Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

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Journal
Nature Genetics
Published
2026-02-01
DOI
https://doi.org/10.1038/s41588-025-02485-8
Citations
1
Primary Topic
Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
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article
Field-Weighted Citation Impact
42.68

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article

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

Adams Mark J., Ottar Bjerkeset, Hüseyin Gedik, T. C. Eley et al.
1 citations
Nature Genetics
Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
42.68
article

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

Adams Mark J., Ottar Bjerkeset, Hüseyin Gedik, T. C. Eley, Kirstin L. Purves, Veterans Affairs Million Veteran Program, John M. Hettema, Ole Kristian Drange, Thomas Laurent, David P.D. Woldbye, Fabiana L. Lopes, Laurie J. Hannigan, Kritika Singh, Zachary L. Fuller, Martin Preisig, Joonas Naamanka, Arun K. Tiwari, Abigail ter Kuile, Georg W. Alpers, Dan J. Stein, Joseph Boden, Börge Schmidt, Lea K. Davis, Tan-Hoang NGUYEN, Miguel Garcia-Argibay, Clement Zai, Daniel F. Levey, Alex S F Kwong, Rujia Wang, Lydia Fehm, Annika Faucon, Kristi Krebs, Karmel Choi, Lili Milani, Enda M. Byrne, Anders D. Børglum, David C Whiteman, Angelika Erhardt-Lehmann, Elisa M. Tasanko, Iiris Hovatta, John-Anker Zwart, Giovanni A. Salum, Rosa Cheesman, Elizabeth C. Corfield, Ole Mors, Brenda W. Penninx, Catherine Olsen, Stefan Herms, Andreas Ströhle, Hermine H. Maes, Elisabeth B. Binder, Per Hoffmann, Glyn Lewis, Nicholas G. Martin, Tilo T. Kircher, Giorgio Pistis, Andreas J. Forstner, Robert Karlsson, Katharina Domschke, Ole A. Andreassen, Andrew M. McIntosh, Hilary Coon, Sarah Medland, Jürgen Deckert, Joel Gelernter, Gerome Breen, Lucia Colodro-Conde, Nathan A. Gillespie, Michelle K. Lupton, Andrey A. Shabalin, Christel M. Middeldorp, Andreas Reif, Baptiste Couvy-Duchesne, Alexandra Havdahl, Stefanie Heilmann-Heimbach, Alexander Teumer, Matthew H. Iveson, Kelli Lehto, Preben B. Mortensen, Brad Verhulst, Anna R. Docherty, Enrique Castelao, Gwyneth Zai, Manuel Mattheisen, Julia Bäckman, James L. Kennedy, Johannes Schumacher, Brittany L. Mitchell, Darina Czamara, Bendik S. Winsvold, Annemarie I. Luik, Nicholas J. Timpson, Archie Campbell, Teemu Palviainen, Donghyung Lee, Heike Weber, Volker Arolt, Yuri Milaneschi, Henrik Larsson, Martin M. Kennedy, Markus M. Nöthen, Sigrid Børte, Jan Gehlen, Dorret I. Boomsma, Daniel E. Adkins, Jordan W. Smoller, Sandra M. Meier, Helga Ask, William E. Copeland, Jaakko Kaprio, Francis J. McMahon, Nirmala Akula, Sandra Van der Auwera, Murray B. Stein, Henning Tiemeier, Catharina A. Hartman, Xin Eric Wang, FinnGen, Christiane A. Melzig, Hans J. Grabe, Naomi R. Wray, Roseann E. Peterson, Rupert Conrad, John Horwood, Eduard Maron, Patrik K. Magnusson, Albertine J. Oldehinkel
article en
1 citations

Abstract

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat-response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

Nature GeneticsVol. 58(2)
Broad Institute (US), South African Medical Research Council (ZA), Tallinn University of Technology (EE), Goethe University Frankfurt (DE), University of Copenhagen (DK), Oslo University Hospital (NO), The University of Sydney (AU), Dalhousie University (CA), Universidade Federal do Rio Grande do Sul (BR), Allen Institute for Brain Science (US), Norwegian Institute of Public Health (NO), University Medical Center Groningen (NL), University of Helsinki (FI), Centre for Addiction and Mental Health (CA), University of Bonn (DE), Harvard University (US), University of Cape Town (ZA), Queensland University of Technology (AU), University of Freiburg (DE), Philipps University of Marburg (DE), The University of Queensland (AU), Huntsman (United States) (US), Forschungszentrum Jülich (DE), University of Mannheim (DE), SUNY Downstate Health Sciences University (US), King's College London (GB), Virginia Commonwealth University (US), University of Oslo (NO), University of Toronto (CA), South London and Maudsley NHS Foundation Trust (GB), Vanderbilt University (US), Aarhus University (DK), Norwegian University of Science and Technology (NO), QIMR Berghofer Medical Research Institute (AU), University of Utah (US), Örebro University (SE), Brown University (US), Universitätsmedizin Greifswald (DE), University Hospital Bonn (DE), Huntsman Cancer Institute (US), University Medical Center Freiburg (DE), Erasmus MC (NL), University of Vermont Medical Center (US), Nord University (NO), Aarhus University Hospital (DK), University Hospital of Basel (CH), Edinburgh Cancer Research (GB), Namsos Hospital (NO), Karolinska Institutet (SE), Yale University (US), University of Bristol (GB), University of California San Diego (US), Humboldt-Universität zu Berlin (DE), University of Oxford (GB), VA Connecticut Healthcare System (US), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Children’s Health Queensland Hospital and Health Service (AU), National Institute of Child Health (HU), Behavioral Pharma (United States) (US), 23andMe (United States) (US), Augenstern (DE), Lovisenberg Diakonale Høgskole (NO), University Hospital Münster (DE), St Olav's University Hospital (NO), Central Institute of Mental Health (DE), NeuroDevelopment Center (US), Amsterdam Neuroscience (NL), Precision for Medicine (United States) (US), Universitätsklinikum Würzburg (DE), Lundbeck Foundation (DK), Department of Biomedicine Basel (CH), University Hospital Frankfurt (DE), Institute for Molecular Medicine Finland (FI), Stockholm Health Care Services (SE), Max Planck Institute of Psychiatry (DE), Public Health Service of Amsterdam (NL), Amsterdam University Medical Centers (NL), National Institute of Mental Health (US), Cognitive Research (United States) (US), Sørlandet Sykehus (NO), National Institute of Mental Health (CZ), University College London (GB), Imperial College London (GB), University of Tartu (EE), University of Duisburg-Essen (DE), Virginia Commonwealth University Medical Center (US), Charité - Universitätsmedizin Berlin (DE), University of Otago (NZ), Ludwig-Maximilians-Universität München (DE), Miami University (US), University of Amsterdam (NL), Vanderbilt University Medical Center (US), Texas A&M University (US), University of Lausanne (CH), University of Edinburgh (GB)
National Science Foundation, U.S. Department of Defense, U.S. Department of Veterans Affairs, Brain and Behavior Research Foundation, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Texas AgriLife Research, Massachusetts General Hospital, Yale University, Biogen, Office of Research and Development, Brown University, Celgene, Vanderbilt University, University of Miami, International OCD Foundation, Harvard University, Aarhus Universitet, Aarhus Universitetshospital, Stiftelsen Kristian Gerhard Jebsen, Helsingin Yliopisto, Johns Hopkins University, University of Otago, Philipps-Universität Marburg, Norges Teknisk-Naturvitenskapelige Universitet, Virginia Commonwealth University, South London and Maudsley NHS Foundation Trust, National Alliance for Research on Schizophrenia and Depression, Wellcome Trust, Huntsman Cancer Institute, Scottish Government, Vanderbilt University Medical Center, QIMR Berghofer Medical Research Institute, Broad Institute, UK Research and Innovation, Centre for Addiction and Mental Health Foundation, Nord universitet, Trond Mohn stiftelse, Georgia Clinical and Translational Science Alliance, Universitätsklinikum Essen, Maze Therapeutics, Jan Dekker Stichting, Physicians' Services Incorporated Foundation, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Scottish Funding Council, Imperial College London, King's College London, University College London, University of Oxford, European Commission, European Science Foundation, University of Bristol, South African Medical Research Council, Cure Kids, Canterbury Medical Research Foundation, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universiteit Leiden, Rijksuniversiteit Groningen, Koninklijke Nederlandse Akademie van Wetenschappen, Queensland University of Technology, Fundação de Amparo à Pesquisa do Estado de São Paulo, ZonMw, Vrije Universiteit Amsterdam, Eesti Teadusagentuur, Academy of Finland, Bundesministerium für Bildung und Forschung, Albert-Ludwigs-Universität Freiburg, Dalhousie University, Else Kröner-Fresenius-Stiftung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Accare, GGZ inGeest, Rivierduinen, GGZ Friesland, GGZ Drenthe, Lundbeckfonden, University of Toronto, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Jacobs Foundation, Karolinska Institutet, Novo Nordisk, Vetenskapsrådet, Helse Midt-Norge, NordForsk, Universidade Federal do Rio Grande do Sul, Universitetet i Bergen, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, Universitetet i Oslo, Norges Forskningsråd, Tallinna Tehnikaülikool, Humboldt-Universität zu Berlin, Sigrid Juséliuksen Säätiö, Université de Lausanne, Centre Hospitalier Universitaire Vaudois, Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Universität Mannheim, University of Cape Town, Gratama Stichting, Freie Universität Berlin, Tartu Ülikool, Universität Duisburg-Essen, University College London Hospitals NHS Foundation Trust, Chinese Society of Clinical Oncology, Lotto New Zealand, Siemens Healthineers, H. Lundbeck A/S, Business Finland, Universität Greifswald, Amsterdam Neuroscience, Ministry of Cultural Affairs, National Institutes of Health, Genentech, University of California, San Diego, Center for Clinical and Translational Science, University of Utah, Stanley Center for Psychiatric Research, Broad Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, NIHR Maudsley Biomedical Research Centre, Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet, Canadian Institutes of Health Research, Medical Research Council, Menzies Centre for Australian Studies, King's College London, University of London, National Health and Medical Research Council, Health Research Council of New Zealand, Helse Sør-Øst RHF, European Regional Development Fund, Erasmus Universitair Medisch Centrum Rotterdam, Faculty of Medicine and Health, University of Sydney, Norwegian Institute of Public Health, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Cancer Institute, National Center for Research Resources, Janssen Biotech, National Center for Advancing Translational Sciences
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Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
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