Genetic Markers of ADHD-Related Variations in Intracranial Volume

Marieke Klein; Raymond K Walters; Ditte Demontis; Jason L Stein; Derrek P Hibar; Hieab H Adams; Janita Bralten; Nina Roth Mota; Russell Schachar; Edmund Sonuga-Barke; Manuel Mattheisen; Benjamin M Neale; Paul M Thompson; Sarah E Medland; Anders D Børglum; Stephen V Faraone; Alejandro Arias-Vasquez; Barbara Franke

doi:10.1176/appi.ajp.2018.18020149

Genetic Markers of ADHD-Related Variations in Intracranial Volume

Am J Psychiatry. 2019 Mar 1;176(3):228-238. doi: 10.1176/appi.ajp.2018.18020149.

Authors

Marieke Klein¹, Raymond K Walters¹, Ditte Demontis¹, Jason L Stein¹, Derrek P Hibar¹, Hieab H Adams¹, Janita Bralten¹, Nina Roth Mota¹, Russell Schachar¹, Edmund Sonuga-Barke¹, Manuel Mattheisen¹, Benjamin M Neale¹, Paul M Thompson¹, Sarah E Medland¹, Anders D Børglum¹, Stephen V Faraone¹, Alejandro Arias-Vasquez¹, Barbara Franke¹

Affiliation

¹ The Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Klein, Bralten, Roth Mota, Arias-Vasquez, Franke); University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands (Klein); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Walters, Neale); Program in Medical and Population Genetics (Walters) and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass (Walters, Neale); the Department of Biomedicine and the Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Mattheisen, Børglum); the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum); the Department of Genetics and the Neuroscience Center, University of North Carolina, Chapel Hill (Stein); the Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Hibar, Thompson); the Department of Epidemiology and the Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (Adams); the Department of Psychiatry and the Research Institute, Hospital for Sick Children, University of Toronto, Toronto (Schachar); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Sonuga-Barke); the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany (Mattheisen); the Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institute, Stockholm (Mattheisen); Stockholm Health Care Services, Stockholm County Council, Stockholm (Mattheisen); the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles (Thompson); the Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia (Medland); the Department of Psychiatry and the Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y. (Faraone); the K.G. Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); and the Department of Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Roth Mota, Arias-Vasquez, Franke).

Abstract

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 (r_g=-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.

Keywords: ADHD; Genetics; MRI Brain Imaging.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amygdala / pathology
Attention Deficit Disorder with Hyperactivity / etiology
Attention Deficit Disorder with Hyperactivity / genetics*
Attention Deficit Disorder with Hyperactivity / pathology
Brain / pathology*
Case-Control Studies
Caudate Nucleus / pathology
Genetic Markers / genetics
Genome-Wide Association Study
Hippocampus / pathology
Humans
Linkage Disequilibrium / genetics
Nucleus Accumbens / pathology
Organ Size / genetics
Polymorphism, Single Nucleotide / genetics
Putamen / pathology
Quantitative Trait Loci / genetics

Substances

Genetic Markers

Grants and funding

U54 EB020403/EB/NIBIB NIH HHS/United States