Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes

Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes (CELSR3, CHD8, SCUBE1 and WWC1) and four genes that overlap with OCD genome-wide association study loci (BRWD1, CELSR3, QRICH1 and SYNE1). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.

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Journal
Nature Neuroscience
Published
2026-09-01
DOI
https://doi.org/10.1038/s41593-026-02419-5
Primary Topic
Obsessive-Compulsive Spectrum Disorders
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article
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0.00

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article

Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes

Ástrid Morer, Guy A. Rouleau, Donald L. Gilbert, Helena Garrido et al.
Nature Neuroscience
Obsessive-Compulsive Spectrum Disorders
article

Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes

Ástrid Morer, Guy A. Rouleau, Donald L. Gilbert, Helena Garrido, Allison Libby, F Visscher, Isobel Heyman, Max A. Tischfield, Sara Sopeña, Dararat Mingbunjerdsuk, Susanne Walitza, Jessica Zakrzewski, Erik M. Elster, Nevan J. Krogan, Stephanie Garayalde, Joshua K. Thackray, Pieter J. Hoekstra, Lyvia Bertolace, Simon Schmitt, Samuel Kuperman, Mehdi Bouhaddou, Starlette Khim, Viviana A. Peskin, Keun‐Ah Cheon, Zsanett Tárnok, Jeanselle Dea, Hyun Ju Hong, Alyssa Rosen, BENNETT L. LEVENTHAL, Ryan J. McCarty, Holan Liang, Dana Feldman, Jennie M. Kuckertz, Kerry James Ressler, Veit Roessner, H J Simpson, Carol A. Mathews, Carolin Fremer, Young S. Kim, Samuel H. Zinner, Kate Bornais, Juliane Ball, H Martin, Allyna-London Howell, Tamar Steinberg, Catherine Paciotti, Michael H. Bloch, Carolin Sophie Klages, Marco Grados, Adam C. Frank, Maria Loreta Lopez, Meitar Timmor, Christina Kappler-Friedrichs, Nadine Kirchen, Ana Vigil-Perez, Anne Uhlmann, Emily Olfson, Denise Chavira, Danea Glover, Jinchuan Xing, Belinda Wang, Carolina Cappi, George Wang, Christopher Pittenger, Nawei Sun, Mindy M. Le, Yuting Liu, Robert A. King, Binh Nguyen, Matthew N. Tran, Lauren Oh, Ashley Ordway, Mary E. McNamara, Martha J. Falkenstein, Charles Ochieng' Olwal, Tourette International Collaborative Genetics (TIC Genetics), Rami Hatem, Tenzin Norbu, Daniel McNeil, Sheng Wang, Cara Nasello, Martin E. Franklin, Yi-Chieh Chang, Barbara J. Coffey, Andrea Dietrich, Euripedes C. Miguel, Kerstin J. Plessen, Tara L. Murphy, Alexander Münchau, Tammy Hedderly, Young Key Kim, Pablo Mir, Marieke Messchendorp, Chaim Huijser, Kirsten R. Müller-Vahl, Osman Malik, Heejoo Kim, Chitra Shukla, Laura Muñoz-Delgado, Noa Benaroya-Milshtein
article en

Abstract

Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes (CELSR3, CHD8, SCUBE1 and WWC1) and four genes that overlap with OCD genome-wide association study loci (BRWD1, CELSR3, QRICH1 and SYNE1). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.

Nature Neuroscience
Rutgers, The State University of New Jersey (US), Budapest University of Economics and Business (HU), Korea Development Institute (KR), University of Southern California (US), University of Iowa (US), Cincinnati Children's Hospital Medical Center (US), Montreal Neurological Institute and Hospital (CA), Gladstone Institutes (US), University Medical Center Groningen (NL), Children's Hospital of Philadelphia (US), Harvard University (US), Johns Hopkins University (US), University of Miami (US), University of California, Los Angeles (US), Tel Aviv University (IL), University of Groningen (NL), Universidade de São Paulo (BR), University of California, San Francisco (US), Baylor College of Medicine (US), King's College London (GB), Neurosciences Institute (US), Yonsei University (KR), Guy's and St Thomas' NHS Foundation Trust (GB), South London and Maudsley NHS Foundation Trust (GB), University of Washington (US), Thomas Jefferson University Hospital (US), Johns Hopkins Medicine (US), Severance Hospital (KR), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), University of Florida Health (US), Mental Health Services (DK), McLean Hospital (US), Instituto de Salud Carlos III (ES), Johnson University (US), Yale University (US), University of Florida (US), Medizinische Hochschule Hannover (DE), University of California San Diego (US), University of Chicago (US), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Centro de Investigación Biomédica en Red de Salud Mental (ES), Behavioral Pharma (United States) (US), Quantitative BioSciences (US), University Hospital of Zurich (CH), Business University of Costa Rica (CR), Seattle Children's Hospital (US), Schneider Children's Medical Center (IL), Rogers Behavioral Health (US), Centro de Investigación Biomédica en Red (ES), Accare (NL), Instituto de Biomedicina de Sevilla (ES), Asociación Psicoanalítica de Buenos Aires (AR), Evelina London Children's Healthcare (GB), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Capital Region of Denmark (DK), Fundação Faculdade de Medicina (BR), Admiraal De Ruyter Ziekenhuis (NL), Amsterdam University Medical Centers (NL), Hospital Universitario Virgen del Rocío (ES), Hallym University Sacred Heart Hospital (KR), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Yonsei University Health System (KR), Vadaskert Alapítvány a Gyermekek Lelki Egészségéért (HU), New York State Psychiatric Institute, University College London (GB), McGill University (CA), University of Rochester (US), Universitat de Barcelona (ES), Columbia University (US), Technische Universität Dresden (DE), Universidad de Sevilla (ES), The University of Texas at Austin (US), RWTH Aachen University (DE), University of Lübeck (DE), University of Lausanne (CH)
Yale University, Tourette Association of America, Deutsche Forschungsgemeinschaft, National Institutes of Health, Instituto de Salud Carlos III, National Institute of Mental Health
Openalex Percentile: Top 38%
Obsessive-Compulsive Spectrum Disorders
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