Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Fotis Tsetsos, Dongmei Yu, Jae Hoon Sul, Alden Y Huang, Cornelia Illmann, Lisa Osiecki, Sabrina M Darrow, Matthew E Hirschtritt, Erica Greenberg, Kirsten R Muller-Vahl, Manfred Stuhrmann, Yves Dion, Guy A Rouleau, Harald Aschauer, Mara Stamenkovic, Monika Schlögelhofer, Paul Sandor, Cathy L Barr, Marco A Grados, Harvey S Singer, Markus M Nöthen, Johannes Hebebrand, Anke Hinney, Robert A King, Thomas V Fernandez, Csaba Barta, Zsanett Tarnok, Peter Nagy, Christel Depienne, Yulia Worbe, Andreas Hartmann, Cathy L Budman, Renata Rizzo, Gholson J Lyon, William M McMahon, James R Batterson, Danielle C Cath, Irene A Malaty, Michael S Okun, Cheston Berlin, Douglas W Woods, Paul C Lee, Joseph Jankovic, Mary M Robertson, Donald L Gilbert, Lawrence W Brown, Barbara J Coffey, Andrea Dietrich, Pieter J Hoekstra, Samuel Kuperman, Samuel H Zinner, Michael Wagner, James A Knowles, A Jeremy Willsey, Jay A Tischfield, Gary A Heiman, Nancy J Cox, Nelson B Freimer, Benjamin M Neale, Lea K Davis, Giovanni Coppola, Carol A Mathews, Jeremiah M Scharf, Peristera Paschou, Cathy L Barr, James R Batterson, Cheston Berlin, Cathy L Budman, Danielle C Cath, 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, Mary M Robertson, Guy A Rouleau, Paul Sandor, Jeremiah M Scharf, Harvey S Singer, Jan H Smit, Jae Hoon Sul, Dongmei Yu, Harald Aschauer Harald Aschauer, Csaba Barta, Cathy L Budman, Danielle C Cath, Christel Depienne, Andreas Hartmann, Johannes Hebebrand, Anastasios Konstantinidis, Carol A Mathews, Kirsten Müller-Vahl, Peter Nagy, Markus M Nöthen, Peristera Paschou, Renata Rizzo, Guy A Rouleau, Paul Sandor, Jeremiah M Scharf, Monika Schlögelhofer, Mara Stamenkovic, Manfred Stuhrmann, Fotis Tsetsos, Zsanett Tarnok, Tomasz Wolanczyk, Yulia Worbe, Lawrence Brown, Keun-Ah Cheon, Barbara J Coffey, Andrea Dietrich, Thomas V Fernandez, Blanca Garcia-Delgar, Donald Gilbert, Dorothy E Grice, Julie Hagstrøm, Tammy Hedderly, Gary A Heiman, Isobel Heyman, Pieter J Hoekstra, Chaim Huyser, Young Key Kim, Young-Shin Kim, Robert A King, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L Leventhal, Marcos Madruga-Garrido, Pablo Mir, Astrid Morer, Alexander Münchau, Kerstin J Plessen, Veit Roessner, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Jay A Tischfield, A Jeremy Willsey, Samuel Zinner, Harald Aschauer, Cathy L Barr, Csaba Barta, James R Batterson, Cheston Berlin, Lawrence Brown, Cathy L Budman, Danielle C Cath, Barbara J Coffey, Giovanni Coppola, Nancy J Cox, Sabrina Darrow, Lea K Davis, Christel Depienne, Andrea Dietrich, Yves Dion, Thomas Fernandez, Nelson B Freimer, Donald Gilbert, Marco A Grados, Erica Greenberg, Andreas Hartmann, Johannes Hebebrand, Gary Heiman, Matthew E Hirschtritt, Pieter Hoekstra, Alden Y Huang, Cornelia Illmann, Joseph Jankovic, Robert A King, Samuel Kuperman, Paul C Lee, Gholson J Lyon, Irene A Malaty, Carol A Mathews, William M McMahon, Kirsten Müller-Vahl, Peter Nagy, Benjamin M Neale, Markus M Nöthen, Michael S Okun, Lisa Osiecki, Peristera Paschou, Renata Rizzo, Mary M Robertson, Guy A Rouleau, Paul Sandor, Jeremiah M Scharf, Monika Schlögelhofer, Harvey S Singer, Mara Stamenkovic, Manfred Stuhrmann, Jae Hoon Sul, Zsanett Tarnok, Jay Tischfield, Fotis Tsetsos, A Jeremy Willsey, Douglas Woods, Yulia Worbe, Dongmei Yu, Samuel Zinner

Journal: Translational psychiatry 2021;11(1):56

PMID: 33462189

Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Address: Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.; Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.; Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.; Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany.; Institute of Human Genetics, Hannover Medical School, Hannover, Germany.; McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal, Canada.; Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.; Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.; Biopsychosocial Corporation, Vienna, Austria.; Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.; Biopsychosocial Corporation, Vienna, Austria.; University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto, Canada.; Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto, Canada.; Johns Hopkins University School of Medicine and the Kennedy Krieger Institute, Baltimore, MD, USA.; Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany.; Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.; Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.; Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary.; Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.; Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.; Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.; Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.; French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.; Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.; Assistance Publique Hôpitaux de Paris, Hopital Saint Antoine, Paris, France.; Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.; French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.; Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.; Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.; Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.; Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, NY, USA.; Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.; Children's Mercy Hospital, Kansas City, MO, USA.; Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands.; Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA.; Pennsylvania State University College of Medicine, Hershey, PA, USA.; Marquette University and University of Wisconsin-Milwaukee, Milwaukee, WI, USA.; Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA.; Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.; Division of Psychiatry, Department of Neuropsychiatry, University College London, London, UK.; Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, Cincinnati, USA.; Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.; Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.; University of Iowa Carver College of Medicine, Iowa City, IA, USA.; Department of Pediatrics, University of Washington, Seattle, WA, USA.; Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.; SUNY Downstate Medical Center Brooklyn, Brooklyn, NY, USA.; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.; Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.; Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA.; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Department of Biological Sciences, Purdue University, West Lafayette, IN, USA. [email protected].; Atlantic Neuroscience Institute, Overlook Hospital, Summit, NJ, USA.; Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.; Department of Psychiatry, VU UniversityMedical Center, Amsterdam, The Netherlands.; Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.; Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria.; Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.; Department of Child Psychiatry, Medical University of Warsaw, 00-001, Warsaw, Poland.; Yonsei University College of Medicine, Yonsei Yoo & Kim Mental Health Clinic, Seoul, South Korea.; Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.; Department of Psychiatry, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.; Tic and Neurodevelopmental Movements Service (TANDeM), Evelina Children's Hospital, Guys and St Thomas' NHS Foundation Trust, London, UK.; Paediatric Neurosciences, Kings College London, London, UK.; UCL Great Ormond Street Institute of Child Health, University College London, London, UK.; Psychological and Mental Health Services, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.; De Bascule, Academic Centre for Child and Adolescent Psychiatry, Amsterdam, The Netherlands.; Yonsei Bom Clinic, Seoul, South Korea.; Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.; The Korea Institute for Children's Social Development, Rudolph Child Research Center, Seoul, South Korea.; Kangbuk Samsung Hospital, Seoul, South Korea.; Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.; Hospital Universitario Virgen del Rocío, Sevilla, Spain.; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.; Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic Universitari, Barcelona, Spain.; Department of Medicine, University of Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Barcelona, Spain.; Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.; Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.; Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.; Department of Child and Adolescent Psychiatry, Faculty of Medicine, University Hospital Carl Gustav CarusTU Dresden, Dresden, Germany.; National Health Insurance Service Ilsan Hospital, Goyang-Si, South Korea.
Bant logo

© Copyright 2026, Nutrition Evidence

NED wishes to thank the following organisations for their support:

We use cookies to improve your experience and analyze site traffic with Google Analytics. By continuing to use our site, you agree to our use of cookies. Learn more.