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Smaller total brain volume but not subcortical structure volume related to common genetic risk for ADHD

Published online by Cambridge University Press:  24 January 2020

Michael A. Mooney
Division of Bioinformatics & Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA OHSU Knight Cancer Institute, Portland, Oregon, USA
Priya Bhatt
Department of Psychiatry, Oregon Health & Science University, Portland, Oregon, USA
Robert J. M. Hermosillo
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA
Peter Ryabinin
Oregon Clinical and Translational Research Institute, Portland, Oregon, USA
Molly Nikolas
Department of Psychological and Brain Sciences, The University of Iowa, Iowa City, Iowa, USA
Stephen V. Faraone
Departments of Psychiatry and Neuroscience & Physiology, State University of New York Upstate Medical University, Syracuse, New York, USA
Damien A. Fair
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA Advanced Imaging Research Center, OHSU, Portland, Oregon, USA
Beth Wilmot
Division of Bioinformatics & Computational Biology, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, USA Oregon Clinical and Translational Research Institute, Portland, Oregon, USA
Joel T. Nigg*
Department of Psychiatry, Oregon Health & Science University, Portland, Oregon, USA Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA
Author for correspondence: Joel Nigg, E-mail:



Mechanistic endophenotypes can inform process models of psychopathology and aid interpretation of genetic risk factors. Smaller total brain and subcortical volumes are associated with attention-deficit hyperactivity disorder (ADHD) and provide clues to its development. This study evaluates whether common genetic risk for ADHD is associated with total brain volume (TBV) and hypothesized subcortical structures in children.


Children 7–15 years old were recruited for a case–control study (N = 312, N = 199 ADHD). Children were assessed with a multi-informant, best-estimate diagnostic procedure and motion-corrected MRI measured brain volumes. Polygenic scores were computed based on discovery data from the Psychiatric Genomics Consortium (N = 19 099 ADHD, N = 34 194 controls) and the ENIGMA + CHARGE consortium (N = 26 577).


ADHD was associated with smaller TBV, and altered volumes of caudate, cerebellum, putamen, and thalamus after adjustment for TBV; however, effects were larger and statistically reliable only in boys. TBV was associated with an ADHD polygenic score [β = −0.147 (−0.27 to −0.03)], and mediated a small proportion of the effect of polygenic risk on ADHD diagnosis (average ACME = 0.0087, p = 0.012). This finding was stronger in boys (average ACME = 0.019, p = 0.008). In addition, we confirm genetic variation associated with whole brain volume, via an intracranial volume polygenic score.


Common genetic risk for ADHD is not expressed primarily as developmental alterations in subcortical brain volumes, but appears to alter brain development in other ways, as evidenced by TBV differences. This is among the first demonstrations of this effect using molecular genetic data. Potential sex differences in these effects warrant further examination.

Original Articles
Copyright © Cambridge University Press 2020

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