Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry

Abstract Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts. We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African and South Asian ancestry samples ( R 2 = 1.2–2.9%). Significant genetic correlations ( r g ) were estimated with mental and physical health traits, including case–control anxiety, neuroticism and depression ( r g = 0.71–0.85), irritable bowel syndrome ( r g = 0.57), coronary artery disease, endometriosis and migraine ( r g = 0.20–0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the discovery power gained from analysing a quantitative trait rather than a case–control phenotype in anxiety genetics.

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Journal
Nature Human Behaviour
Published
2026-06-09
DOI
https://doi.org/10.1038/s41562-026-02476-7
Primary Topic
Genetic Associations and Epidemiology
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article
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article

Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry

Kadri Kõiv, P Grimes, Silviu‐Alin Bacanu, Sigrid Børte et al.
Nature Human Behaviour
Genetic Associations and Epidemiology
article

Genome-wide meta-analysis of quantitatively measured generalized anxiety symptoms in individuals of European ancestry

Kadri Kõiv, P Grimes, Silviu‐Alin Bacanu, Sigrid Børte, Hüseyin Gedik, Daniel E. Adkins, Enrique Castelao, Nora I. Strom, Karmel W. Choi, Lili Milani, Elham Assary, Giorgio Pistis, Peter J. van der Most, A V Campbell, Ole Kristian Drange, E Binder, Iiris Hovatta, Alan E Murphy, Johanne Hagen Pettersen, Alex S. F. Kwong, Laurie J. Hannigan, Kritika Singh, Kristi Krebs, Jan Gehlen, Eystein Stordal, Geneviève Morneau‐Vaillancourt, Megan Skelton, Laurent F. Thomas, Fabiana L. Lopes, Lydia Fehm, D Czamara, Mark J. Adams, Christel Maria Middeldorp, Elizabeth C. Corfield, Swapnil Awasthi, Francis J. McMahon, Lea K. Davis, Tan-Hoang Nguyen, Julia Bäckmann, Zachary Fuller, Clement Zai, Rujia Wang, Ole Mors, Catherine Olsen, Hermine H. Maes, Matthew H. Iveson, Preben B. Mortensen, Gwyneth Zai, Bendik S. Winsvold, Martin M. Kennedy, Sandra M. Meier, Joseph Boden, Sandra van der Auwera, Abigail R. ter Kuile, Arun K. Tiwari, Kirstin L. Purves, Ottar Bjerkeset, Xin Wang, Nirmala Akula, Stephan Ripke, Stefan Herms, Lucia Colodro-Conde, John-Anker Zwart, Danyang Li, Nicholas J. Timpson, Roseann E. Peterson, Robert Karlsson, Glyn Lewis, Donghyung Lee, Enda M. Byrne, John Horwood, Daniel F. Levey, Andreas Ströhle, Baptiste Couvy-Duchesne, Brittany L. Mitchell, Dan J. Stein, Jaakko Kaprio, James L. Kennedy, David Whiteman, Per Hoffmann, Miguel Garcia-Argibay, Elisa M. Tasanko, Markus M. Nöthen, Andreas J. Forstner, David P. Woldbye, Giovanni A. Salum, Teemu Palviainen, Nathan A. Gillespie, Börge Schmidt, Andrey A. Shabalin, Anders D. Børglum, Jihua Hu, Henning Tiemeier, Annika B. Faucon, Stefanie Heilmann-Heimbach, Alexander Teumer, Rosa Cheesman, Sergi Papiol, Johannes Schumacher
article en

Abstract

Abstract Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts. We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African and South Asian ancestry samples ( R 2 = 1.2–2.9%). Significant genetic correlations ( r g ) were estimated with mental and physical health traits, including case–control anxiety, neuroticism and depression ( r g = 0.71–0.85), irritable bowel syndrome ( r g = 0.57), coronary artery disease, endometriosis and migraine ( r g = 0.20–0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the discovery power gained from analysing a quantitative trait rather than a case–control phenotype in anxiety genetics.

Nature Human Behaviour
Broad Institute (US), South African Medical Research Council (ZA), University of Copenhagen (DK), Oslo University Hospital (NO), 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), Johns Hopkins University (US), University of Cape Town (ZA), Queensland University of Technology (AU), Philipps University of Marburg (DE), The University of Queensland (AU), University of Groningen (NL), Forschungszentrum Jülich (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), Douglas Mental Health University Institute (CA), Instituto de Salud Carlos III (ES), Erasmus MC (NL), Nord University (NO), Aarhus University Hospital (DK), University Hospital of Basel (CH), Edinburgh Cancer Research (GB), Namsos Hospital (NO), Karolinska Institutet (SE), LMU Klinikum (DE), Yale University (US), University of Bristol (GB), Humboldt-Universität zu Berlin (DE), VA Connecticut Healthcare System (US), Massachusetts General Hospital (US), National Human Genome Research Institute (US), Centro de Investigación Biomédica en Red de Salud Mental (ES), Children’s Health Queensland Hospital and Health Service (AU), National Institute of Child Health (HU), 23andMe (United States) (US), Lovisenberg Diakonale Høgskole (NO), St Olav's University Hospital (NO), NeuroDevelopment Center (US), Precision for Medicine (United States) (US), UK Dementia Research Institute (GB), Lundbeck Foundation (DK), Department of Biomedicine Basel (CH), Institute for Molecular Medicine Finland (FI), Stockholm Health Care Services (SE), Max Planck Institute of Psychiatry (DE), National Institute of Mental Health (US), National Institute of Mental Health (CZ), University College London (GB), Imperial College London (GB), University of Tartu (EE), University of Duisburg-Essen (DE), Université de Montréal (CA), Virginia Commonwealth University Medical Center (US), Charité - Universitätsmedizin Berlin (DE), University of Otago (NZ), Ludwig-Maximilians-Universität München (DE), Miami University (US), Vanderbilt University Medical Center (US), University of Lausanne (CH), University of Edinburgh (GB)
National Science Foundation, GlaxoSmithKline, Office of Research and Development, NHS Blood and Transplant, South London and Maudsley NHS Foundation Trust, Queensland Health, Wellcome Trust, Scottish Government, Maudsley Charity, UK Research and Innovation, Trond Mohn stiftelse, Jan Dekker Stichting, National Institute for Health and Care Research, Department of Health and Social Care, Scottish Funding Council, King's College London, European Science Foundation, University of Bristol, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Rijksuniversiteit Groningen, ZonMw, Eesti Teadusagentuur, Bundesministerium für Bildung und Forschung, Ministerie van Volksgezondheid, Welzijn en Sport, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Accare, Novo Nordisk, NordForsk, Universitetet i Bergen, Universitair Medisch Centrum Groningen, Universitetet i Oslo, Norges Forskningsråd, Wetenschappelijk Onderzoek- en Documentatiecentrum, Tartu Ülikool, Novo Nordisk Fonden, UK Dementia Research Institute, Chief Scientist Office, Scottish Government Health and Social Care Directorate, NIHR BioResource, Medical Research Council, National Health and Medical Research Council, Helse Sør-Øst RHF, Norwegian Institute of Public Health
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Genetic Associations and Epidemiology
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