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Genetic markers of ADHD-related variations in intracranial volume

View ORCID ProfileMarieke 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: https://doi.org/10.1101/184192
Marieke Klein
1Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands
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  • ORCID record for Marieke Klein
Raymond K. Walters
2Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
4Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
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Ditte Demontis
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
7The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark
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Jason L. Stein
8Department of Genetics & Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, USA
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Derrek P. Hibar
9Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, USA
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Hieab H. Adams
10Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
11Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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Janita Bralten
1Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands
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Nina Roth Mota
1Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands
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Russell Schachar
12Department of Psychiatry and Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada
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Edmund Sonuga-Barke
13Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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Manuel Mattheisen
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
7The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark
14Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
15Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
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Benjamin M. Neale
16Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, USA
17Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, USA
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Paul M. Thompson
9Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of Southern California, Los Angeles, USA
18Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Sarah E. Medland
19Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Anders D. Børglum
5Department of Biomedicine, Aarhus University, Aarhus, Denmark
6Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
7The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark
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Stephen V. Faraone
20Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
21K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway
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Alejandro Arias-Vasquez
1Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands
22Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands
23Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands
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Barbara Franke
1Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Human Genetics, Nijmegen, The Netherlands
22Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Psychiatry, Nijmegen, The Netherlands
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  • For correspondence: barbara.franke@radboudumc.nl
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ABSTRACT

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters.

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Posted September 12, 2017.
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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
bioRxiv 184192; doi: https://doi.org/10.1101/184192
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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
bioRxiv 184192; doi: https://doi.org/10.1101/184192

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