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      Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome

      research-article
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      Neuron
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          SUMMARY

          Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (<1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (>1 Mb), singleton events (OR=2.28, 95%CI [1.39–3.79], p=1.2×10 −3) and known, pathogenic CNVs (OR=3.03 [1.85–5.07], p=1.5×10 −5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk ( NRXN1 deletions, OR=20.3, 95%CI [2.6–156.2]; CNTN6 duplications, OR=10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

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          Author and article information

          Journal
          8809320
          1600
          Neuron
          Neuron
          Neuron
          0896-6273
          1097-4199
          5 July 2017
          21 June 2017
          21 June 2018
          : 94
          : 6
          : 1101-1111.e7
          Affiliations
          [1 ]Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
          [2 ]Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA
          [3 ]Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
          [4 ]Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
          [5 ]Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
          [6 ]Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
          [7 ]Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
          [8 ]Moscow Institute of Physics and Technology, Dolgoprudny, Institusky 9, Moscow, Russian Federation
          [9 ]Department of Psychology, University of Denver, Denver, CO, USA
          [10 ]Toronto Western Hospital, University Health Network and Youthdale Treatment Centres, University of Toronto, Toronto, Canada
          [11 ]Krembil Research Institute, University Health Network, Toronto, Canada
          [12 ]Johns Hopkins University School of Medicine, Baltimore, MD, USA
          [13 ]Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
          [14 ]Institute of Human Genetics, University of Bonn, Bonn, Germany
          [15 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
          [16 ]Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA
          [17 ]University of Montréal, Montreal, Canada
          [18 ]Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
          [19 ]Hofstra Northwell School of Medicine, Hempstead, NY, USA
          [20 ]Département de Médicine Translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
          [21 ]Brain and Spine Institute, UPMC/INSERM UMR_S1127, Paris, France
          [22 ]Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
          [23 ]Institute of Human Genetics, Hannover Medical School, Hannover, Germany
          [24 ]Medical University Vienna, Department of Psychiatry and Psychotherapy, Vienna, Austria
          [25 ]Biopsychosocial Corporation, Vienna, Austria
          [26 ]Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria
          [27 ]Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
          [28 ]Department of Psychiatry, University of Utah, UT, USA
          [29 ]Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
          [30 ]Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary
          [31 ]Children’s Mercy Hospital, Kansas City, KS, USA
          [32 ]Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Catania, Italy
          [33 ]Department of Psychiatry, University Medical Center Groningen & Drenthe Mental Health Center, Groningen, the Netherlands
          [34 ]Department of Clinical Psychology, Utrecht University, Utrecht, the Netherlands
          [35 ]Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland
          [36 ]Penn State University College of Medicine, Hershey, PA, USA
          [37 ]Department of Neurology and Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, FL, USA
          [38 ]Marquette University, Milwaukee, WI, USA
          [39 ]University of Wisconsin-Milwaukee, Milwaukee, WI, USA
          [40 ]Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales, United Kingdom
          [41 ]SUNY Downstate Medical Center, Brooklyn, NY, USA
          [42 ]Department of Psychiatry & Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
          [43 ]Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, the Netherlands
          [44 ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
          [45 ]Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA
          [46 ]Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
          [47 ]Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
          Author notes
          [* ]Correspondence: jscharf@ 123456partners.org (J.M.S.), gcoppola@ 123456ucla.edu (G.C.)
          [48]

          Senior author.

          [‡]

          Lead Contact

          CONSORTIA

          Members of the Tourette Syndrome Association International Consortium for Genetics are: Cathy L. Barr, James R. Batterson, Cheston Berlin, Ruth D. Bruun, Cathy L. Budman, Danielle C. Cath, Sylvain Chouinard, Giovanni Coppola, Nancy J. Cox, Sabrina Darrow, Lea K. Davis, Yves Dion, Nelson B. Freimer, Marco A. Grados, Erica Greenberg, Matthew E. Hirschtritt, Alden Y. Huang, Cornelia Illmann, Robert A. King, Roger Kurlan, James F. Leckman, Gholson J. Lyon, Irene A. Malaty, Carol A. Mathews, William M. McMahon, Benjamin M. Neale, Michael S. Okun, Lisa Osiecki, David L. Pauls, Danielle Posthuma, Vasily Ramensky, Mary M. Robertson, Guy A. Rouleau, Paul Sandor, Jeremiah M. Scharf, Harvey S. Singer, Jan Smit, Jae-Hoon Sul, Dongmei Yu

          Members of the Gilles de la Tourette Syndrome Genome-wide Association Study Replication Initiative are: Harald Aschauer, Csaba Barta, Cathy Budman, Danielle C. Cath, Christel Depienne, Andreas Hartmann, Johannes Hebebrand, Anastasios Konstantinidis, Carol Mathews, Kirsten R. Muller-Vahl, Peter Nagy, Markus M. Nöthen, Peristera Paschou, Renata Rizzo, Guy Rouleau, Paul Sandor, Jeremiah Scharf, Monika Schlögelhofer, Mara Stamenkovic, Manfred Stuhrmann, Fotis Tsetsos, Zsanett Tarnok, Tomasz Wolanczyk, Yulia Worbe

          Article
          PMC5568251 PMC5568251 5568251 nihpa889208
          10.1016/j.neuron.2017.06.010
          5568251
          28641109
          7da3d196-1f57-48bf-a246-d7a44966e4a5
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