TY - JOUR
T1 - Genetic markers of ADHD-related variations in intracranial volume
AU - Klein, Marieke
AU - Walters, Raymond K.
AU - Demontis, Ditte
AU - Stein, Jason L.
AU - Hibar, Derrek P.
AU - Adams, Hieab H.
AU - Bralten, Janita
AU - Mota, Nina Roth
AU - Schachar, Russell
AU - Sonuga-Barke, Edmund
AU - Mattheisen, Manuel
AU - Neale, Benjamin M.
AU - Thompson, Paul M.
AU - Medland, Sarah E.
AU - Børglum, Anders D.
AU - Faraone, Stephen V.
AU - Arias-Vasquez, Alejandro
AU - Franke, Barbara
N1 - Funding Information:
Supported by the Dutch National Science Agenda NeurolabNL project (grant 400-17-602) and the Netherlands Organization for Scientific Research (NWO) Vici Innovation Program (grant 016-130-669 to Dr. Franke). Additional support was received from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreements 602805 (Aggressotype), 602450 (IMAGEMEND), and 278948 (TACTICS) as well as from the European Community’s Horizon 2020 Programme (H2020/2014–2020) under grant agreements 643051 (MiND) and 667302 (CoCA). The work was also supported by the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724 to iPSYCH/Dr. Børglum), by grant U54 EB020403 to the ENIGMA Consortium from the BD2K Initiative, a cross-NIH partnership, and by the European College of Neuropsychopharmacology (ECNP) Network “ADHD Across the Lifespan.” Dr. Medland is supported by an Australian National Health and Medical Research Council fellowship (SRFB-1103623). This work was partly carried out on the Dutch national e-infrastructure with the support of SURF Foundation.
Funding Information:
Dr. Hibar has been an employee of Genentech and Janssen Research and Development. Dr. Schachar has received funding from the Canadian Institutes of Health Research, the Ontario Brain Institute, and DNA Genotek, and he has equity in Ehave, a tech company that makes tools forcognitiveassessment.Dr.Sonuga-Barkehasreceivedresearchfunding
Funding Information:
In this study, we set out to investigate genetic covariance between ADHD risk and structural brain phenotypes. We found significant, though modest, genetic covariation between ADHD risk and brain volumes, both on global and gene-wide/single variant levels. On the global level, significant negative genetic correlation between ADHD and ICV was demonstrated. The direction of effect was supported by SNP effect concordance analysis. Our ICV finding was highly consistent across approaches and in the expected direction, given the previous observation that patients with ADHD have smaller ICV relative to control subjects (3). For most subcortical brain volumes, pleiotropic effects were also found. On the single variant and gene-wide levels, meta-analyses found significant loci associated with both ADHD risk and brain volumes. We identified SEMA6D, KIZ, and MEF2C as potential key loci contributing to both ADHD risk and ICV, and exploratory gene-set analysis revealed association of ADHD–ICV overlap with variation in neurite outgrowth genes.
Funding Information:
Supported by the Dutch National Science Agenda NeurolabNL project (grant 400-17-602) and the Netherlands Organization for Scientific Research (NWO) Vici Innovation Program (grant 016-130-669 to Dr. Franke). Additional support was received from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreements 602805 (Aggressotype), 602450 (IMAGEMEND), and 278948 (TACTICS) as well as from the European Community's Horizon 2020 Programme (H2020/2014-2020) under grant agreements 643051 (MiND) and 667302 (CoCA). The work was also supported by the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724 to iPSYCH/Dr. Børglum), by grant U54 EB020403 to the ENIGMA Consortium from the BD2K Initiative, a cross-NIH partnership, and by the European College of Neuropsychopharmacology (ECNP) Network “ADHD Across the Lifespan.” Dr. Medland is supported by an Australian National Health and Medical Research Council fellowship (SRFB-1103623). This work was partly carried out on the Dutch national e-infrastructure with the support of SURF Foundation.
Publisher Copyright:
© 2019 American Psychiatric Association. All rights reserved.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062890841&partnerID=8YFLogxK
U2 - 10.1176/appi.ajp.2018.18020149
DO - 10.1176/appi.ajp.2018.18020149
M3 - Article
C2 - 30818988
AN - SCOPUS:85062890841
SN - 0002-953X
VL - 176
SP - 228
EP - 238
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 3
ER -