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PMID

42374129

TITLE

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 ; 157,447 N ). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 N ; 117,064 N ). 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 = 0.87; P = 9.32 × 10 ). 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.
� 2026. The Author(s).

DATE PUBLISHED

2026 Jun 29

HISTORY

PUBSTATUS	PUBSTATUSDATE
received	2025/03/18
accepted	2026/06/03
revised	2026/05/05
medline	2026/06/30 04:10
pubmed	2026/06/30 04:10
entrez	2026/06/29 23:43

AUTHORS

NAME	COLLECTIVENAME	LASTNAME	FORENAME	INITIALS	AFFILIATION	AFFILIATIONINFO
Ter Kuile AR		Ter Kuile	Abigail R	AR		Department of Clinical, Educational, and Health Psychology, University College London, London, UK.
Mitchell BL		Mitchell	Brittany L	BL		School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Lee SH		Lee	Sang Hyuck	SH		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Morneau-Vaillancourt G		Morneau-Vaillancourt	Geneviève	G		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Skelton M		Skelton	Megan	M		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Coleman JRI		Coleman	Jonathan R I	JRI		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Davies HL		Davies	Helena L	HL		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Mundy J		Mundy	Jessica	J		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Peel AJ		Peel	Alicia J	AJ		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Hübel C		Hübel	Christopher	C		Clinic for Child and Adolescent Psychiatry, Psychotherapy and Psychosomatics, German Red Cross Hospitals Berlin Westend, Berlin, Germany.
Davies MR		Davies	Molly R	MR		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Fürtjes AE		Fürtjes	Anna E	AE		School of Philosophy, Psychology and Language Sciences, The University of Edinburgh, Edinburgh, UK.
Ahmad Z		Ahmad	Zain	Z		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Lin Y		Lin	Yuhao	Y		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Adey BN		Adey	Brett N	BN		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
McGregor T		McGregor	Thomas	T		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Palmos A		Palmos	Alish	A		Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Zvrskovec J		Zvrskovec	Johan	J		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Hotopf M		Hotopf	Matthew	M		South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK.
Kalsi G		Kalsi	Gursharan	G		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Smith DJ		Smith	Daniel J	DJ		Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
Veale D		Veale	David	D		South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Kent, UK.
Walters JTR		Walters	James T R	JTR		Centre for Neuropsychiatric Genetics and Genomics, National Centre for Mental Health, Cardiff University, Cardiff, UK.
Armour C		Armour	Chérie	C		Research Centre for Stress, Trauma, and Related Conditions, School of Psychology, Queen's University Belfast, Belfast, Northern Ireland, UK.
Hirsch CR		Hirsch	Colette R	CR		South London and Maudsley NHS Foundation Trust, Maudsley Hospital, London, UK.
McIntosh AM		McIntosh	Andrew M	AM		Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, UK.
Wray NR		Wray	Naomi R	NR		Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Medland SE		Medland	Sarah E	SE		School of Psychology and Counselling, Queensland University of Technology, Brisbane, QLD, Australia.
Byrne EM		Byrne	Enda M	EM		Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia.
Martin NG		Martin	Nicholas G	NG		Brain and Mental Health program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Kingston N		Kingston	Nathalie	N		National Institute for Health and Care Research (NIHR) BioResource, Cambridge Biomedical Campus, Cambridge University Hospitals, Cambridge, UK.
Bradley JR		Bradley	John R	JR		National Institute for Health and Care Research (NIHR) BioResource, Cambridge Biomedical Campus, Cambridge University Hospitals, Cambridge, UK.
	NIHR BioResource
Breen G		Breen	Gerome	G		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Eley TC		Eley	Thalia C	TC		National Institute for Health and Care Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK. thalia.eley@kcl.ac.uk.

INVESTIGATORS

LASTNAME	FORENAME	INITIALS	AFFILIATION
Bradley	John R	JR
Stark	Hannah	H
Kanz	Carola	C
Moulton	Alexei	A
Ovington	Nigel	N
Lee	Jacinta	J
Clapham-Riley	Debbie	D
Mills	Katie	K

JOURNAL

VOLUME:

ISSUE:

TITLE: Molecular psychiatry

ISOABBREVIATION: Mol Psychiatry

YEAR: 2026

MONTH: Jun

DAY: 29

MEDLINEDATE:

SEASON:

CITEDMEDIUM: Internet

ISSN: 1476-5578

ISSNTYPE: Electronic

MEDLINE JOURNAL

MEDLINETA: Mol Psychiatry

COUNTRY: England

ISSNLINKING: 1359-4184

NLMUNIQUEID: 9607835

PUBLICATION TYPE

PUBLICATIONTYPE TEXT

Journal Article

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