Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Fotis Tsetsos; Apostolia Topaloudi; Pritesh Jain; Zhiyu Yang; Dongmei Yu; Petros Kolovos; Zeynep Tumer; Renata Rizzo; Andreas Hartmann; Christel Depienne; Yulia Worbe; Kirsten R Müller-Vahl; Danielle C Cath; Dorret I Boomsma; Tomasz Wolanczyk; Cezary Zekanowski; Csaba Barta; Zsofia Nemoda; Zsanett Tarnok; Shanmukha S Padmanabhuni; Joseph D Buxbaum; Dorothy Grice; Jeffrey Glennon; Hreinn Stefansson; Bastian Hengerer; Evangelia Yannaki; John A Stamatoyannopoulos; Noa Benaroya-Milshtein; Francesco Cardona; Tammy Hedderly; Isobel Heyman; Chaim Huyser; Pablo Mir; Astrid Morer; Norbert Mueller; Alexander Munchau; Kerstin J Plessen; Cesare Porcelli; Veit Roessner; Susanne Walitza; Anette Schrag; Davide Martino; PGC TS Working Group; TSAICG; TSGeneSEE Initiative; EMTICS Collaborative Group; TS-EUROTRAIN Network; TIC Genetics Collaborative Group; Jay A Tischfield; Gary A Heiman; A Jeremy Willsey; Andrea Dietrich; Lea K Davis; James J Crowley; Carol A Mathews; Jeremiah M Scharf; Marianthi Georgitsi; Pieter J Hoekstra; Peristera Paschou

doi:10.1016/j.biopsych.2023.01.023

Genome-wide Association Study Points to Novel Locus for Gilles de la Tourette Syndrome

Biol Psychiatry. 2023 Feb 2:S0006-3223(23)00051-3. doi: 10.1016/j.biopsych.2023.01.023. Online ahead of print.

Authors

Fotis Tsetsos¹, Apostolia Topaloudi², Pritesh Jain², Zhiyu Yang², Dongmei Yu³, Petros Kolovos¹, Zeynep Tumer⁴, Renata Rizzo⁵, Andreas Hartmann⁶, Christel Depienne⁷, Yulia Worbe⁸, Kirsten R Müller-Vahl⁹, Danielle C Cath¹⁰, Dorret I Boomsma¹¹, Tomasz Wolanczyk¹², Cezary Zekanowski¹³, Csaba Barta¹⁴, Zsofia Nemoda¹⁴, Zsanett Tarnok¹⁵, Shanmukha S Padmanabhuni², Joseph D Buxbaum¹⁶, Dorothy Grice¹⁷, Jeffrey Glennon¹⁸, Hreinn Stefansson¹⁹, Bastian Hengerer²⁰, Evangelia Yannaki²¹, John A Stamatoyannopoulos²², Noa Benaroya-Milshtein²³, Francesco Cardona²⁴, Tammy Hedderly²⁵, Isobel Heyman²⁶, Chaim Huyser²⁷, Pablo Mir²⁸, Astrid Morer²⁹, Norbert Mueller³⁰, Alexander Munchau³¹, Kerstin J Plessen³², Cesare Porcelli³³, Veit Roessner³⁴, Susanne Walitza³⁵, Anette Schrag³⁶, Davide Martino³⁷; PGC TS Working Group; TSAICG; TSGeneSEE Initiative; EMTICS Collaborative Group; TS-EUROTRAIN Network; TIC Genetics Collaborative Group; Jay A Tischfield³⁸, Gary A Heiman³⁸, A Jeremy Willsey³⁹, Andrea Dietrich⁴⁰, Lea K Davis⁴¹, James J Crowley⁴², Carol A Mathews⁴³, Jeremiah M Scharf⁴⁴, Marianthi Georgitsi⁴⁵, Pieter J Hoekstra⁴⁶, Peristera Paschou⁴⁷

Collaborators

Cathy L Barr, James R Batterson, Cheston Berlin, Cathy L Budman, Giovanni Coppola, Nancy J Cox, Sabrina Darrow, 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, William M McMahon, Benjamin M Neale, Michael S Okun, Lisa Osiecki, Mary M Robertson, Guy A Rouleau, Paul Sandor, Harvey S Singer, Jan H Smit, Jae Hoon Sul, Christos Androutsos, Entela Basha, Luca Farkas, Jakub Fichna, Piotr Janik, Mira Kapisyzi, Iordanis Karagiannidis, Anastasia Koumoula, Peter Nagy, Joanna Puchala, Natalia Szejko, Urszula Szymanska, Vaia Tsironi, Alan Apter, Juliane Ball, Benjamin Bodmer, Emese Bognar, Judith Buse, Marta Correa Vela, Carolin Fremer, Blanca Garcia-Delgar, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Marcos Madruga-Garrido, Peter Nagy, Alessandra Pellico, Daphna Ruhrman, Jaana Schnell, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Friederike Tagwerker Gloor, Victoria L Turner, Elif Weidinger, John Alexander, Tamas Aranyi, Wim R Buisman, Jan K Buitelaar, Nicole Driessen, Petros Drineas, Siyan Fan, Natalie J Forde, Sarah Gerasch, Odile A van den Heuvel, Cathrine Jespersgaard, Ahmad S Kanaan, Harald E Möller, Muhammad S Nawaz, Ester Nespoli, Luca Pagliaroli, Geert Poelmans, Petra J W Pouwels, Francesca Rizzo, Dick J Veltman, Ysbrand D van der Werf, Joanna Widomska, Nuno R Zilhäo, Lawrence W Brown, Keun-Ah Cheon, Barbara J Coffey, Thomas V Fernandez, Blanca Garcia-Delgar, Donald L Gilbert, Julie Hagstrøm, Hyun Ju Hong, Laura Ibanez-Gomez, Eun-Joo Kim, Young Key Kim, Young-Shin Kim, Robert A King, Yun-Joo Koh, Sodahm Kook, Samuel Kuperman, Bennett L Leventhal, Marcos Madruga-Garrido, Athanasios Maras, Tara L Murphy, Eun-Young Shin, Dong-Ho Song, Jungeun Song, Matthew W State, Frank Visscher, Sheng Wang, Samuel H Zinner

Affiliations

¹ Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
² Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
³ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁴ Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵ Child and Adolescent Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
⁶ Department of Neurology, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁷ Institute for Human Genetics, University Hospital Essen, Essen, Germany.
⁸ Assistance Publique Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France; French Reference Centre for Gilles de la Tourette Syndrome, Sorbonne University, Faculty of Medicine, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
⁹ Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
¹⁰ Department of Clinical and Health Psychology, Utrecht University, Utrecht, Netherlands.
¹¹ Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany; EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, the Netherlands.
¹² Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
¹³ Department of Neurogenetics and Functional Genomics, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
¹⁴ Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis Egyetem, Budapest, Hungary.
¹⁵ Vadaskert Clinic for Child and Adolescent Psychiatry, Budapest, Hungary.
¹⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁷ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Tics, OCD, and Related Disorders, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁸ Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ deCODE Genetics, Amgen, Iceland.
²⁰ Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Research, Biberach, Germany.
²¹ Hematology Department, Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, George Papanikolaou Hospital, Thessaloniki, Greece; Department of Medicine, University of Washington, Seattle, Washington.
²² Altius Institute for Biomedical Sciences, Seattle, Washington; Department of Genome Sciences, University of Washington, Seattle, Washington; Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington.
²³ Child and Adolescent Psychiatry Department, Schneider Children's Medical Center of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
²⁴ Department of Human Neurosciences, University La Sapienza of Rome, Rome, Italy.
²⁵ Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
²⁶ Psychological Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
²⁷ Levvel Academic Center for Child and Adolescent Psychiatry, Amsterdam, the Netherlands; Amsterdam UMC, Department of Child and Adolescent Psychiatry, Amsterdam, the Netherlands.
²⁸ Unidad de Trastornos del Movimiento, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
²⁹ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; Centro de Investigacion en Red de Salud Mental, Instituto Carlos III, Madrid, Spain.
³⁰ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
³¹ Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany.
³² Child and Adolescent Mental Health Centre, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark; Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
³³ ASL BA, Maternal and Childood Department, Adolescence and Childhood Neuropsychiatry Unit, Bari, Italy.
³⁴ Department of Child and Adolescent Psychiatry, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.
³⁵ Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zürich, Zurich, Switzerland.
³⁶ Department of Clinical Neuroscience, UCL Institute of Neurology, University College London, London, UK.
³⁷ Department of Clinical Neurosciences, Cumming School of Medicine & Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
³⁸ Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, New Jersey.
³⁹ Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, California.
⁴⁰ University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, Groningen, the Netherlands.
⁴¹ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center Nashville, Nashville, Tennessee; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
⁴² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁴³ Department of Psychiatry and Genetics Institute, University of Florida College of Medicine, Gainesville, Florida.
⁴⁴ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
⁴⁵ 1st Laboratory of Medical Biology-Genetics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
⁴⁶ University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, Groningen, the Netherlands. Electronic address: p.hoekstra@accare.nl.
⁴⁷ Department of Biological Sciences, Purdue University, West Lafayette, Indiana. Electronic address: ppaschou@purdue.edu.

PMID: 36738982
PMCID: PMC10783199 (available on 2024-08-02)
DOI: 10.1016/j.biopsych.2023.01.023

Abstract

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year.

Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.

Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.

Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Keywords: GWAS; Meta-analysis; NR2F1; Tourette syndrome.

Abstract

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