title: SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder.
abstract: BACKGROUND
  Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome-wide screening approach for copy number variants (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory-inhibitory balance impacting both brain development and activity-dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for GLUT3 dysfunction in ADHD.
  
  
  METHODS
  Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EEG recordings during neurocognitive tasks, and ratings of food energy content.
  
  
  RESULTS
  Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food.
  
  
  CONCLUSIONS
  Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk.
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: Sören
authors.initials: S
authors.lastname: Merker
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: Georg C
authors.initials: GC
authors.lastname: Ziegler
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Mayer
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Ehlis
authors.affiliation: Department of Psychology I, University of Würzburg, Würzburg, Germany.|Department of Child and Adolescent Psychiatry, University of Tübingen, Tübingen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Conzelmann
authors.affiliation: K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Müller-Reible
authors.affiliation: Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Max-Planck Institute for Molecular Genetics, Berlin, Germany.|Bundeswehr Institute of Radiobiology, University of Ulm, Ulm, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ullmann
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Romanos
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Fallgatter
authors.affiliation: Department of Psychology I, University of Würzburg, Würzburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Pauli
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.|Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: Charline
authors.initials: C
authors.lastname: Jansch
authors.affiliation: Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alejandro Arias
authors.initials: AA
authors.lastname: Vasquez
authors.affiliation: Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.|Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.affiliation: Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ribasés
authors.affiliation: Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.|Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain.|Department of Psychiatry and Legal Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Josep Antoni
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.affiliation: Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.|Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D016022:Case-Control Studies; D002648:Child; D056915:DNA Copy Number Variations; D056344:Executive Function / Q000502:physiology*; D020440:Gene Duplication; D055106:Genome-Wide Association Study; D005858:Germany; D051274:Glucose Transporter Type 3 / Q000235:genetics*; D006801:Humans; D009664:Norway; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D013030:Spain; D055815:Young Adult
chemical_list: D051274:Glucose Transporter Type 3; C495687:SLC2A3 protein, human
keywords: 
  SLC2A3
  ; Attention-deficit/hyperactivity disorder; copy number variants; duplication; energy homeostasis; frontostriatal network; glucose transporter; single-nucleotide polymorphisms