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

Michael A. Mooney, Priya Bhatt, Robert Hermosillo, Peter Ryabinin, Molly Nikolas, Stephen V. Faraone, Damien A. Fair, Beth Wilmot, Joel T. Nigg

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Background 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. Methods 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). Results 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. Conclusion 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 languageEnglish (US)
Pages (from-to)1279-1288
Number of pages10
JournalPsychological medicine
Issue number8
Early online dateJan 24 2020
StatePublished - Jun 2021

Bibliographical note

Funding Information:
Financial support. This work was supported by funding from the National Institutes of Mental Health (J.N., R01MH099064 and R01MH086654; D.F. and J.N., R01MH115357; D.F., R01MH096773).

Funding Information:
Conflict of interest. Dr Nikolas has received research grants for non-pharmacological research from Shire (USA-000594). Dr Fair is non-shareholding Vice President and Chief Scientific Officer (CSO) of Nous Imaging Inc, and co-inventor of Framewise Integrated Real Time Motion Monitoring. Dr Nigg receives royalties from Guilford Press for two books, What Causes ADHD (2006) and Getting Ahead of ADHD (2017). In the past year, Dr Faraone received income, potential income, travel expenses continuing education support and/or research support from Lundbeck, Rhodes, Arbor, KenPharm, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA, Sunovion, Genomind, and Neurolifesciences. With his institution, Dr Faraone has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, Dr Faraone received support from: Shire, Neurovance, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. Dr Faraone receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health, Oxford University Press: Schizophrenia: The Facts, and Elsevier: ADHD: Non-Pharmacologic Interventions. Dr Faraone is the principal investigator of Dr Faraone is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no 602805; the European Union’s Horizon 2020 research and innovation program under grant agreement No 667302; and National Institute of Mental Health grants 5R01MH101519 and U01 MH109536-01. All other authors report no competing interests.

Publisher Copyright:
Copyright © Cambridge University Press 2020.


  • ADHD
  • brain volume
  • genetics
  • imaging
  • polygenic scores
  • subcortical structures

PubMed: MeSH publication types

  • Journal Article


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