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

Ter Kuile, Abigail, Mitchell, Brittany L., Lee, Sang Hyuck, Morneau-Vaillancourt, Geneviève, Skelton, Megan, Coleman, Jonathan R. I., Davies, Helena L., Mundy, Jessica, Peel, Alicia J. and Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053 2026. Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder. Molecular Psychiatry 10.1038/s41380-026-03677-2

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB)

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 Ncases; 157,447 Ncontrols). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 Ncases; 117,064 Ncontrols). 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 (rg = 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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Please follow DOI link for a full list of authors.
Publisher:	Springer Science and Business Media LLC
ISSN:	1359-4184
Date of First Compliant Deposit:	30 June 2026
Date of Acceptance:	3 June 2026
Last Modified:	30 Jun 2026 08:57
URI:	https://orca.cardiff.ac.uk/id/eprint/187815

Actions (repository staff only)

Edit Item