Synaptic processes and immune-related pathways implicated in Tourette syndrome,Translational Psychiatry

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Synaptic processes and immune-related pathways implicated in Tourette syndrome
Translational Psychiatry ( IF 6.8 ) Pub Date : 2021-01-18 , DOI: 10.1038/s41398-020-01082-z
Fotis Tsetsos ₁ , Dongmei Yu _{2,

3} , Jae Hoon Sul _{4,

5} , Alden Y Huang _{4,

5,

6} , Cornelia Illmann ₂ , Lisa Osiecki ₂ , Sabrina M Darrow ₇ , Matthew E Hirschtritt ₇ , Erica Greenberg ₈ , Kirsten R Muller-Vahl ₉ , Manfred Stuhrmann ₁₀ , Yves Dion ₁₁ , Guy A Rouleau ₁₂ , Harald Aschauer _{13,

14} , Mara Stamenkovic ₁₃ , Monika Schlögelhofer ₁₄ , Paul Sandor ₁₅ , Cathy L Barr ₁₆ , Marco A Grados ₁₇ , Harvey S Singer ₁₇ , Markus M Nöthen ₁₈ , Johannes Hebebrand ₁₉ , Anke Hinney ₁₉ , Robert A King ₂₀ , Thomas V Fernandez ₂₀ , Csaba Barta ₂₁ , Zsanett Tarnok ₂₂ , Peter Nagy ₂₂ , Christel Depienne _{23,

24} , Yulia Worbe _{24,

25,

26,

27} , Andreas Hartmann _{24,

25,

26} , Cathy L Budman ₂₈ , Renata Rizzo ₂₉ , Gholson J Lyon ₃₀ , William M McMahon ₃₁ , James R Batterson ₃₂ , Danielle C Cath ₃₃ , Irene A Malaty ₃₄ , Michael S Okun ₃₄ , Cheston Berlin ₃₅ , Douglas W Woods ₃₆ , Paul C Lee ₃₇ , Joseph Jankovic ₃₈ , Mary M Robertson ₃₉ , Donald L Gilbert ₄₀ , Lawrence W Brown ₄₁ , Barbara J Coffey ₄₂ , Andrea Dietrich ₄₃ , Pieter J Hoekstra ₄₃ , Samuel Kuperman ₄₄ , Samuel H Zinner ₄₅ , Michael Wagner ₄₆ , James A Knowles ₄₇ , A Jeremy Willsey ₄₈ , Jay A Tischfield ₄₉ , Gary A Heiman ₄₉ , Nancy J Cox ₅₀ , Nelson B Freimer _{4,

5} , Benjamin M Neale _{2,

3,

51} , Lea K Davis ₅₀ , Giovanni Coppola _{4,

5} , Carol A Mathews ₅₂ , Jeremiah M Scharf _{2,

3,

53} , Peristera Paschou ₅₄ , , Cathy L Barr ₁₆ , James R Batterson ₃₂ , Cheston Berlin ₃₅ , Cathy L Budman ₂₈ , Danielle C Cath ₃₃ , Giovanni Coppola _{4,

5} , Nancy J Cox ₅₀ , Sabrina Darrow ₇ , Lea K Davis ₅₀ , Yves Dion ₁₁ , Nelson B Freimer _{4,

5} , Marco A Grados ₁₇ , Erica Greenberg ₈ , Matthew E Hirschtritt ₇ , Alden Y Huang _{4,

5,

6} , Cornelia Illmann ₂ , Robert A King ₂₀ , Roger Kurlan ₅₅ , James F Leckman ₅₆ , Gholson J Lyon ₃₀ , Irene A Malaty ₃₄ , Carol A Mathews ₅₂ , William M McMahon ₃₁ , Benjamin M Neale _{2,

3,

51} , Michael S Okun ₃₄ , Lisa Osiecki ₂ , Mary M Robertson ₃₉ , Guy A Rouleau ₁₂ , Paul Sandor ₁₅ , Jeremiah M Scharf _{2,

3,

53} , Harvey S Singer ₁₇ , Jan H Smit ₅₇ , Jae Hoon Sul _{4,

5} , Dongmei Yu _{2,

3} , , Harald Aschauer Harald Aschauer _{13,

14} , Csaba Barta ₂₁ , Cathy L Budman ₂₈ , Danielle C Cath ₃₃ , Christel Depienne _{23,

24} , Andreas Hartmann _{24,

25,

26} , Johannes Hebebrand ₁₉ , Anastasios Konstantinidis _{13,

58} , Carol A Mathews ₅₂ , Kirsten Müller-Vahl ₉ , Peter Nagy ₂₂ , Markus M Nöthen ₁₈ , Peristera Paschou ₅₄ , Renata Rizzo ₂₉ , Guy A Rouleau ₁₂ , Paul Sandor ₁₅ , Jeremiah M Scharf _{2,

3,

53} , Monika Schlögelhofer ₁₄ , Mara Stamenkovic ₁₃ , Manfred Stuhrmann ₁₀ , Fotis Tsetsos ₁ , Zsanett Tarnok ₂₂ , Tomasz Wolanczyk ₅₉ , Yulia Worbe _{24,

25,

26,

27} , , Lawrence Brown ₄₁ , Keun-Ah Cheon ₆₀ , Barbara J Coffey ₄₂ , Andrea Dietrich ₄₃ , Thomas V Fernandez ₂₀ , Blanca Garcia-Delgar ₆₁ , Donald Gilbert ₄₀ , Dorothy E Grice ₆₂ , Julie Hagstrøm ₆₃ , Tammy Hedderly _{64,

65} , Gary A Heiman ₄₉ , Isobel Heyman _{66,

67} , Pieter J Hoekstra ₄₃ , Chaim Huyser ₆₈ , Young Key Kim ₆₉ , Young-Shin Kim ₇₀ , Robert A King ₂₀ , Yun-Joo Koh ₇₁ , Sodahm Kook ₇₂ , Samuel Kuperman ₄₄ , Bennett L Leventhal ₇₀ , Marcos Madruga-Garrido ₇₃ , Pablo Mir _{74,

75} , Astrid Morer _{76,

77,

78} , Alexander Münchau ₇₉ , Kerstin J Plessen _{80,

81,

82} , Veit Roessner ₈₃ , Eun-Young Shin ₆₀ , Dong-Ho Song ₆₀ , Jungeun Song ₈₄ , Jay A Tischfield ₄₉ , A Jeremy Willsey ₄₈ , Samuel Zinner ₄₅ , , Harald Aschauer _{13,

14} , Cathy L Barr ₁₆ , Csaba Barta ₂₁ , James R Batterson ₃₂ , Cheston Berlin ₃₅ , Lawrence Brown ₄₁ , Cathy L Budman ₂₈ , Danielle C Cath ₃₃ , Barbara J Coffey ₄₂ , Giovanni Coppola _{4,

5} , Nancy J Cox ₅₀ , Sabrina Darrow ₇ , Lea K Davis ₅₀ , Christel Depienne _{23,

24} , Andrea Dietrich ₄₃ , Yves Dion ₁₁ , Thomas Fernandez ₂₀ , Nelson B Freimer _{4,

5} , Donald Gilbert ₄₀ , Marco A Grados ₁₇ , Erica Greenberg ₈ , Andreas Hartmann _{24,

25,

26} , Johannes Hebebrand ₁₉ , Gary Heiman ₄₉ , Matthew E Hirschtritt ₇ , Pieter Hoekstra ₄₃ , Alden Y Huang _{4,

5,

6} , Cornelia Illmann ₂ , Joseph Jankovic ₃₈ , Robert A King ₂₀ , Samuel Kuperman ₄₄ , Paul C Lee ₃₇ , Gholson J Lyon ₃₀ , Irene A Malaty ₃₄ , Carol A Mathews ₅₂ , William M McMahon ₃₁ , Kirsten Müller-Vahl ₉ , Peter Nagy ₂₂ , Benjamin M Neale _{2,

3,

51} , Markus M Nöthen ₁₈ , Michael S Okun ₃₄ , Lisa Osiecki ₂ , Peristera Paschou ₅₄ , Renata Rizzo ₂₉ , Mary M Robertson ₃₉ , Guy A Rouleau ₁₂ , Paul Sandor ₁₅ , Jeremiah M Scharf _{2,

3,

53} , Monika Schlögelhofer ₁₄ , Harvey S Singer ₁₇ , Mara Stamenkovic ₁₃ , Manfred Stuhrmann ₁₀ , Jae Hoon Sul _{4,

5} , Zsanett Tarnok ₂₂ , Jay Tischfield ₄₉ , Fotis Tsetsos ₁ , A Jeremy Willsey ₄₈ , Douglas Woods ₃₆ , Yulia Worbe _{24,

25,

26,

27} , Dongmei Yu _{2,

3} , Samuel Zinner ₄₅

Affiliation

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.
Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, 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.
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.
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.
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.
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.
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.
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.
Center for Mental Health Muldenstrasse, BBRZMed, Linz, Austria.
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.

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.

中文翻译：

抽动秽语综合症涉及的突触过程和免疫相关通路

抽动秽语综合症（TS）是一种神经精神疾病，其遗传结构复杂，涉及多个相互作用的基因。在这里，我们试图通过全基因组分析来阐明该疾病的神经生物学基础途径。我们分析了 3581 名 TS 个体和 7682 名血统匹配对照个体的全基因组基因型数据，并研究了 TS 与在特定细胞类型中表达并在特定神经元和神经胶质功能中发挥作用的基因组的关联。我们采用独立的基于集合的关联方法（SBA）以及使用个体水平基因型数据的竞争基因集方法（MAGMA）来对 TS 的生物学背景进行全面调查。我们的 SBA 分析在 Bonferroni 校正后确定了三个重要的基因集，涉及配体门控离子通道信号传导、淋巴细胞、细胞粘附和跨突触信号传导过程。MAGMA 分析进一步支持细胞粘附和跨突触信号基因集的参与。淋巴细胞基因集是由FLT3变异驱动的，提出了一个有趣的假设，即神经炎症元件参与 TS 发病机制。配体门控离子通道信号传导的参与表明强化了 GABA 在 TS 中的作用，而细胞粘附和跨突触信号传导基因组的关联为粘附分子在神经精神疾病中的作用提供了额外的支持。这项研究强化了之前的发现，但也为 TS 的神经生物学提供了新的见解。

更新日期：2021-01-18

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