Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder

Abstract Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to “any anxiety diagnosis”. Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one independent genome-wide significant locus and three gene-level associations with fear (up to 35,523 N cases ; 157,447 N controls ). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 N cases ; 117,064 N controls ). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (r g = 0.87; P = 9.32 × 10 −3 ). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

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Publication Details

Journal
Molecular Psychiatry
Published
2026-06-29
DOI
https://doi.org/10.1038/s41380-026-03677-2
Primary Topic
Genetic Associations and Epidemiology
Type
article
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article

Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder

Alish Palmos, Matthew H. Hotopf, Thalia Catherine Eley, Andrew Mark McIntosh et al.
Molecular Psychiatry
Genetic Associations and Epidemiology
article

Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder

Alish Palmos, Matthew H. Hotopf, Thalia Catherine Eley, Andrew Mark McIntosh, Gerome D. Breen, Brett N. Adey, Chérie Armour, Sarah Elizabeth Medland, Nicholas G. Martin, James Walters, J J Lee, Alicia J. Peel, Molly Rose Davies, Nathalie Kingston, Hannah Stark, Thomas McGregor, Debbie Clapham-Riley, Colette R. Hirsch, Brittany L. Mitchell, Enda M. Byrne, Daniel J. Smıth, Gursharan Kalsi, Johan Zvrskovec, Yuhao Lin, David Veale, Naomi R. Wray, Anna E. Fürtjes, John R. Bradley, NIHR BioResource, Christopher Hübel, Jonathan R. I. Coleman, Geneviève Morneau‐Vaillancourt, Megan Skelton, Zain Ahmad, Abigail ter Kuile, Alexei Moulton, Sang Hyuck Lee, Helena L. Davies, Carola Kanz, Jessica Mundy, Katie Mills, Nigel Ovington
article en

Abstract

Abstract Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to “any anxiety diagnosis”. Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one independent genome-wide significant locus and three gene-level associations with fear (up to 35,523 N cases ; 157,447 N controls ). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 N cases ; 117,064 N controls ). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (r g = 0.87; P = 9.32 × 10 −3 ). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

Molecular Psychiatry
Queen's University Belfast (GB), Queensland University of Technology (AU), The University of Queensland (AU), King's College London (GB), South London and Maudsley NHS Foundation Trust (GB), Aarhus University (DK), QIMR Berghofer Medical Research Institute (AU), German Red Cross (DE), Bethlem Royal Hospital (GB), Centre for Mental Health (GB), National Institute for Health and Care Research (GB), Maudsley Hospital (GB), University College London (GB), Cardiff University (GB), University of Edinburgh (GB)
Openalex Percentile: Top 8%
Genetic Associations and Epidemiology
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