Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Molecular Psychiatry
Authors: Abigail R. ter Kuile, Brittany L. Mitchell, Sang Hyuck Lee, Geneviève Morneau-Vaillancourt, Megan Skelton, Jonathan R. I. Coleman, Helena L. Davies, Jessica Mundy, Alicia J. Peel, Christopher Hübel, Molly R. Davies, Anna E. Fürtjes, Zain Ahmad, Yuhao Lin, Brett N. Adey, Thomas McGregor, Alish Palmos, Johan Zvrskovec, Matthew Hotopf, Gursharan Kalsi, Daniel J. Smith, David Veale, James T. R. Walters, Chérie Armour, Colette R. Hirsch, Andrew M. McIntosh, Naomi R. Wray, Sarah E. Medland, Enda M. Byrne, Nicholas G. Martin, Nathalie Kingston, John R. Bradley, NIHR BioResource, John R. Bradley, Hannah Stark, Carola Kanz, Alexei Moulton, Nigel Ovington, Jacinta Lee, Debbie Clapham-Riley, Katie Mills, Gerome Breen, Thalia C. Eley
Institutions: King's College London, South London and Maudsley NHS Foundation Trust, National Institute for Health and Care Research, NIHR Maudsley Biomedical Research Centre, University College London, The University of Queensland, QIMR Berghofer Medical Research Institute, Aarhus University, German Red Cross, University of Edinburgh, Maudsley Hospital, Bethlem Royal Hospital, Cardiff University, Queen's University Belfast, Institute for Molecular Bioscience, Queensland University of Technology, University of Cambridge, NIHR BioResource
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: NHS Blood and Transplant, Health and Care Research Wales, Maudsley Charity, National Institute for Health and Care Research, Department of Health and Social Care, King's College London, European Commission, Public Health Agency, NIHR BioResource, Social Sciences and Humanities Research Council of Canada, Medical Research Council, National Health and Medical Research Council, Health Data Research UK
Awards: G1112956173, G1280483720, Which modifiable risk factors actually cause cancer?, G131530194, G1932948828, G200864789, G2365632633, G3108930451, G3210000672, Advancing our understanding of Psychiatric Disorders through Imaging and Genetics, G4214616087, Understanding the Genetic Basis of Treatment Response for Depression, The effect of Plasmodium GPIs on mammalian cells and its role on the course of malaria infections, G5201614120, G531235076, G5453711237, Tackling heterogeneity in the etiology of major depressive disorder, G6206044308, Violence against women in the mainstream press: the discursive construction of dominant ideologies, G6739327530, Generating the evidence to control cancer and optimise outcomes, G6995567651, Studies in cancer control, Using genomics and imaging to advance our understanding of mental health challenges, G842161117
OpenAlex ID: W7166554547