Genome-Wide Association Analysis of Tic Disorders Reveals 6 Independent Risk Loci and Highlights Tic-Associated Cell Types and Brain Circuitry

Abstract Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3 , and CELSR3 . Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

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Journal
medRxiv
Published
2026-04-10
DOI
https://doi.org/10.64898/2026.04.09.26350245
Primary Topic
Obsessive-Compulsive Spectrum Disorders
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article
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article

Genome-Wide Association Analysis of Tic Disorders Reveals 6 Independent Risk Loci and Highlights Tic-Associated Cell Types and Brain Circuitry

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medRxiv
Obsessive-Compulsive Spectrum Disorders
article

Genome-Wide Association Analysis of Tic Disorders Reveals 6 Independent Risk Loci and Highlights Tic-Associated Cell Types and Brain Circuitry

Jeffrey Colm Glennon, Donald L. Gilbert, Valentina Baglioni, Isobel Heyman, Tyne W. Miller‐Fleming, Siyan Fan, Christel Depienne, Dararat Mingbunjerdsuk, Luis Diego Herrera-Amighetti, Marieke Messchendorp, J Kaprio, Erik M. Elster, M. Kapisyzi, Andreas Hartmann, Helga Ask, Nora I. Strom, Blanca García-Delgar, Cathy L. Budman, Cathrine Jespersgaard, Alexandra Havdahl, Laura Domènech, Daníel F. Guðbjartsson, Sudhanshu Shekhar, Judith Buse, Emily Gantz, Pieter J. Hoekstra, David A. Isaacs, Samuel Kuperman, Jakob Grove, Jakub Fichna, Thomas Fernandez, Jonas Bybjerg‐Grauholm, Iordanis Karagiannidis, Cathy L. Barr, Teemu Palviainen, Najah Khalifa, Piotr E. Janik, Ahmad S. Kanaan, Dana Feldman, Marco A. Grados, Yun‐Joo Koh, Csaba Barta, Noa Benaroya-Milshtein, Hyun Ju Hong, Anastasia Koumoula, BENNETT L. LEVENTHAL, Matthew Halvorsen, P. Mir, Francesco Cardona, Natalie J. Forde, Christos Androutsos, Larisa H. Cavallari, Holan Liang, Danea Glover, Ábel Fóthi, Fortu Benarroch, Dorret Irene Boomsma, Bastian Hengerer, Niklas Dahl, Petros Drineas, Keun-Ah Anna Cheon, Behrang Mahjani, Christine Löchner, Zachary F. Gerring, Elizabeth C. Corfield, Andrea Dietrich, Franjo Ivankovic, Guðmundur Einarsson, Marianthi Georgitsi, Carolin Fremer, Young S. Kim, J. Buitelaar, Alden Huang, William M. McMahon, Marcos Madruga-Garrido, Juliane Ball, T. Hedderly, Entela BASHA, James R. Batterson, Luz M Porras, Carolin Sophie Klages, Anders Borglum, Dongmei Yu, Alan Apter, Danielle C. Cath, Apostolia Topaloudi, James F. Leckman, Chaim Huijser, Maria Loreta Lopez, Robert A. King, Christina Kappler-Friedrichs, Sandra Melanie Meier, Osman Malik, Seulgi Jung, Erica L. Greenberg, Nadine Kirchen, Joseph Jankovic, Irene A. Malaty, Barbara J. Coffey
article en

Abstract

Abstract Tourette Syndrome and other tic disorders (TD) are common, highly heritable neurodevelopmental conditions with complex genetic architectures. We conducted a genome-wide association study of 13,247 TD cases and 536,217 European ancestry controls and identified six independent genome-wide significant loci, including a pleiotropic signal at 3p21 shared with attention-deficit/hyperactivity disorder, among other traits. Gene prioritization highlighted 20 genes, including PCDH9, HCN1, NCKIPSD, WDR6, DALRD3 , and CELSR3 . Integrative analyses provide genetic support for the role of cortico-striato-thalamo-cortical circuits in TD pathophysiology and further localize TD genetic risk to specific cell types, including dopamine D1- and D2-receptor-positive medium spiny neurons, cortical pyramidal neurons, and oligodendrocyte-lineage cells. We further demonstrate extensive genetic correlations with neurodevelopmental and psychiatric traits, but not with neurological disorders. These findings advance our understanding of the genetic basis of TD, pinpointing specific genes and cell types that drive pathophysiology and providing a foundation for future mechanistic studies.

medRxiv
University College Dublin (IE), Semmelweis University (HU), Statens Serum Institut (DK), Broad Institute (US), South African Medical Research Council (ZA), University of North Carolina at Chapel Hill (US), Uppsala University (SE), University of North Texas (US), University of Iowa (US), Cincinnati Children's Hospital Medical Center (US), Netherlands Institute for Neuroscience (NL), Dalhousie University (CA), Monroe Carell Jr. Children's Hospital (US), Northwell Health (US), University Health Network (CA), deCODE Genetics (Iceland) (IS), Children's Mercy Hospital (US), Boehringer Ingelheim (Germany) (DE), Norwegian Institute of Public Health (NO), University Medical Center Groningen (NL), Children's Hospital of Philadelphia (US), University of Helsinki (FI), Johns Hopkins University (US), University of Miami (US), Radboud University Nijmegen (NL), Democritus University of Thrace (GR), University of California, Los Angeles (US), Tel Aviv University (IL), University of North Texas Health Science Center (US), The University of Melbourne (AU), University of Groningen (NL), Baylor College of Medicine (US), University of Oslo (NO), University of Toronto (CA), American Academy of Child and Adolescent Psychiatry (US), Yonsei University (KR), Walter and Eliza Hall Institute of Medical Research (AU), South London and Maudsley NHS Foundation Trust (GB), Aarhus University (DK), QIMR Berghofer Medical Research Institute (AU), Purdue University West Lafayette (US), University of Utah (US), University of Cambridge (GB), Stellenbosch University (ZA), Medical University of Warsaw (PL), North East London NHS Foundation Trust (GB), Johns Hopkins Medicine (US), Hadassah Medical Center (IL), Severance Hospital (KR), Great Ormond Street Hospital (GB), Mother Teresa Hospital (AL), Sismanoglio General Hospital (GR), Huntsman Cancer Institute (US), Hospital for Sick Children (CA), Instituto de Salud Carlos III (ES), Copenhagen University Hospital (DK), Radboud University Medical Center (NL), University of Alabama at Birmingham (US), Yale University (US), University of Florida (US), Medizinische Hochschule Hannover (DE), University of Bristol (GB), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Hospital San Juan de la Cruz (ES), Massachusetts General Hospital (US), Cambridge School (PT), Bridge University (SS), GGZ Drenthe (NL), Pediatric Nephrology of Alabama (US), University Hospital of Zurich (CH), Dell Children's Medical Center of Central Texas (US), Institute of Biochemistry (HU), Lovisenberg Diakonale Høgskole (NO), NeuroDevelopment Center (US), Seattle Children's Hospital (US), Schneider Children's Medical Center (IL), Dialyse Centrum Groningen (NL), Michigan Institute for Neurological Disorders (US), Kings Health Partners (GB), Brain (Germany) (DE), Centro de Investigación Biomédica en Red (ES), Institute of Human Genetics (PL), Accare (NL), Pitié-Salpêtrière Hospital (FR), Lundbeck Foundation (DK), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Institute for Molecular Medicine Finland (FI), Instituto de Biomedicina de Sevilla (ES), Stockholm Health Care Services (SE), SickKids Foundation (CA), Lovisenberg Diakonale Sykehus (NO), Evelina London Children's Healthcare (GB), Hospital Universitari de Vic (ES), DELL (United States) (US), Hospital Metropolitano (EC), Child Development Center (QA), Amsterdam University Medical Centers (NL), Hospital Universitario Virgen del Rocío (ES), Mossakowski Medical Research Institute, Polish Academy of Sciences (PL), Hallym University Sacred Heart Hospital (KR), Cognitive Research (United States) (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University College London (GB), University of Duisburg-Essen (DE), University of Missouri–Kansas City (US), Technische Universität Dresden (DE), Universidad de Sevilla (ES), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Sapienza University of Rome (IT), The University of Texas at Austin (US), Vanderbilt University Medical Center (US), Florida College (US), Icahn School of Medicine at Mount Sinai (US)
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