Sören Merker1, Andreas Reif2, Georg C Ziegler1, Heike Weber1,2, Ute Mayer1, Ann-Christine Ehlis3, Annette Conzelmann4,5, Stefan Johansson6, Clemens Müller-Reible7, Indrajit Nanda7, Thomas Haaf7, Reinhard Ullmann8,9, Marcel Romanos10, Andreas J Fallgatter3, Paul Pauli4, Tatyana Strekalova1,11,12, Charline Jansch1, Alejandro Arias Vasquez13,14, Jan Haavik15,16, Marta Ribasés17,18, Josep Antoni Ramos-Quiroga17,18,19, Jan K Buitelaar14, Barbara Franke13, Klaus-Peter Lesch1,11,12. 1. Division of Molecular Psychiatry, ADHD Clinical Research Unit, Laboratory of Translational Neuroscience, Center of Mental Health, University of Würzburg, Würzburg, Germany. 2. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany. 3. Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany. 4. Department of Psychology I, University of Würzburg, Würzburg, Germany. 5. Department of Child and Adolescent Psychiatry, University of Tübingen, Tübingen, Germany. 6. K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway. 7. Department of Human Genetics, Biozentrum, University of Würzburg, Würzburg, Germany. 8. Max-Planck Institute for Molecular Genetics, Berlin, Germany. 9. Bundeswehr Institute of Radiobiology, University of Ulm, Ulm, Germany. 10. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany. 11. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. 12. Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. 13. Departments of Human Genetics and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 14. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 15. Division of Psychiatry, Haukeland University Hospital, Bergen, Norway. 16. Department of Biomedicine, K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway. 17. Psychiatric Genetics Unit, Institute Vall d'Hebron Research (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain. 18. Biomedical Network Research Centre on Mental Health (CIBERSAM), Barcelona, Spain. 19. Department of Psychiatry and Legal Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain.
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.
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 ADHDpatients, 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: Bo-Chul Shin; Carlos Cepeda; Ana María Estrada-Sánchez; Michael S Levine; Laya Hodaei; Yun Dai; Jai Jung; Amit Ganguly; Peter Clark; Sherin U Devaskar Journal: J Neurosci Date: 2018-09-19 Impact factor: 6.167
Authors: Kim R Simpfendorfer; Wentian Li; Andrew Shih; Hongxiu Wen; Harini P Kothari; Edward A Einsidler; Arthur Wuster; Julie Hunkapiller; Timothy W Behrens; Robert R Graham; Michael J Townsend; Doron M Behar; Rui Hu; Elliott Greenspan; Peter K Gregersen Journal: Mol Genet Metab Rep Date: 2019-04-06
Authors: Jordi Corominas; Marieke Klein; Barbara Franke; Klaus-Peter Lesch; Tetyana Zayats; Olga Rivero; Georg C Ziegler; Marc Pauper; Kornelia Neveling; Geert Poelmans; Charline Jansch; Evgeniy Svirin; Julia Geissler; Heike Weber; Andreas Reif; Alejandro Arias Vasquez; Tessel E Galesloot; Lambertus A L M Kiemeney; Jan K Buitelaar; Josep-Antoni Ramos-Quiroga; Bru Cormand; Marta Ribasés; Kristian Hveem; Maiken Elvestad Gabrielsen; Per Hoffmann; Sven Cichon; Jan Haavik; Stefan Johansson; Christian P Jacob; Marcel Romanos Journal: Mol Psychiatry Date: 2018-08-16 Impact factor: 15.992
Authors: Georg C Ziegler; Ann-Christine Ehlis; Heike Weber; Maria Rosaria Vitale; Johanna E M Zöller; Hsing-Ping Ku; Miriam A Schiele; Laura I Kürbitz; Marcel Romanos; Paul Pauli; Raffael Kalisch; Peter Zwanzger; Katharina Domschke; Andreas J Fallgatter; Andreas Reif; Klaus-Peter Lesch Journal: Genes (Basel) Date: 2021-08-29 Impact factor: 4.096