ArticlemedRxiv : the preprint server for health sciences2025
Rare coding mutations identify 36 large-effect risk genes in obsessive-compulsive disorder and chronic tic disorders.
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Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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65 authors.
Belinda WangDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0001-5563-894X
Matthew N TranDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0001-9694-7378
Sheng WangDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Yuting LiuDepartment of Neuroscience, Yale School of Medicine, New Haven, CT, USA.ORCID 0000-0001-8380-2882
Emily OlfsonChild Study Center, Yale School of Medicine, New Haven, CT, USA.ORCID 0000-0002-6438-0079
George WangDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0009-0005-7879-3519
Nawei SunDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-1599-5990
Jeanselle DeaDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0003-3831-3558
Charles Ochieng' OlwalDepartment of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.ORCID 0000-0003-1747-2963
Lyvia BertolaceDepartment of Psychiatry, University of Rochester, Rochester, NY, USA.
Michael H BlochChild Study Center, Yale School of Medicine, New Haven, CT, USA.
Carolina CappiDepartment of Psychiatry, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.ORCID 0000-0001-6661-3756
Yi-Chieh ChangCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.
Denise ChaviraDepartment of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
Barbara J CoffeyDepartment of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.
Martha J FalkensteinOCD Institute, McLean Hospital, Belmont, MA, USA.ORCID 0000-0001-5074-3409
Adam C FrankDepartment of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.ORCID 0000-0001-8203-8480
Martin E FranklinRogers Behavioral Health, Philadelphia, PA, USA.
Stephanie GarayaldeCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.
Helena GarridoPrivate practice, San José, Costa Rica.
Marco GradosDepartment of Psychiatry and Behavioral Sciences, Child and Adolescent Psychiatry, Johns Hopkins University, Baltimore, MD, USA.ORCID 0000-0002-0178-1764
Rami HatemDepartment of Psychiatry and Human Behavior, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
Allyna-London HowellOCD Institute, McLean Hospital, Belmont, MA, USA.
Starlette KhimDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Jennie M KuckertzOCD Institute, McLean Hospital, Belmont, MA, USA.ORCID 0000-0002-3929-2683
Mindy M LeCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.ORCID 0009-0007-2357-8568
Allison LibbyDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Ryan J McCartyDepartment of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0003-1630-9072
Mary E McNamaraOCD Institute, McLean Hospital, Belmont, MA, USA.ORCID 0000-0001-7062-700X
Daniel McNeilCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.ORCID 0000-0001-6050-5682
Euripedes C MiguelDepartamento de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Cara NaselloDepartment of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
Binh NguyenCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.ORCID 0000-0003-1824-7362
Tenzin NorbuDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Lauren OhOCD Institute, McLean Hospital, Belmont, MA, USA.
Ashley OrdwayCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.
Catherine PaciottiCenter for OCD, Anxiety and Related Disorders, University of Florida, Gainesville, FL, USA.
Viviana A PeskinAsociación de Psiquiatras de Argentina, Buenos Aires, Argentina.
Christopher PittengerDepartment of Psychiatry, Yale School of Medicine, New Haven, CT, USA.ORCID 0000-0003-2117-9321
Helen Blair SimpsonDepartment of Psychiatry, Columbia University, New York, NY, USA.ORCID 0000-0002-9332-2839
Heather Simpson MartinUF Health Rehab Center, Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.ORCID 0000-0003-3701-5495
Max A TischfieldDepartment of Cell Biology and Neuroscience, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
Jinchuan XingDepartment of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.ORCID 0000-0001-6469-8733
Jessica J ZakrzewskiDepartment of Psychiatry, University of California, San Diego, San Diego, CA, USA.ORCID 0000-0002-6821-2603
Tourette International Collaborative Genetics (TIC Genetics)
Andrea DietrichDepartment of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.ORCID 0000-0002-2538-6136
Donald L GilbertDivision of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.ORCID 0000-0002-9245-6878
Pieter J HoekstraDepartment of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.ORCID 0000-0001-7260-4119
Young Shin KimDepartment of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas at Austin, Austin, TX, USA.ORCID 0000-0002-6766-1722
Samuel KupermanDepartment of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.ORCID 0000-0002-5995-1981
Alyssa RosenDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Samuel H ZinnerDepartment of Pediatrics, Division of Developmental Medicine, University of Washington School of Medicine, Seattle, WA, USA.ORCID 0000-0002-7736-9629
Mehdi BouhaddouDepartment of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
Robert A KingChild Study Center, Yale School of Medicine, New Haven, CT, USA.
Guy RouleauDepartment of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada.
Kerry J ResslerOCD Institute, McLean Hospital, Belmont, MA, USA.ORCID 0000-0002-5158-1103
Carol A MathewsDepartment of Psychiatry, University of Florida, Gainesville, FL, USA.ORCID 0000-0003-2208-7058
Nevan J KroganQuantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0003-4902-337X
Nenad SestanDepartment of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Jay A TischfieldDepartment of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.ORCID 0000-0003-3217-8287
A Moses LeeDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Gary A HeimanDepartment of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.ORCID 0000-0001-5859-0259
Thomas V FernandezChild Study Center, Yale School of Medicine, New Haven, CT, USA.ORCID 0000-0003-0830-022X
A Jeremy WillseyDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0002-9922-3612
Matthew W StateDepartment of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.ORCID 0000-0003-1624-8302
Funding
Understanding Risk Gradients from Environment on Native American Child Health Trajectories: Toxicants, Immunomodulation, Metabolic syndromes, & Metals ExposureUG3OD023344 · OD · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI LEWIS, JOHNNYE L, MACKENZIE, DEBRA · 2016 to 2024
$14.1MFellowship on Biological Psychiatry and NeuroscienceT32MH018399 · NIMH · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Pei-an (Betty) Shih · 1986 to 2026
$7.3M1/7 Collaborative Genomic Studies of Tourette Disorder.R01MH115958 · NIMH · RUTGERS, THE STATE UNIV OF N.J. · PI HEIMAN, GARY A., TISCHFIELD, JAY ARNOLD · 2018 to 2023
$6.8MTRAINING THE NEXT GENERATION OF MENTAL HEALTH RESEARCHERSR25MH060482 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI DANIEL H MATHALON, Susan M. Voglmaier · 2000 to 2026
$5.2M2/7-Collaborative genomic studies of Tourette DisorderR01MH115963 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STATE, MATTHEW W., WILLSEY, ARTHUR JEREMY · 2018 to 2022
$4.9MResearch Training for Medical Students & Physician-Scientists in Child PsychiatryR25MH077823 · NIMH · YALE UNIVERSITY · PI ANDRES S MARTIN · 2006 to 2026
$4.0MDysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNOR01MH130609 · NIMH · YALE UNIVERSITY · PI Christopher John Pittenger · 2022 to 2026
$3.7MBrain Network Changes Accompanying and Predicting Responses to Pharmacotherapy in OCDR01MH116038 · NIMH · YALE UNIVERSITY · PI ANTICEVIC, ALAN, PITTENGER, CHRISTOPHER JOHN · 2019 to 2023
$3.7MNeurogenetic Investigations of Obsessive-Compulsive DisorderR01MH114927 · NIMH · YALE UNIVERSITY · PI FERNANDEZ, THOMAS V · 2018 to 2022
$2.8MLeveraging Machine Learning Approaches to Understand Mechanisms of Exposure Therapy in Real-World SettingsR01MH135899 · NIMH · SAN DIEGO STATE UNIVERSITY · PI Jennie M Kuckertz · 2024 to 2026
$2.3MNeurogenomic Investigations of Trichotillomania and Excoriation DisorderK08MH128665 · NIMH · YALE UNIVERSITY · PI Emily Hunt Olfson · 2022 to 2026
$1.0MInterpretation Bias as a Mechanism of Treatment Response in OCD - Administrative SupplementK23MH126193 · NIMH · MCLEAN HOSPITAL · PI Martha J Falkenstein · 2021 to 2026
$1.0MNIH HHS UG3 OD023344NIMH NIH HHS K08 MH128665NIMH NIH HHS K23 MH066284NIMH NIH HHS K23 MH125018NIMH NIH HHS K23 MH126193NIMH NIH HHS K99 MH128540NIMH NIH HHS R00 MH128540NIMH NIH HHS R01 MH114927NIMH NIH HHS R01 MH115958NIMH NIH HHS R01 MH115959NIMH NIH HHS R01 MH115960NIMH NIH HHS R01 MH115961NIMH NIH HHS R01 MH115962NIMH NIH HHS R01 MH115963NIMH NIH HHS R01 MH115993NIMH NIH HHS R01 MH116038NIMH NIH HHS R01 MH130609NIMH NIH HHS R01 MH135899NIMH NIH HHS R25 MH060482NIMH NIH HHS R25 MH077823NIMH NIH HHS T32 MH018399
Abstract
Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD) are highly heritable. Recent progress in OCD genomics has highlighted small-effect common alleles. Rare mutations have previously been found to carry large risks for OCD and CTD but only four high-confidence (hc) genes have been identified. We analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTD, or both, including 2,418 trios. We find an excess in cases of
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