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

Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. We performed a genome-wide association meta-analysis of generalised 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 novel for anxiety. SNP-based heritability was 5.9% (posterior SD = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African, and South Asian ancestry samples (r2=1.2%–2.9%). Significant genetic correlations were estimated with mental and physical health traits, including case-control anxiety, neuroticism and depression (rg=0.71–0.85), irritable bowel syndrome (rg=0.57), coronary artery disease, endometriosis, and migraine (rg=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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Research Portal (King's College London)
Published
2026-04-13
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, Enrique Castelao, Elham Assary et al.
Research Portal (King's College London)
Genetic Associations and Epidemiology
article

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

Kadri Kõiv, P Grimes, Enrique Castelao, Elham Assary, Giorgio Pistis, Enda M. Byrne, Alex S. F. Kwong, Geneviève Morneau‐Vaillancourt, Elizabeth Corfield, Thalia Eley, Megan; id_orcid 0000-0002-7619-349X Skelton, Hu Jihua, Rujia; id_orcid 0000-0003-2574-990X Wang, Sergi Papiol, Gerome; id_orcid 0000-0003-2053-1792 Breen, Alan E Murphy, Jonathan; id_orcid 0000-0002-6759-0944 Coleman, Abigail R ter Kuile, Pettersen Johanne H, Mark Adams, Brittany L. Mitchell, Danyang Li, Nora Strom, Laurie Hannigan
article en

Abstract

Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. We performed a genome-wide association meta-analysis of generalised 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 novel for anxiety. SNP-based heritability was 5.9% (posterior SD = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African, and South Asian ancestry samples (r2=1.2%–2.9%). Significant genetic correlations were estimated with mental and physical health traits, including case-control anxiety, neuroticism and depression (rg=0.71–0.85), irritable bowel syndrome (rg=0.57), coronary artery disease, endometriosis, and migraine (rg=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.

Research Portal (King's College London)
National Science Foundation, GlaxoSmithKline, Office of Research and Development, NHS Blood and Transplant, 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 Commission, 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, South East Regional Health Authority, National Institutes of Health, 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, National Institute of Mental Health
Good health and well-being
Openalex Percentile: Top 19%
Genetic Associations and Epidemiology
Open Access PDFOpenAlex
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