics; MRI Brain Imaging
• ISSN: 0002-953X; 1535-7228; 1535-7228
• DOI: 10.1176/appi.ajp.2018.18020149

Objective:Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder.Methods:The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221–24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level.Results:Analyses revealed a significant negative genetic correlation between ADHD and ICV (rg=−0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes.Conclusions:This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.