Genetic markers of ADHD-related variations in intracranial volume

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  • Marieke Klein, Radboud University Nijmegen Medical Centre, University Medical Center Utrecht, Utrecht
  • ,
  • Raymond K. Walters, Massachusetts General Hospital, Boston, Broad Institute
  • ,
  • Ditte Demontis
  • Jason L. Stein, The University of North Carolina at Chapel Hill, Department of Genetics, Chapel Hill, United States
  • ,
  • Derrek P. Hibar, Keck School of Medicine of USC
  • ,
  • Hieab H. Adams, Erasmus University Medical Center
  • ,
  • Janita Bralten, Radboud University Nijmegen Medical Centre
  • ,
  • Nina Roth Mota, Radboud University Nijmegen Medical Centre
  • ,
  • Russell Schachar, The Hospital for Sick Children
  • ,
  • Edmund Sonuga-Barke, King's College London
  • ,
  • Manuel Mattheisen
  • Benjamin M. Neale, Massachusetts General Hospital, Boston, Broad Institute
  • ,
  • Paul M. Thompson, Keck School of Medicine of USC
  • ,
  • Sarah E. Medland, QIMR Berghofer Medical Research Institute
  • ,
  • Anders D. Børglum
  • Stephen V. Faraone, State University of New York Upstate Medical University, Universitetet i Bergen
  • ,
  • Alejandro Arias-Vasquez, Radboud University Nijmegen Medical Centre
  • ,
  • Barbara Franke, Radboud University Nijmegen Medical Centre

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 =20.22). 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.

Original languageEnglish
JournalAmerican Journal of Psychiatry
Volume176
Issue3
Pages (from-to)228-238
Number of pages11
ISSN0002-953X
DOIs
Publication statusPublished - 2019

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