Journal article
Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes
Nature neuroscience
09/01/2026
DOI: 10.1038/s41593-026-02419-5
PMID: 42680906
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.
Details
- Title: Subtitle
- Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes
- Creators
- Belinda Wang - University of California, San FranciscoMatthew N Tran - University of California, San FranciscoSheng Wang - University of California, San FranciscoYuting Liu - Yale UniversityEmily Olfson - Yale UniversityGeorge Wang - University of California, San FranciscoNawei Sun - University of California, San FranciscoJeanselle Dea - University of California, San FranciscoCharles Ochieng' Olwal - University of California, Los AngelesLyvia Bertolace - University of RochesterMichael H Bloch - Yale UniversityCarolina Cappi - Rutgers, The State University of New JerseyYi-Chieh Chang - University of FloridaDenise Chavira - University of California, Los AngelesBarbara J Coffey - University of MiamiMartha J Falkenstein - Harvard UniversityAdam C Frank - University of Southern CaliforniaMartin E Franklin - Rogers Behavioral HealthStephanie Garayalde - University of FloridaHelena Garrido - Business University of Costa RicaMarco Grados - Johns Hopkins UniversityRami Hatem - Thomas Jefferson University HospitalAllyna-London Howell - McLean HospitalStarlette Khim - University of California, San FranciscoJennie M Kuckertz - Harvard UniversityMindy M Le - University of FloridaAllison Libby - University of California, San FranciscoRyan J McCarty - Baylor College of MedicineMary E McNamara - Harvard UniversityDaniel McNeil - University of FloridaEuripedes C Miguel - Universidade de São PauloCara Nasello - Rutgers, The State University of New JerseyBinh Nguyen - University of FloridaTenzin Norbu - University of California, San FranciscoLauren Oh - McLean HospitalAshley Ordway - University of FloridaCatherine Paciotti - University of FloridaViviana A Peskin - Asociación Psicoanalítica de Buenos AiresChristopher Pittenger - Yale UniversityHelen Blair Simpson - New York State Psychiatric InstituteHeather Simpson Martin - UF Health Rehab Center, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USAMax A Tischfield - Rutgers, The State University of New JerseyJinchuan Xing - Rutgers, The State University of New JerseyJessica J Zakrzewski - University of California San DiegoAndrea Dietrich - University Medical Center GroningenDonald L Gilbert - Cincinnati Children's Hospital Medical CenterPieter J Hoekstra - University Medical Center GroningenYoung Shin Kim - The University of Texas at AustinSamuel Kuperman - University of IowaAlyssa Rosen - Children's Hospital of PhiladelphiaSamuel H Zinner - University of WashingtonMehdi Bouhaddou - University of California, Los AngelesRobert A King - Yale UniversityGuy Rouleau - McGill UniversityKerry J Ressler - McLean HospitalCarol A Mathews - University of FloridaNevan J Krogan - University of California, San FranciscoNenad Sestan - Yale UniversityJay A Tischfield - Rutgers, The State University of New JerseyA Moses Lee - University of California, San FranciscoGary A Heiman - Rutgers, The State University of New JerseyThomas V Fernandez - Yale UniversityA Jeremy Willsey - University of California, San FranciscoMatthew W State - University of California, San FranciscoTourette International Collaborative Genetics (TIC Genetics)
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience
- DOI
- 10.1038/s41593-026-02419-5
- PMID
- 42680906
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Publisher
- Springer Nature
- Grant note
- K23MH126193 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115963 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R25MH060482 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) K23MH066284 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH114927 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115962 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115958 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115993 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH116038 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH115961 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
- Language
- English
- Electronic publication date
- 09/01/2026
- Academic Unit
- Psychiatry
- Record Identifier
- 9985222742702771
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