Peer-reviewedCC BY 4.0Nature Neuroscience
Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes
40 affiliations
- 1Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA USA
- 2Department of Neuroscience, Yale School of Medicine, New Haven, CT USA
- 3Child Study Center, Yale University School of Medicine, New Haven, CT USA
- 4Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA USA
- 5Department of Psychiatry, University of Rochester, Rochester, NY USA
- 6Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, NJ USA
- 7Center for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL USA
- 8Department of Psychology, University of California, Los Angeles, CA USA
- 9Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL USA
- 10OCD Institute, McLean Hospital, Belmont, MA USA
- 11Department of Psychiatry, Harvard Medical School, Boston, MA USA
- 12Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA USA
- 13Rogers Behavioral Health, Philadelphia, PA USA
- 14Private practice, San Jose, Costa Rica
- 15Department of Psychiatry and Behavioral Sciences, Child and Adolescent Psychiatry, Johns Hopkins University, Baltimore, MD USA
- 16Department of Psychiatry and Human Behavior, Thomas Jefferson University Hospital, Philadelphia, PA USA
- 17Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX USA
- 18Departamento de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil
- 19Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ USA
- 20Asociación de Psiquiatras de Argentina, Buenos Aires, Argentina
- 21Department of Psychiatry, Yale University School of Medicine, New Haven, CT USA
- 22Department of Neuroscience, Yale University School of Medicine, New Haven, CT USA
- 23Department of Psychology, Yale University Graduate School of Arts and Sciences, New Haven, CT USA
- 24Center for Brain and Mind Health, Yale University School of Medicine, New Haven, CT USA
- 25Wu-Tsai Institute, Yale University, New Haven, CT USA
- 26Department of Psychiatry, Columbia University, New York, NY USA
- 27Center for OCD and Related Disorders, New York State Psychiatric Institute, New York, NY USA
- 28UF Health Rehab Center, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL USA
- 29Department of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, NJ USA
- 30Child Health Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ USA
- 31Department of Psychiatry, University of California, San Diego, CA USA
- 32University Hospital of Psychiatry Zurich, Child and Adolescent Psychiatry and Psychotherapy, Zurich, Switzerland
- 33Department of Child Psychiatry, Feinberg Child Study Center, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
- 34Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- 35Department of Human Genetics, McGill University, Montreal, Québec Canada
- 36Yonsei University College of Medicine, Severance Hospital, Seoul, South Korea
- 37Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Dresden, Germany
- 38Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany
- 39Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
- 40School of Life Sciences and Medicine, King’s College London, London, UK
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.
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BibTeX
@article{wang2026wholeexome,
title = {{Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes}},
author = {Belinda Wang and Matthew N. Tran and Sheng Wang and Yuting Liu and Emily Olfson and George Wang and Nawei Sun and Jeanselle Dea and Charles Ochieng’ Olwal and Lyvia Bertolace and Michael H. Bloch and Carolina Cappi and Yi-Chieh Chang and Denise Chavira and Barbara J. Coffey and Martha J. Falkenstein and Adam C. Frank and Martin E. Franklin and Stephanie Garayalde and Helena Garrido and Marco Grados and Rami Hatem and Allyna-London Howell and Starlette Khim and Jennie M. Kuckertz and Mindy M. Le and Allison Libby and Ryan J. McCarty and Mary E. McNamara and Daniel McNeil and Euripedes C. Miguel and Cara Nasello and Binh Nguyen and Tenzin Norbu and Lauren Oh and Ashley Ordway and Catherine Paciotti and Viviana A. Peskin and Christopher Pittenger and Helen Blair Simpson and Heather Simpson Martin and Max A. Tischfield and Jinchuan Xing and Jessica J. Zakrzewski and Belinda Wang and Belinda Wang and Sheng Wang and Barbara J. Coffey and Cara Nasello and Max A. Tischfield and Jinchuan Xing and Juliane Ball and Noa Benaroya-Milshtein and Kate Bornais and Keun-Ah Cheon and Erik M. Elster and Dana Feldman and Carolin Fremer and Danea Glover and Tammy Hedderly},
journal = {Nature Neuroscience},
year = {2026},
month = sep,
doi = {10.1038/s41593-026-02419-5},
url = {https://doi.org/10.1038/s41593-026-02419-5},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Whole-exome sequencing in individuals with obsessive–compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes
AU - Belinda Wang
AU - Matthew N. Tran
AU - Sheng Wang
AU - Yuting Liu
AU - Emily Olfson
AU - George Wang
AU - Nawei Sun
AU - Jeanselle Dea
AU - Charles Ochieng’ Olwal
AU - Lyvia Bertolace
AU - Michael H. Bloch
AU - Carolina Cappi
AU - Yi-Chieh Chang
AU - Denise Chavira
AU - Barbara J. Coffey
AU - Martha J. Falkenstein
AU - Adam C. Frank
AU - Martin E. Franklin
AU - Stephanie Garayalde
AU - Helena Garrido
AU - Marco Grados
AU - Rami Hatem
AU - Allyna-London Howell
AU - Starlette Khim
AU - Jennie M. Kuckertz
AU - Mindy M. Le
AU - Allison Libby
AU - Ryan J. McCarty
AU - Mary E. McNamara
AU - Daniel McNeil
AU - Euripedes C. Miguel
AU - Cara Nasello
AU - Binh Nguyen
AU - Tenzin Norbu
AU - Lauren Oh
AU - Ashley Ordway
AU - Catherine Paciotti
AU - Viviana A. Peskin
AU - Christopher Pittenger
AU - Helen Blair Simpson
AU - Heather Simpson Martin
AU - Max A. Tischfield
AU - Jinchuan Xing
AU - Jessica J. Zakrzewski
AU - Belinda Wang
AU - Belinda Wang
AU - Sheng Wang
AU - Barbara J. Coffey
AU - Cara Nasello
AU - Max A. Tischfield
AU - Jinchuan Xing
AU - Juliane Ball
AU - Noa Benaroya-Milshtein
AU - Kate Bornais
AU - Keun-Ah Cheon
AU - Erik M. Elster
AU - Dana Feldman
AU - Carolin Fremer
AU - Danea Glover
AU - Tammy Hedderly
PY - 2026
DA - 2026/09/01
JO - Nature Neuroscience
DO - 10.1038/s41593-026-02419-5
UR - https://doi.org/10.1038/s41593-026-02419-5
AB - 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.
SN - 1097-6256
SN - 1546-1726
ER -