Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder. ### Competing Interest Statement Chris German is employed by and hold stock or stock options in 23andMe, Inc. Erika L. Nurmi is on the Scientific Advisory Board for Myriad Genetics and Medical Advisory Board for Tourette Association of America and received Clinical trial funding from Emalex and Octapharma Pharmaceuticals. Jeremy Veenstra-VanderWeele has served on advisory boards or consulted with Roche, Novartis, and SynapDx; received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, Forest, Janssen, Acadia, Yamo, and MapLight; received stipends for editorial work from Wiley and Springer. Jens R. Wendland is a current employee and shareholder of Takeda Pharmaceuticals and a past employee and shareholder of F. Hoffmann-La Roche, Pfizer and Nestle Health Science. Cynthia M. Bulik reports: Pearson (author, royalty recipient).Peter Falkai reports no conflict of interest regarding this study and reports to have received financial support and Advisory Board: Richter, Recordati, Boehringer-Ingelheim, Otsuka, Janssen and Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. Ian B. Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca, Janssen Cilag) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and Neumora. Christopher Pittenger consults and/or receives research support from Biohaven Pharmaceuticals, Freedom Biosciences, Ceruvia Lifesciences, Transcend Therapeutics, UCB BioPharma, and F-Prime Capital Partners. He owns equity in Alco Therapeutics. These relationships are not related to the current work. Dan J. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L'Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Eric A. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He was formerly a consultant for Brainsway and Biohaven Pharmaceuticals in the past 12 months. He owns stock less than $5000 in NView/Proem for distribution related to the YBOCS scales. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Ole A. Andreasson reports to be a consultant to Cortechs.ai, Precision Health AS, speakers honorarium from Otsuka, Lundbeck, Sunovion, Janssen. Anders D. Borglum has received speaker fee from Lundbeck. David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, and personal fees for editorial work from Elsevier, all unrelated to the current work. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, Otsuka, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). Joel Gelernter is paid for editorial work by the journal Complex Psychiatry. Pino Alonso has received funding from Biohaven, Boston Scientific, Medtronic. All other authors report no conflicts of interest. ### Funding Statement EGOS was supported by a grant from the Beatrice and Samuel A. Seaver Foundation to DEG. The genotyping of HUNT was financed by the National Institute of health (NIH), University of Michigan, The Norwegian Research council, and Central Norway Regional Health Authority and the Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU). This research is based in part on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards CSP575b, I01CX001849-01, 1P1HX002375, and the National Center for PTSD Research. MVP was supported by funding from the Department of Veterans Affairs Office of Research and Development, USVA, grants CSP575B and I01CX001849, MVP-025, and the VA Cooperative Studies Program study, no. 575B; the VA National Center for PTSD Research, and the West Haven VA Mental Illness Research, Education and Clinical Center; and by NIH grant R01 AA026364 (JG). D.F.L. is supported by a Career Development Award CDA-2 from the Veterans Affairs Office of Research and Development (1IK2BX005058-01A2) and is Aimee Mann Fellow of Psychiatric Genetics. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. The EPOC study was funded by the Deutsche Forschungsgemeinschaft (DFG; KA815/6-1 and WA731/10-1). LifeGene was supported by the Swedish Research Council, the Karolinska Institutet/Stockholm County Council research grants, AFA Insurance and the Torsten and Ragnar Soederbergs Foundation. Thomas V Fernandez: Research reported in this publication was supported by the National Institute Of Mental Health of the National Institutes of Health under Award Number R01MH114927. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work (GENOS) was supported by the German Research Fundation (GR 1912/1-1). The OCD Collaborative Genetics Association Study (OCGAS) is a collaborative research study and was funded by the following NIMH Grant Numbers: MH071507, MH079489, MH079487, MH079488 and MH079494. This work (OCGAS and IOCDF) is supported by the Netherlands Organization for Scientific Research-Gravitation project 'BRAINSCAPES: a Roadmap from Neurogenetics to Neurobiology' (024.004.012) and the European Research Council advanced grant 'From GWAS to Function' (ERC- 2018-ADG 834057). The OCGAS and IOCDF samples are supported through NIMH Grant Numbers: MH071507 (G N), MH079489 (DAG), MH079487 (JM), MH079488 (AF), and MH079494 (JK). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724, and R248-2017-2003), NIH/NIMH (1R01MH124851-01 to A.D.B.) and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). A.D.B. was also supported by the EU's HORIZON-HLTH-2021-STAYHLTH-01programme, project number 101057385: Risk and Resilience in Developmental Diversity and Mental Health (R2D2-MH). NORDiC was supported by the Swedish Research Council (grants 2012-07111 and 2018-02487), Swedish Research Council for Health, Working Life and Welfare 2018-00221 and Center for Innovative Medicine - CIMED. Nicholas G Martin has received funding from a project grant from Australian NHMRC. The AGDS was primarily funded by National Health and Medical Research Council (NHMRC) of Australia grant 1086683. This work was further supported by NHMRC grants 1145645, 1078901 and 1087889. LCC is supported by a QIMR Berghofer Institute fellowship. NORDiC is funded by NIMH R01 MH110427 (PI Crowley), NIMH R01 MH105500 (PI Crowley) and the Swedish Research Council grant number 2015-02271 (PI Mataix-Cols). The work done by the EstBB team has received funding from the European Union's Horizon 2020 Research and Innovation Programme under Grant agreement 847776 (CoMorMent). This work (Mental-Cat and INSchool) was supported by the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, 2017SGR-1461, 2021SGR-00840), the Instituto de Salud Carlos III (PI20/00041, PI23/00404 and PI23/00026), the European Regional Development Fund (ERDF); the ECNP Network 'ADHD across the Lifespan'; "la Marato de TV3" (202228-30 and 202228-31). The Research Council of Norway supported H. Ask, A. Havdahl and T. Reichborn-Kjennerud (274611). A. Havdahl was also supported by South East Norway Health Authority (2020022). Grant support for the MoBa team was also provided from RCN (273291, 262656, 248778, 223273) and the KG Jebsen Stiftelsen.). BioVU: CTSA (SD, Vanderbilt Resources) was supported by the National Center for Research Resources, Grant UL1 RR024975-01, and is now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.The dataset(s) used for the analyses (BioVU) described were obtained from Vanderbilt University Medical Center's BioVU which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/ Zachary F. Gerring is supported by NIH/NIA AG068026. Marco Galimberti received support from the following grants (Joel Gelernter): CSP575b, I01CX001849-01, 1P1HX002375, National Center for PTSD Research, 5R01DA054869-01. Abdel Abdellaoui was supported by the Foundation Volksbond Rotterdam. Tim Bigdeli is supported by NIMH grant 7R01MH103657 (GPC-OCD). Jonathan Coleman: This study represents independent research part funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Christina Barlassina was supported by grant EU FP7-HEALTH-2007-A-201550, and grant MIUR-CNR PB05. Enda Byrne was supported by the NHMRC Project Grant 1145645; University of Queensland Health Research Accelerator Program (HeRA).Carolina Cappi was supported by grant K99MH128540-01A1. Valentina Ciullo was supported by the Italian Ministry of Health grant RC-18-19-20-21/A. Richard Delorme: INSERM @ APHP granted the study. Marco A. Grados was supported by NIMH K23 MH066284. Jan Haavik was supported by Stiftelsen KG Jebsen (SKGJ MED-02). Kristen Hagen was supported by the Trond Mohn Foundation. Elinor K. Karlsson was supported by NIH R21 MH109938. Paul S. Nestadt was supported by R01MH071507. Fabrizio & Federica Piras are supported by the Italian Ministry of Health RC18-19-20-21/A grant. This work was in part supported by the German Research Foundation (DFG) grants: [RA1971/8-1], [RA1971/7-1]; and by the Bundesministerium fuer Bildung und Forschung (BMBF) grant: 01ED2007A to Alfredo Ramirez. Stephan Ripke was supported by research grant 1R01MH124873-01. Maria Soler Artigas was supported by the The Instituto de Salud Carlos III (P19/01224, PI22/00464 and CP22/00128) and the European Regional Development Fund (ERDF). Arpana Agrawal was supported from grant U10AA008401. Pino Alonso was supported by the Spanish Ministry of Science, Innovation and Universities (ISCIII PI22/00752) and Fundacio La Marato 202201-30. Cynthia M. Bulik was supported by R01 MH124871 (Sullivan/Bulik) PGC4. Howard Edenberg was supported by grant U10AA008401. Dan A. Geller was supported by NIMH (OCGAS and OCGS). Gregory L Hanna was supported by the National Institute of Mental Health (R01 MH58376), National Institute of Mental Health (K20 MH01065), National Institute of Mental Health (R01 MH101493), National Institute of Mental Health (R01 MH085321) Norbert Kathmann has received funding from Deutsche Forschungsgemeinschaft (DFG) KA815/6-1. Sarah E. Medland is supported by an Australian NHMRC Investigator Grant (APP1172917). Benjamin M. Neale is funded by grant R01MH124851. Michele Pato and Carlos Pato have received support from R01MH103657 and R01MH079494 from the National Institutes of Mental Health (NIMH) and the Della Martin Foundation, Los Angeles CA. John Piacentini has received support through the National Institute of Mental Health: R01MH50214: Collaborative OCD Genetics Study (G. Nestadt, PI; J. McCracken, UCLA PI). Margaret A. Richter was supported by funding from the Canadian Institutes for Health Research and the Ontario Mental Health Foundation. David R. Rosenberg was supported by NIMH R01MH059299. Jack F. Samuels was supported by NIMH Grant Number: MH071507. Gianfranco Spalletta is supported by the Italian Ministry of Health RC18-19-20-21/A grant. Eric A. Storch collected data as part of the following NIH grant: 1R01MH093381. Ole A. Andreassen (MoBa) has received grant support from RCN (324499,273291,262656,248778,223273), KG Jebsen Stiftelsen, NordForsk #164218. Jaakko Kaprio has been supported by the Academy of Finland (grant 336823). Paul D. Arnold is supported by the Alberta Innovates Translational Health Chair in Child and Youth Mental Health. Dorothy E. Grice is supported by the grant MH124679-01. James A. Knowles is supported through the following grants: R01MH103657 and R01MH079494 from the National Institutes of Mental Health (NIMH) and the Della Martin Foundation, Los Angeles CA. Karin J.H. Verweij is supported by the Foundation Volksbond Rotterdam. Lea K. Davis was supported by grants from the National Institutes of Health including R01NS102371, R01MH113362, R01MH118223, R01NS105746, and R56MH120736. JS was supported by NIH training grant in Human Genetics, 2T32GM080178. James Crowley was supported by NIH grants R01MH105500 and R01MH110427. Murray B. Stein has been funded by the Veterans Affairs Administration (United States VA). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 23andMe: Participants provided informed consent and volunteered to participate in the research online, under a protocol approved by the external AAHRPP-accredited IRB, Ethical & Independent (E&I) Review Services. As of 2022, E&I Review Services is part of Salus IRB (https://www.versiticlinicaltrials.org/salusirb). AGDS: All study protocols were approved by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee. The protocol for approaching participants through the DHS, enrolling them in the study, and consenting for all phases of the study (including invitation to future related studies) and accessing MBS and PBS records was approved by the Ethics Department of the Department of Human Services. BioVU: The Vanderbilt University Medical Center Institutional Review Board oversees BioVU and approved this project (IRB201609). COGA: Institutional review boards at all sites approved the study and all participants provided informed consent. EGOS: Ethical approvals were obtained from the Institutional Review Board (IRB) at the Icahn School of Medicine at Mount Sinai, New York, NY, and the Regional Ethical Review Board in Stockholm. EPOC: The study was in accordance with the revised Declaration of Helsinki and approved by the local ethics committees of the Charite University Medicine Berlin and the University Hospital Bonn. EstBB: At recruitment, participants signed a consent allowing follow-up linkage of their electronic health records (EHRs), thereby providing a longitudinal collection of their phenotypic information. FinnGen: The Ethical Review Board of the Hospital District of Helsinki and Uusimaa approved the FinnGen study protocol Nr. HUS/990/2017. The FinnGen project was approved by Finnish Institute for Health and Welfare (THL), approval numbers THL/2031/6.02.00/2017, amendments THL/341/6.02.00/2018, THL/2222/6.02.00/2018, and THL/283/6.02.00/2019. HUNT: The HUNT study was approved by the Regional Committee for Medical and Health Research Ethics, Norway (2015/575). IOCDF/OCGAS: This work was approved by the relevant IRBs at all participating sites, and all participants provided written informed consent. iPSYCH: The study was approved by the Regional Scientific Ethics Committee in Denmark and the Danish Data Protection Agency. MVP: The U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP) is collecting genetic and electronic health record (EHR) data in the U.S with ethical approval given by the Central VA Institutional Review Board (IRB) and site-specific IRBs. All relevant ethical regulations for work with human subjects were followed in the conduct of the study, and informed consent was obtained from all participants. MoBa: The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is now based on regulations related to the Norwegian Health Registry Act. NORDiC-SWE: This study was approved by the Regional Ethics Committee, Stockholm (EPN Stockholm) and the Institutional Review Board (IRB) at the University of North Carolina at Chapel Hill and all subjects provided informed consent. NORDiC-NOR: The NORDiC-NOR study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics (IRB00001872 REK West) under project number 2018/52 REKVest (PI: Bjarne Hansen) and project number: 2014/75 REKVest (PI: Jan Haavik) and all subjects provided informed consent. OCGAS-all: Ethics approvals for the OCGAS study were obtained from the Hopkins Medicine Institutional Review Boards, the Butler Institutional Review Board, the UCLA Institutional Review Boards, the Mass General Brigham Human Research Committee, the Columbia University Institutional Review Boards, and the National Institutes of Health Institutional Review Board (NIH IRB). OCGAS-nestadt: Ethics approvals for the OCGAS study were obtained from the Hopkins Medicine Institutional Review Boards. OCGAS-ab: The study was approved by REB at Hospital for Sick Children. Ethics approvals for the OCGAS study were obtained from the Hopkins Medicine Institutional Review Boards. OCGAS-gh: Informed written consent was obtained in all cases by the participants or their parents. The study was approved by the ethical commissions of all involved universities in accordance with the latest version of the Declaration of Helsinki, including an ethical permission granted by the Ethic Committees from Aachen, Wuerzburg, Marburg, Freiburg, and the Cantonal Ethic Commission of Zuerich (Ref. Nr. 39/97, 140/3 and EK: KEK-ZHNr. 2010-0340/3). OCD-WWF: The study was approved by the ethics committee of the University of Wuerzburg, Germany and was conducted according to the ethical principles of the Helsinki Declaration. All patients gave written informed consent prior to participation. Psych_Broad: Both studies have been approved by the Clinical Research Ethics Committee (CREC) of Hospital Universitari Vall d'Hebron. All methods were performed in accordance with the relevant guidelines and regulations and written informed consent was obtained from participant parents before inclusion into the study. UKBB: Research on the UK Biobank is conducted under a generic Research Tissue Bank approval from the UK North West Multi-centre Research Ethics Committee (MREC). This research was approved to be conducted under that approval by the governing Research Ethics Committee of the UK Biobank. The analyses in this paper were performed under an approved extension to project 16577. Yale-Penn: Participants were recruited from eastern U.S sites and provided written informed consent as approved by the institutional review board at each site. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The meta-analyzed summary statistics (not including 23andMe data) will be made available via the Psychiatric Genomics Consortium Download page (https://www.med.unc.edu/pgc/download-results/). The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Datasets will be made available at no cost for academic use. Please visit https://research.23andme.com/collaborate/#dataset-access/ for more information and to apply to access the data. MVP summary statistics are made available through dbGAP request under accession phs001672.v7.p1.