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Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
Nora I. Strom, Zachary F. Gerring, Marco Galimberti, Dongmei Yu, Matthew Halvorsen, Abdel Abdellaoui, Cristina Rodriguez‐Fontenla, Julia Sealock, Tim B. Bigdeli, Jonathan R. I. Coleman, Behrang Mahjani, Jackson G. Thorp, Katharina Bey, Christie L. Burton, Jurjen J. Luykx, Gwyneth Zai, Silvia Alemany, Christine André, Kathleen D. Askland, Julia Boberg, Nerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O. Joseph Bienvenu, Donald W. Black, Michael H. Bloch, Sigrid Børte, Rosa Bosch, Michael S. Breen, Brian P. Brennan, Helena Brentani, Joseph D. Buxbaum, Jonas Bybjerg‐Grauholm, Enda M. Byrne, Judit Cabana‐Domínguez, Beatríz Camarena, Adrian Camarena, Carolina Cappi, Ãngel Carracedo, Miguel Casas, Maria Cristina Cavallini, Valentina Ciullo, Edwin H. Cook, Jesse M. Crosby, Bernadette Cullen, Elles de Schipper, Richard Delorme, Srdjan Djurovic, Jason A. Elias, Xavier Estivill, Martha J. Falkenstein, Bengt T. Fundín, Lauryn E. Garner, Christina Gironda, Fernando S. Goes, Marco A. Grados, Jakob Grove, Wei Guo, Jan Haavik, Kristen Hagen, Kelly Harrington, Alexandra Havdahl, Kira D. Höffler, Ana Gabriela Hounie, Donald Hucks, Christina M. Hultman, Magdalena Janecka, Eric Jenike, Elinor K. Karlsson, Kara N. Kelley, Julia Klawohn, Janice Krasnow, Kristi Krebs, Christoph Lange, Nuria Lanzagorta, Daniel F. Levey, Kerstin Lindblad‐Toh, Fabìo Macciardi, Brion S. Maher, Brittany M. Mathes, Evonne McArthur, Nathaniel W. McGregor, Nicole McLaughlin, Sandra Meier, Eurı́pedes Constantino Miguel, Maureen Mulhern, Paul S. Nestadt, Erika L. Nurmi, Kevin S. O’Connell, Lisa Osiecki, Olga Therese Ousdal, Teemu Palviainen, Nancy L. Pedersen, Fabrizio Piras, Federica Piras, Sriramya Potluri, Raquel Rabionet, Alfredo Ramı́rez, Scott L. Rauch, Abraham Reichenberg, Mark A. Riddle, Stephan Ripke, Maria Conceição do Rosário, Aline S. Sampaio, Miriam A. Schiele, Anne Heidi Skogholt, Laura Sloofman, Jan Smit, María Soler Artigas, Laurent F. Thomas, Eric D. Tifft, Homero Vallada, Nathaniel Van Kirk, Jeremy Veenstra‐VanderWeele, Nienke Vulink, Christopher Walker, Ying Wang, Jens R. Wendland, Bendik S. Winsvold, Yin Yao, Hang Zhou, Arpana Agrawal, Pino Alonso, Götz Berberich, Kathleen K. Bucholz, Cynthia M. Bulik, Daniëlle C. Cath, Damiaan Denys, Valsamma Eapen, Howard J. Edenberg, Peter Falkai, Thomas Fernandez, Abby J. Fyer, J. Michael Gaziano, Daniel Geller, Hans J. Grabe, Benjamin D. Greenberg, Gregory L. Hanna, Ian B. Hickie, David M. Hougaard, Norbert Kathmann, James L. Kennedy, Dongbing Lai, Mikael Landén, Stéphanie Le Hellard, Marion Leboyer, Christine Löchner, James T. McCracken, Sarah E. Medland, Preben Bo Mortensen, Benjamin M. Neale, Humberto Nicolini, Merete Nordentoft, Michele T. Pato, Carlos N. Pato, David L. Pauls, John Piacentini, Christopher Pittenger, Daniëlle Posthuma, Josep Antoni Ramos‐Quiroga, Steven A. Rasmussen, Margaret A. Richter, David R. Rosenberg, Stephan Ruhrmann, Jack Samuels, Sven Sandin, Paul Sandor, Gianfranco Spalletta, Dan J. Stein, S. Evelyn Stewart, Eric A. Storch, Barbara E. Stranger, Maurizio Turiel, Thomas Werge, Ole A. Andreassen, Anders D. Børglum, Susanne Walitza, Kristian Hveem, Bjarne Hansen, Christian Rück, Nicholas G. Martin, Lili Milani, Ole Mors, Ted Reichborn‐Kjennerud, Marta Ribasés, Gerd Kvale, David Mataix‐Cols, Katharina Domschke, Edna Grünblatt, Michael Wagner, John‐Anker Zwart, Gerome Breen, Gerald Nestadt, Jaakko Kaprio, Paul Arnold, Dorothy E. Grice, James A. Knowles, Helga Ask, Karin J. H. Verweij, Lea K. Davis, Dirk J. A. Smit, James J. Crowley, Jeremiah M. Scharf, Murray B. Stein, Joel Gelernter, Carol A. Mathews, Eske M. Derks, Manuel Mattheisen
Bibliographic record
VenueNature Genetics · 2025
Typereview
Languageen
FieldPsychology
TopicObsessive-Compulsive Spectrum Disorders
Canadian institutionsUniversity of CalgaryBC Mental Health & Substance Use ServicesHealth Sciences CentreSunnybrook Health Science CentreMcMaster UniversityBC Children's HospitalDalhousie UniversityUniversity of TorontoCentre for Addiction and Mental HealthUniversity of British ColumbiaHospital for Sick Children
FundersFP7 HealthJane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los AngelesEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNIH Clinical CenterNational Center for Research ResourcesNational Institute of Neurological Disorders and StrokeNational Institute on Drug AbuseNational Institute of Mental HealthNational Heart, Lung, and Blood InstituteNational Institute on AgingNational Institute on Alcohol Abuse and AlcoholismNorwegian Institute of Public HealthFaculty of Medicine and Health, University of SydneyNational Institute of General Medical SciencesCenter for Innovative MedicineNeuroscience Center Zurich, University of ZurichAgència de Gestió d'Ajuts Universitaris i de RecercaNational Health and Medical Research CouncilNational Human Genome Research InstituteDepartment of Psychiatry, Columbia UniversityYale UniversityFeinberg School of MedicineInstituto Nacional de Medicina GenómicaNational Institutes of HealthIngham Institute for Applied Medical ResearchCumming School of Medicine, University of CalgaryGentofte HospitalKing's College LondonSt. Olavs Hospital Universitetssykehuset i TrondheimDeutsche ForschungsgemeinschaftOntario Council on Graduate Studies, Council of Ontario UniversitiesAssistance publique-Hôpitaux de ParisDepartment of Health and Social CareNovo Nordisk FondenUniversität zu KölnUniversitat de BarcelonaForskningsrådet om Hälsa, Arbetsliv och VälfärdH. Lundbeck A/SInstitut National de la Santé et de la Recherche MédicaleHumboldt-Universität zu BerlinU.S. Department of Veterans AffairsRegion HovedstadenUniversitetet i BergenHelse Midt-NorgeVetenskapsrådetNovo NordiskUniversitetet i OsloLundbeckfondenUniversité Paris-Est Créteil Val-de-MarneUniversiteit StellenboschAFA FörsäkringKoninklijke Nederlandse Akademie van WetenschappenInstitute of Psychiatry, Psychology and Neuroscience, King’s College LondonBrown UniversityNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungKarolinska InstitutetDepartment of Psychiatry, Faculty of Medicine, University of British ColumbiaNational Institute for Health and Care ResearchUniversity of QueenslandNIHR Maudsley Biomedical Research CentreRijksuniversiteit GroningenMinistero della SaluteCentro de Investigación Biomédica en Red de Salud MentalNational Research FoundationSouth African Medical Research CouncilDeutsches Zentrum für Neurodegenerative ErkrankungenNational Center for PTSD, U.S. Department of Veterans AffairsQueensland HealthMathison Centre for Mental Health Research and EducationStichting Volksbond RotterdamDella Martin FoundationQIMR Berghofer Medical Research InstituteVanderbilt University Medical CenterEuropean College of NeuropsychopharmacologyVrije Universiteit AmsterdamAmsterdam NeuroscienceAarhus UniversitetshospitalBeatrice and Samuel A. Seaver FoundationAarhus UniversitetStockholms Läns LandstingNorges ForskningsrådMinistero dell’Istruzione, dell’Università e della RicercaFakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige UniversitetInstituto de Salud Carlos IIIUniversità degli Studi di MilanoFudan UniversityGöteborgs UniversitetTrond Mohn stiftelseHospital for Sick ChildrenMassachusetts General HospitalKlarman Family FoundationMinisterio de Ciencia, Innovación y UniversidadesBC Children's HospitalHelse- og OmsorgsdepartementetSouth London and Maudsley NHS Foundation TrustOffice of Research and DevelopmentUniversitair Medisch Centrum GroningenEuropean Regional Development FundInternational OCD FoundationUniversitat Autònoma de BarcelonaEidgenössische Technische Hochschule ZürichEuropean Social FundMedical Research CouncilTartu ÜlikoolFundació la Marató de TV3Johns Hopkins UniversityNorthwestern UniversityEuropean CommissionHelsingin YliopistoUniversität ZürichUniversity of Cape TownGeorgia Clinical and Translational Science AllianceSchool of Medicine, Indiana UniversityUniversity of New South WalesUniversity of North Carolina at Chapel HillWayne State UniversityUniversitätsspital ZürichVanderbilt University
KeywordsGenome-wide association studyBiologyGeneticsGenetic architectureHeritabilityGenetic associationSingle-nucleotide polymorphismGenePhenotypeGenotype
Abstract
Abstract Obsessive–compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6 , DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D 1 and D 2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.001
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: none
GenreCandidate signal: Review · Consensus signal: Review
Teacher disagreement score0.002
Threshold uncertainty score0.008
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.026
GPT teacher head0.384
Teacher spread0.357 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreReview
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations48
Published2025
Admission routes2
Has abstractyes