Meta-Analysis

. 2019 Mar 1;176(3):228-238.

doi: 10.1176/appi.ajp.2018.18020149.

Genetic Markers of ADHD-Related Variations in Intracranial Volume

Marieke Klein¹, Raymond K Walters¹, Ditte Demontis¹, Jason L Stein¹, Derrek P Hibar¹, Hieab H Adams¹, Janita Bralten¹, Nina Roth Mota¹, Russell Schachar¹, Edmund Sonuga-Barke¹, Manuel Mattheisen¹, Benjamin M Neale¹, Paul M Thompson¹, Sarah E Medland¹, Anders D Børglum¹, Stephen V Faraone¹, Alejandro Arias-Vasquez¹, Barbara Franke¹

Affiliations

Affiliation

¹ The Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Klein, Bralten, Roth Mota, Arias-Vasquez, Franke); University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands (Klein); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Walters, Neale); Program in Medical and Population Genetics (Walters) and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass (Walters, Neale); the Department of Biomedicine and the Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Mattheisen, Børglum); the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum); the Department of Genetics and the Neuroscience Center, University of North Carolina, Chapel Hill (Stein); the Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Hibar, Thompson); the Department of Epidemiology and the Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (Adams); the Department of Psychiatry and the Research Institute, Hospital for Sick Children, University of Toronto, Toronto (Schachar); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Sonuga-Barke); the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany (Mattheisen); the Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institute, Stockholm (Mattheisen); Stockholm Health Care Services, Stockholm County Council, Stockholm (Mattheisen); the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles (Thompson); the Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia (Medland); the Department of Psychiatry and the Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y. (Faraone); the K.G. Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); and the Department of Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Roth Mota, Arias-Vasquez, Franke).

PMID: 30818988
PMCID: PMC7780894
DOI: 10.1176/appi.ajp.2018.18020149

Meta-Analysis

Genetic Markers of ADHD-Related Variations in Intracranial Volume

Marieke Klein et al. Am J Psychiatry. 2019.

. 2019 Mar 1;176(3):228-238.

doi: 10.1176/appi.ajp.2018.18020149.

Authors

Affiliation

¹ The Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Klein, Bralten, Roth Mota, Arias-Vasquez, Franke); University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands (Klein); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Walters, Neale); Program in Medical and Population Genetics (Walters) and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass (Walters, Neale); the Department of Biomedicine and the Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Mattheisen, Børglum); the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum); the Department of Genetics and the Neuroscience Center, University of North Carolina, Chapel Hill (Stein); the Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Hibar, Thompson); the Department of Epidemiology and the Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (Adams); the Department of Psychiatry and the Research Institute, Hospital for Sick Children, University of Toronto, Toronto (Schachar); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Sonuga-Barke); the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany (Mattheisen); the Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institute, Stockholm (Mattheisen); Stockholm Health Care Services, Stockholm County Council, Stockholm (Mattheisen); the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles (Thompson); the Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia (Medland); the Department of Psychiatry and the Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y. (Faraone); the K.G. Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); and the Department of Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Roth Mota, Arias-Vasquez, Franke).

PMID: 30818988
PMCID: PMC7780894
DOI: 10.1176/appi.ajp.2018.18020149

Abstract

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=-0.22). 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.

Keywords: ADHD; Genetics; MRI Brain Imaging.

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Figures

**FIGURE 1.. Common genetic variants associated with ADHD, intracranial volume (ICV), and the combined analysis of ADHD and ICV^a**
A. ADHD GWAS Meta-Analysis (PGC and iPSYCH Data) B. ICV GWAS Meta-Analysis (ENIGMA and CHARGE Data) C. Combined ADHD and ICV Weighted GWAS Meta-Analysis ^aShown here are Manhattan plots, in which every point represents a single genetic variant plotted according to its genomics position (x-axis) and its −log₁₀(p) value for association with the respective trait (y-axis). The solid red line represents the study-wide genome-wide significance of p<8.33×10⁻⁹, and the dashed red line represents the genome-wide significance of p<5×10⁻⁸. ADHD=attention deficit hyperactivity disorder; CHARGE=Cohorts for Heart and Aging Research in Genomic Epidemiology; ENIGMA=Enhancing Neuroimaging Genetics Through Meta-Analysis; GWAS=genome-wide association study; PGC=Psychiatric Genomics Consortium.

**FIGURE 2.. Regional association of genome-wide significant loci of ADHD and brain volume GWAS meta-analyses^a**
^a For each panel, zoomed-in association plots (±300 kb from the top SNP, indexed by purple diamond) are shown. Plots are zoomed to highlight the genomic region that likely harbors the causal variant(s). ADHD=attention deficit hyperactivity disorder; nMA=naive meta-analysis of ADHD and brain volume; wMA=weighted meta-analysis of ADHD and brain volume; SNP=single-nucleotide polymorphism.

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Genetic Markers of ADHD-Related Variations in Intracranial Volume

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