. 2021 Jan 18;11(1):56.

doi: 10.1038/s41398-020-01082-z.

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Fotis Tsetsos¹, Dongmei Yu^{2

3}, Jae Hoon Sul^{4

5}, Alden Y Huang^{4

5

6}, Cornelia Illmann², Lisa Osiecki², Sabrina M Darrow⁷, Matthew E Hirschtritt⁷, Erica Greenberg⁸, Kirsten R Muller-Vahl⁹, Manfred Stuhrmann¹⁰, Yves Dion¹¹, Guy A Rouleau¹², Harald Aschauer^{13

14}, Mara Stamenkovic¹³, Monika Schlögelhofer¹⁴, Paul Sandor¹⁵, Cathy L Barr¹⁶, Marco A Grados¹⁷, Harvey S Singer¹⁷, Markus M Nöthen¹⁸, Johannes Hebebrand¹⁹, Anke Hinney¹⁹, Robert A King²⁰, Thomas V Fernandez²⁰, Csaba Barta²¹, Zsanett Tarnok²², Peter Nagy²², Christel Depienne^{23

24}, Yulia Worbe^{24

25

26

27}, Andreas Hartmann^{24

25

26}, Cathy L Budman²⁸, Renata Rizzo²⁹, Gholson J Lyon³⁰, William M McMahon³¹, James R Batterson³², Danielle C Cath³³, Irene A Malaty³⁴, Michael S Okun³⁴, Cheston Berlin³⁵, Douglas W Woods³⁶, Paul C Lee³⁷, Joseph Jankovic³⁸, Mary M Robertson³⁹, Donald L Gilbert⁴⁰, Lawrence W Brown⁴¹, Barbara J Coffey⁴², Andrea Dietrich⁴³, Pieter J Hoekstra⁴³, Samuel Kuperman⁴⁴, Samuel H Zinner⁴⁵, Michael Wagner⁴⁶, James A Knowles⁴⁷, A Jeremy Willsey⁴⁸, Jay A Tischfield⁴⁹, Gary A Heiman⁴⁹, Nancy J Cox⁵⁰, Nelson B Freimer^{4

5}, Benjamin M Neale^{2

3

51}, Lea K Davis⁵⁰, Giovanni Coppola^{4

5}, Carol A Mathews⁵², Jeremiah M Scharf^{2

3

53}, Peristera Paschou⁵⁴; Tourette Association of America International Consortium for Genetics; Cathy L Barr¹⁶, James R Batterson³², Cheston Berlin³⁵, Cathy L Budman²⁸, Danielle C Cath³³, Giovanni Coppola^{4

5}, Nancy J Cox⁵⁰, Sabrina Darrow⁷, Lea K Davis⁵⁰, Yves Dion¹¹, Nelson B Freimer^{4

5}, Marco A Grados¹⁷, Erica Greenberg⁸, Matthew E Hirschtritt⁷, Alden Y Huang^{4

5

6}, Cornelia Illmann², Robert A King²⁰, Roger Kurlan⁵⁵, James F Leckman⁵⁶, Gholson J Lyon³⁰, Irene A Malaty³⁴, Carol A Mathews⁵², William M McMahon³¹, Benjamin M Neale^{2

3

51}, Michael S Okun³⁴, Lisa Osiecki², Mary M Robertson³⁹, Guy A Rouleau¹², Paul Sandor¹⁵, Jeremiah M Scharf^{2

3

53}, Harvey S Singer¹⁷, Jan H Smit⁵⁷, Jae Hoon Sul^{4

5}, Dongmei Yu^{2

3}; Gilles de la Tourette GWAS Replication Initiative; Harald Aschauer Harald Aschauer^{13

14}, Csaba Barta²¹, Cathy L Budman²⁸, Danielle C Cath³³, Christel Depienne^{23

24}, Andreas Hartmann^{24

25

26}, Johannes Hebebrand¹⁹, Anastasios Konstantinidis^{13

58}, Carol A Mathews⁵², Kirsten Müller-Vahl⁹, Peter Nagy²², Markus M Nöthen¹⁸, Peristera Paschou⁵⁹, Renata Rizzo²⁹, Guy A Rouleau¹², Paul Sandor¹⁵, Jeremiah M Scharf^{2

3

53}, Monika Schlögelhofer¹⁴, Mara Stamenkovic¹³, Manfred Stuhrmann¹⁰, Fotis Tsetsos¹, Zsanett Tarnok²², Tomasz Wolanczyk⁶⁰, Yulia Worbe^{24

25

26

27}; Tourette International Collaborative Genetics Study; Lawrence Brown⁴¹, Keun-Ah Cheon⁶¹, Barbara J Coffey⁴², Andrea Dietrich⁴³, Thomas V Fernandez²⁰, Blanca Garcia-Delgar⁶², Donald Gilbert⁴⁰, Dorothy E Grice⁶³, Julie Hagstrøm⁶⁴, Tammy Hedderly^{65

66}, Gary A Heiman⁴⁹, Isobel Heyman^{67

68}, Pieter J Hoekstra⁴³, Chaim Huyser⁶⁹, Young Key Kim⁷⁰, Young-Shin Kim⁷¹, Robert A King²⁰, Yun-Joo Koh⁷², Sodahm Kook⁷³, Samuel Kuperman⁴⁴, Bennett L Leventhal⁷¹, Marcos Madruga-Garrido⁷⁴, Pablo Mir^{75

76}, Astrid Morer^{77

78

79}, Alexander Münchau⁸⁰, Kerstin J Plessen^{81

82

83}, Veit Roessner⁸⁴, Eun-Young Shin⁶¹, Dong-Ho Song⁶¹, Jungeun Song⁸⁵, Jay A Tischfield⁴⁹, A Jeremy Willsey⁴⁸, Samuel Zinner⁴⁵; Psychiatric Genomics Consortium Tourette Syndrome Working Group; Harald Aschauer^{13

14}, Cathy L Barr¹⁶, Csaba Barta²¹, James R Batterson³², Cheston Berlin³⁵, Lawrence Brown⁴¹, Cathy L Budman²⁸, Danielle C Cath³³, Barbara J Coffey⁴², Giovanni Coppola^{4

5}, Nancy J Cox⁵⁰, Sabrina Darrow⁷, Lea K Davis⁵⁰, Christel Depienne^{23

24}, Andrea Dietrich⁴³, Yves Dion¹¹, Thomas Fernandez²⁰, Nelson B Freimer^{4

5}, Donald Gilbert⁴⁰, Marco A Grados¹⁷, Erica Greenberg⁸, Andreas Hartmann^{24

25

26}, Johannes Hebebrand¹⁹, Gary Heiman⁴⁹, Matthew E Hirschtritt⁷, Pieter Hoekstra⁴³, Alden Y Huang^{4

5

6}, Cornelia Illmann², Joseph Jankovic³⁸, Robert A King²⁰, Samuel Kuperman⁴⁴, Paul C Lee³⁷, Gholson J Lyon³⁰, Irene A Malaty³⁴, Carol A Mathews⁵², William M McMahon³¹, Kirsten Müller-Vahl⁹, Peter Nagy²², Benjamin M Neale^{2

3

51}, Markus M Nöthen¹⁸, Michael S Okun³⁴, Lisa Osiecki², Peristera Paschou⁵⁹, Renata Rizzo²⁹, Mary M Robertson³⁹, Guy A Rouleau¹², Paul Sandor¹⁵, Jeremiah M Scharf^{2

3

53}, Monika Schlögelhofer¹⁴, Harvey S Singer¹⁷, Mara Stamenkovic¹³, Manfred Stuhrmann¹⁰, Jae Hoon Sul^{4

5}, Zsanett Tarnok²², Jay Tischfield⁴⁹, Fotis Tsetsos¹, A Jeremy Willsey⁴⁸, Douglas Woods³⁶, Yulia Worbe^{24

25

26

27}, Dongmei Yu^{2

3}, Samuel Zinner⁴⁵

Affiliations

¹ Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
² Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
⁶ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
⁷ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁸ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁹ Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany.
¹⁰ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
¹¹ McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal, Canada.
¹² Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
¹³ Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
¹⁴ Biopsychosocial Corporation, Vienna, Austria.
¹⁵ University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto, Canada.
¹⁶ Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto, Canada.
¹⁷ Johns Hopkins University School of Medicine and the Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁸ Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany.
¹⁹ Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁰ Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
²¹ Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
²² Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.
²³ Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁴ Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.
²⁵ French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
²⁶ Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
²⁷ Assistance Publique Hôpitaux de Paris, Hopital Saint Antoine, Paris, France.
²⁸ Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁹ Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
³⁰ Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, NY, USA.
³¹ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
³² Children's Mercy Hospital, Kansas City, MO, USA.
³³ Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands.
³⁴ Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA.
³⁵ Pennsylvania State University College of Medicine, Hershey, PA, USA.
³⁶ Marquette University and University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
³⁷ Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA.
³⁸ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
³⁹ Division of Psychiatry, Department of Neuropsychiatry, University College London, London, UK.
⁴⁰ Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, Cincinnati, USA.
⁴¹ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴² Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴³ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴⁴ University of Iowa Carver College of Medicine, Iowa City, IA, USA.
⁴⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁴⁶ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
⁴⁷ SUNY Downstate Medical Center Brooklyn, Brooklyn, NY, USA.
⁴⁸ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
⁴⁹ Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
⁵⁰ Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵² Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA.
⁵³ Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁵⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA. ppaschou@gmail.com.
⁵⁵ Atlantic Neuroscience Institute, Overlook Hospital, Summit, NJ, USA.
⁵⁶ Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
⁵⁷ Department of Psychiatry, VU UniversityMedical Center, Amsterdam, The Netherlands.
⁵⁸ Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria.
⁵⁹ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
⁶⁰ Department of Child Psychiatry, Medical University of Warsaw, 00-001, Warsaw, Poland.
⁶¹ Yonsei University College of Medicine, Yonsei Yoo & Kim Mental Health Clinic, Seoul, South Korea.
⁶² Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
⁶³ Department of Psychiatry, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁴ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.
⁶⁵ Tic and Neurodevelopmental Movements Service (TANDeM), Evelina Children's Hospital, Guys and St Thomas' NHS Foundation Trust, London, UK.
⁶⁶ Paediatric Neurosciences, Kings College London, London, UK.
⁶⁷ UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶⁸ Psychological and Mental Health Services, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁶⁹ De Bascule, Academic Centre for Child and Adolescent Psychiatry, Amsterdam, The Netherlands.
⁷⁰ Yonsei Bom Clinic, Seoul, South Korea.
⁷¹ Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
⁷² The Korea Institute for Children's Social Development, Rudolph Child Research Center, Seoul, South Korea.
⁷³ Kangbuk Samsung Hospital, Seoul, South Korea.
⁷⁴ Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
⁷⁵ Hospital Universitario Virgen del Rocío, Sevilla, Spain.
⁷⁶ Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
⁷⁷ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic Universitari, Barcelona, Spain.
⁷⁸ Department of Medicine, University of Barcelona, Barcelona, Spain.
⁷⁹ Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Barcelona, Spain.
⁸⁰ Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
⁸¹ Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.
⁸² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁸³ Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
⁸⁴ Department of Child and Adolescent Psychiatry, Faculty of Medicine, University Hospital Carl Gustav CarusTU Dresden, Dresden, Germany.
⁸⁵ National Health Insurance Service Ilsan Hospital, Goyang-Si, South Korea.

PMID: 33462189
PMCID: PMC7814139
DOI: 10.1038/s41398-020-01082-z

Synaptic processes and immune-related pathways implicated in Tourette syndrome

Fotis Tsetsos et al. Transl Psychiatry. 2021.

. 2021 Jan 18;11(1):56.

doi: 10.1038/s41398-020-01082-z.

Authors

Affiliations

¹ Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
² Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁵ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
⁶ Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
⁷ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁸ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁹ Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany.
¹⁰ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
¹¹ McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal, Canada.
¹² Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada.
¹³ Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
¹⁴ Biopsychosocial Corporation, Vienna, Austria.
¹⁵ University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto, Canada.
¹⁶ Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto, Canada.
¹⁷ Johns Hopkins University School of Medicine and the Kennedy Krieger Institute, Baltimore, MD, USA.
¹⁸ Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany.
¹⁹ Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁰ Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
²¹ Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
²² Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.
²³ Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁴ Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.
²⁵ French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
²⁶ Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
²⁷ Assistance Publique Hôpitaux de Paris, Hopital Saint Antoine, Paris, France.
²⁸ Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
²⁹ Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
³⁰ Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, NY, USA.
³¹ Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
³² Children's Mercy Hospital, Kansas City, MO, USA.
³³ Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands.
³⁴ Department of Neurology, Norman Fixel Institute for Neurological Diseases, University of Florida Health, Gainesville, FL, USA.
³⁵ Pennsylvania State University College of Medicine, Hershey, PA, USA.
³⁶ Marquette University and University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
³⁷ Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA.
³⁸ Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
³⁹ Division of Psychiatry, Department of Neuropsychiatry, University College London, London, UK.
⁴⁰ Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center; Department of Pediatrics, University of Cincinnati, Cincinnati, USA.
⁴¹ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁴² Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
⁴³ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴⁴ University of Iowa Carver College of Medicine, Iowa City, IA, USA.
⁴⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
⁴⁶ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany.
⁴⁷ SUNY Downstate Medical Center Brooklyn, Brooklyn, NY, USA.
⁴⁸ Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
⁴⁹ Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
⁵⁰ Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵² Department of Psychiatry, Genetics Institute, University of Florida, Gainesville, FL, USA.
⁵³ Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁵⁴ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA. ppaschou@gmail.com.
⁵⁵ Atlantic Neuroscience Institute, Overlook Hospital, Summit, NJ, USA.
⁵⁶ Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
⁵⁷ Department of Psychiatry, VU UniversityMedical Center, Amsterdam, The Netherlands.
⁵⁸ Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria.
⁵⁹ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
⁶⁰ Department of Child Psychiatry, Medical University of Warsaw, 00-001, Warsaw, Poland.
⁶¹ Yonsei University College of Medicine, Yonsei Yoo & Kim Mental Health Clinic, Seoul, South Korea.
⁶² Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
⁶³ Department of Psychiatry, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁴ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.
⁶⁵ Tic and Neurodevelopmental Movements Service (TANDeM), Evelina Children's Hospital, Guys and St Thomas' NHS Foundation Trust, London, UK.
⁶⁶ Paediatric Neurosciences, Kings College London, London, UK.
⁶⁷ UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶⁸ Psychological and Mental Health Services, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁶⁹ De Bascule, Academic Centre for Child and Adolescent Psychiatry, Amsterdam, The Netherlands.
⁷⁰ Yonsei Bom Clinic, Seoul, South Korea.
⁷¹ Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
⁷² The Korea Institute for Children's Social Development, Rudolph Child Research Center, Seoul, South Korea.
⁷³ Kangbuk Samsung Hospital, Seoul, South Korea.
⁷⁴ Sección de Neuropediatría, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
⁷⁵ Hospital Universitario Virgen del Rocío, Sevilla, Spain.
⁷⁶ Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
⁷⁷ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic Universitari, Barcelona, Spain.
⁷⁸ Department of Medicine, University of Barcelona, Barcelona, Spain.
⁷⁹ Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Barcelona, Spain.
⁸⁰ Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
⁸¹ Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.
⁸² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁸³ Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
⁸⁴ Department of Child and Adolescent Psychiatry, Faculty of Medicine, University Hospital Carl Gustav CarusTU Dresden, Dresden, Germany.
⁸⁵ National Health Insurance Service Ilsan Hospital, Goyang-Si, South Korea.

PMID: 33462189
PMCID: PMC7814139
DOI: 10.1038/s41398-020-01082-z

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.

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Conflict of interest statement

I.M. has participated in research funded by the Parkinson Foundation, Tourette Association, Dystonia Coalition, AbbVie, Biogen, Boston Scientific, Eli Lilly, Impax, Neuroderm, Prilenia, Revance, Teva but has no owner interest in any pharmaceutical company. She has received travel compensation or honoraria from the Tourette Association of America, Parkinson Foundation, International Association of Parkinsonism and Related Disorders, Medscape, and Cleveland Clinic, and royalties for writing a book with Robert rose publishers. K.M.V. has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kroner-Fresenius-Stiftung, and GW, Almirall, Abide Therapeutics, and Therapix Biosiences and has received consultant’s honoraria from Abide Therapeutics, Tilray, Resalo Vertrieb GmbH, and Wayland Group, speaker’s fees from Tilray and Cogitando GmbH, and royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer; and is a consultant for Nuvelution TS Pharma Inc., Zynerba Pharmaceuticals, Resalo Vertrieb GmbH, CannaXan GmbH, Therapix Biosiences, Syqe, Nomovo Pharma, and Columbia Care. B.M.N. is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. M.M.N. has received fees for memberships in Scientific Advisory Boards from the Lundbeck Foundation and the Robert-Bosch-Stiftung, and for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt. M.M.N. was reimbursed travel expenses for a conference participation by Shire Deutschland GmbH. M.M.N. receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All this concerned activities outside the submitted work. M.S.O. serves as a consultant for the Parkinson’s Foundation, and has received research grants from NIH, Parkinson’s Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. M.S.O.’s DBS research is supported by NIH R01 NR014852 and R01NS096008. M.S.O. is PI of the NIH R25NS108939 Training Grant. M.S.O. has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). M.S.O. is an associate editor for New England Journal of Medicine Journal Watch Neurology. M.S.O. has participated in CME and educational activities on movement disorders sponsored by the Academy for Healthcare Learning, PeerView, Prime, QuantiaMD, WebMD/Medscape, Medicus, MedNet, Einstein, MedNet, Henry Stewart, American Academy of Neurology, Movement Disorders Society, and by Vanderbilt University. The institution and not M.S.O. receives grants from Medtronic, Abbvie, Boston Scientific, Abbott and Allergan and the PI has no financial interest in these grants. M.S.O. has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations. D.W. receives royalties for books on Tourette Syndrome with Guilford Press, Oxford University Press, and Springer Press. The rest of the authors declare that they have no conflict of interest.

Figures

**Fig. 1. Results of gene set analysis as implemented by MAGMA.**
The gene set that crossed the significance threshold is depicted in red.

**Fig. 2. Results of gene set analysis as implemented by SBA.**
The gene sets that crossed the significance threshold are depicted in red.

See this image and copyright information in PMC

References

1. Robertson MM, Cavanna AE, Eapen V. Gilles de la Tourette syndrome and disruptive behavior disorders: prevalence, associations, and explanation of the relationships. J. Neuropsychiatry Clin. Neurosci. 2015;27:33–41. doi: 10.1176/appi.neuropsych.13050112. - DOI - PubMed
1. Scharf JM, et al. Population prevalence of Tourette syndrome: a systematic review and meta-analysis. Mov. Disord. 2015;30:221–228. doi: 10.1002/mds.26089. - DOI - PubMed
1. Robertson MM, Eapen V, Cavanna AE. he international prevalence, epidemiology, and clinical phenomenology of Tourette syndrome: a cross-cultural perspective. J. Psychosom. Res. 2009;67:475–483. doi: 10.1016/j.jpsychores.2009.07.010. - DOI - PubMed
1. Davis, L. K. Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genetics9, e1003864 (2013). - PMC - PubMed
1. Robertson MM. Gilles de la Tourette syndrome. Nat. Rev. Dis. Prim. 2017;3:16097. doi: 10.1038/nrdp.2016.97. - DOI - PubMed

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Synaptic processes and immune-related pathways implicated in Tourette syndrome

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Synaptic processes and immune-related pathways implicated in Tourette syndrome

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