This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2024 Jul 5:2024.07.03.24309466.

doi: 10.1101/2024.07.03.24309466.

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

Nora I Strom^{1

2

3}, Brad Verhulst⁴, Silviu-Alin Bacanu⁵, Rosa Cheesman⁶, Kirstin L Purves⁷, Hüseyin Gedik^{8

9

10}, Brittany L Mitchell^{11

12}, Alex S Kwong^{13

14}, Annika B Faucon¹⁵, Kritika Singh^{16

17}, Sarah Medland¹¹, Lucia Colodro-Conde^{11

18}, Kristi Krebs¹⁹, Per Hoffmann^{20

21}, Stefan Herms^{20

22

21}, Jan Gehlen²³, Stephan Ripke^{24

25}, Swapnil Awasthi²⁴, Teemu Palviainen²⁶, Elisa M Tasanko²⁷, Roseann E Peterson^{8

5}, Daniel E Adkins²⁸, Andrey A Shabalin²⁸, Mark J Adams²⁹, Matthew H Iveson²⁹, Archie Campbell³⁰, Laurent F Thomas^{31

32

33

34}, Bendik S Winsvold^{35

36

37}, Ole Kristian Drange^{38

39

40

41

42}, Sigrid Børte^{43

44

36}, Abigail R Ter Kuile^{7

45

46}, Tan-Hoang Nguyen¹⁰, Sandra M Meier⁴⁷, Elizabeth C Corfield^{48

49}, Laurie Hannigan^{50

48

51}, Daniel F Levey^{52

53}, Darina Czamara⁵⁴, Heike Weber⁵⁵, Karmel W Choi^{56

57}, Giorgio Pistis⁵⁸, Baptiste Couvy-Duchesne^{11

59

60}, Sandra Van der Auwera⁶¹, Alexander Teumer^{62

61}, Robert Karlsson⁶³, Miguel Garcia-Argibay^{64

63}, Donghyung Lee⁶⁵, Rujia Wang⁶⁶, Ottar Bjerkeset^{67

38}, Eystein Stordal^{68

38}, Julia Bäckmann³, Giovanni A Salum^{69

70}, Clement C Zai^{71

72

73

74

75}, James L Kennedy^{71

72

73}, Gwyneth Zai^{71

72

73}, Arun K Tiwari^{71

72

73}, Stefanie Heilmann-Heimbach²⁰, Börge Schmidt⁷⁶, Jaakko Kaprio²⁶, Martin M Kennedy⁷⁷, Joseph Boden⁷⁸, Alexandra Havdahl^{48

50

6

13}, Christel M Middeldorp^{79

80}, Fabiana L Lopes^{81

82}, Nirmala Akula⁸³, Francis J McMahon^{83

84}, Elisabeth B Binder⁵⁴, Lydia Fehm⁸⁵, Andreas Ströhle⁸⁶, Enrique Castelao⁵⁸, Henning Tiemeier^{87

88}, Dan J Stein⁸⁹, David Whiteman⁹⁰, Catherine Olsen⁹⁰, Zachary Fuller⁹¹, Xin Wang⁹¹, Naomi R Wray^{60

92}, Enda M Byrne⁷⁹, Glyn Lewis⁹³, Nicholas J Timpson^{51

13}, Lea K Davis¹⁶, Ian B Hickie⁹⁴, Nathan A Gillespie⁵, Lili Milani¹⁹, Johannes Schumacher²³, David P Woldbye⁹⁵, Andreas J Forstner^{20

96

23}, Markus M Nöthen²⁰, Iiris Hovatta⁹⁷, John Horwood⁷⁸, William E Copeland⁹⁸, Hermine H Maes^{10

5

99}, Andrew M McIntosh²⁹, Ole A Andreassen^{40

41

100}, John-Anker Zwart^{43

36

44}, Ole Mors^{101

102}, Anders D Børglum^{103

102

104}, Preben B Mortensen¹⁰⁵, Helga Ask^{48

6}, Ted Reichborn-Kjennerud^{48

40}, Jackob M Najman¹⁰⁶, Murray B Stein^{107

108}, Joel Gelernter^{52

109

110}, Yuri Milaneschi¹¹¹, Brenda W Penninx¹¹¹, Dorret I Boomsma^{112

113}, Eduard Maron^{114

115}, Angelika Erhardt-Lehmann^{54

116}, Christian Rück³, Tilo T Kircher¹¹⁷, Christiane A Melzig^{118

119}, Georg W Alpers¹²⁰, Volker Arolt¹²¹, Katharina Domschke^{122

123}, Jordan W Smoller^{57

56}, Martin Preisig⁵⁸, Nicholas G Martin¹¹, Michelle K Lupton^{11

12

124}, Annemarie I Luik¹²⁵, Andreas Reif¹²⁶, Hans J Grabe⁶¹, Henrik Larsson^{64

63}, Patrik K Magnusson⁶³, Albertine J Oldehinkel¹²⁷, Catharina A Hartman¹²⁷, Gerome Breen⁷, Anna R Docherty^{128

129

5}, Hilary Coon¹²⁸, Rupert Conrad¹³⁰, Kelli Lehto¹⁹; Million Veteran Program, FinnGen, 23andMe; Jürgen Deckert¹¹⁶, Thalia C Eley⁷, Manuel Mattheisen^{131

132

2}, John M Hettema¹³³

Affiliations

¹ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
³ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
⁴ Psychiatry and Behavioral Sciences, Texas A&M University, College Station, Texas, USA.
⁵ Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.
⁶ PROMENTA Centre, Department of Psychology, University of Oslo, Oslo, Norway.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Institute for Genomics in Health, Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA.
⁹ Life Sciences, Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, Richmond, Virginia, USA.
¹⁰ Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹² Faculty of Medicine, Queensland University , Brisbane, Queensland, Australia.
¹³ Bristol Medical School, Population Health Sciences, MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁴ Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹⁵ Division of Medicine, Human Genetics, Vanderbilt University, Nashville, Tennessee, USA.
¹⁶ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁸ School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
¹⁹ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²⁰ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²¹ Department of Biomedicine, Human Genomics Research Group, University of Basel; University Hospital Basel, Basel, Switzerland.
²² Institute of Medical Genetics and Pathology, Medical Faculty, University Hospital Basel, Basel, Switzerland.
²³ Center for Human Genetics, University of Marburg, Marburg, Germany.
²⁴ Dept. of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
²⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁶ Helsinki Institute of Life Science, Institute for Molecular Medicine Finland - FIMM, University of Helsinki, Helsinki, Finland.
²⁷ Faculty of Medicine, Department of Psychology and Logopedics, SleepWell Research Program, University of Helsinki, Helsinki, Finland.
²⁸ School of Medicine, Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA.
²⁹ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
³⁰ College of Medicine and Veterinary Medicine, Institute of Genetics and Cancer; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
³¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³² HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³³ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
³⁴ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
³⁵ Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway.
³⁶ Department of Public Health and Nursing, HUNT Center for Molecular and Clinical Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway.
³⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
³⁸ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
³⁹ Division of Mental Health, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁴⁰ NORMENT Centre, University of Oslo, Oslo, Norway.
⁴¹ Centre of Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁴² Department of Psychiatry, Sørlandet Hospital, Kristiansand, Norway.
⁴³ Division of Clinical Neuroscience, Department of Research and Innovation; Musculoskeletal Health, Oslo University Hospital, Oslo, Norway.
⁴⁴ Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴⁵ National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
⁴⁶ Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom.
⁴⁷ Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁴⁸ PsychGen Centre for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁴⁹ Nic Waals Institute , Lovisenberg Diaconal Hospital, Oslo, Norway.
⁵⁰ Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁵¹ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
⁵² Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
⁵³ Psychiatry, Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
⁵⁴ Department of Genes and Environment, Max-Planck Institute of Psychiatry, Munich, Germany.
⁵⁵ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
⁵⁶ Psychiatry, Center for Precision Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁷ Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁸ Psychiatric Epidemiology and Psychopathology Research Center, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland.
⁵⁹ ARAMIS laboratory, Paris Brain Institute, Paris, France.
⁶⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁶¹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁶³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶⁴ School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
⁶⁵ Department of Statistics, Miami University, Oxford, Ohio, USA.
⁶⁶ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁶⁷ Faculty of Nursing and Health Science, Nord University, Levanger, Norway.
⁶⁸ Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trustt, Namsos, Norway.
⁶⁹ Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
⁷⁰ Child Psychiatry, National Institute of Developmental Psychiatry, São Paulo, Brazil.
⁷¹ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Sciences Department, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁷² Department of Psychiatry, Division of Neurosciences and Clinical Translation, University of Toronto, Toronto, Ontario, Canada.
⁷³ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁷⁴ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷⁵ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁷⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
⁷⁷ Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁷⁸ Psychological Medicine, University of Otago, Christchurch, New Zealand.
⁷⁹ Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia.
⁸⁰ Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia.
⁸¹ National Institute of Mental Health, Human Genetics Branch, National Institutes of Health, Bethesda, Maryland, USA.
⁸² Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁸³ National Institute of Mental Health, Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health, Bethesda, Maryland, USA.
⁸⁴ Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
⁸⁵ Department of Psychology, Zentrum für Psychotherapie, Humboldt-Universität zu Berlin, Berlin, Germany.
⁸⁶ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁸⁷ Social and Behavioral Science, T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁸⁸ Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands.
⁸⁹ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹⁰ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹¹ 23andMe, Sunnyvale, CA, USA.
⁹² Department of Psychiatry, University of Oxford, Oxford, UK.
⁹³ UCL Division of Psychiatry, University College London, London, UK.
⁹⁴ Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁹⁵ Department of Neuroscience, Laboratory of Neural Plasticity, University of Copenhagen, Copenhagen, Denmark.
⁹⁶ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁹⁷ Faculty of Medicine, Department of Psychology and Logopedics and SleepWell Research Program, University of Helsinki, Helsinki, Finland.
⁹⁸ UVM Medical Center, Department of Psychiatry, University of Vermont, Burlington, Vermont, USA.
⁹⁹ Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
¹⁰⁰ K. G. Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo, Norway.
¹⁰¹ Department of Psychiatry, Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark.
¹⁰² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.
¹⁰³ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹⁰⁴ Center for Genomics and Personalised Medicine, Aarhus University, Aarhus, Denmark.
¹⁰⁵ The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
¹⁰⁶ Faculty of Medicine, School of Public Health, University of Queensland, Herston, Queensland, Australia.
¹⁰⁷ Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁰⁸ School of Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰⁹ Psychiatry Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
¹¹⁰ Departments of Genetics and Neuroscience, Yale University of Medicine, New Haven, Connecticut, USA.
¹¹¹ Amsterdam Neuroscience; Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, Netherlands.
¹¹² Twin Register and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹¹³ Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, Netherlands.
¹¹⁴ Psychiatry, University of Tartu, Tartu, Estonia.
¹¹⁵ Department of Medicine, Centre for Neuropsychopharmacology,, Division of Brain Sciences, Imperial College London, London, UK.
¹¹⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
¹¹⁷ Department of Psychiatry, University of Marburg, Marburg, Germany.
¹¹⁸ Psychology, Clinical Psychology, Experimental Psychopathology and Psychotherapy, University of Marburg, Marburg, Germany.
¹¹⁹ Psychology, Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany.
¹²⁰ School of Social Sciences, Department of Psychology, University of Mannheim, Mannheim, Germany.
¹²¹ Department of Mental Health, Institute for Translational Psychiatry, University of Muenster, Muenster, Germany.
¹²² Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹²³ German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany.
¹²⁴ Faculty of Health, Queensland University of technology, Queensland, Australia.
¹²⁵ Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
¹²⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt - Goethe University, Frankfurt, Germany.
¹²⁷ Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
¹²⁸ School of Medicine, Psychiatry, University of Utah, Salt Lake City, Utah, USA.
¹²⁹ School of Medicine, Psychiatry; Huntsman Mental Health Institute, University of Utah, Salt Lake City, Utah, USA.
¹³⁰ Department of Psychosomatic Medicine and Psychotherapy, University Hospital Münster, Münster, Germany.
¹³¹ Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³² Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³³ Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas, USA.

PMID: 39006447
PMCID: PMC11245051
DOI: 10.1101/2024.07.03.24309466

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

Nora I Strom et al. medRxiv. 2024.

[Preprint]. 2024 Jul 5:2024.07.03.24309466.

doi: 10.1101/2024.07.03.24309466.

Authors

Affiliations

¹ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
³ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
⁴ Psychiatry and Behavioral Sciences, Texas A&M University, College Station, Texas, USA.
⁵ Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.
⁶ PROMENTA Centre, Department of Psychology, University of Oslo, Oslo, Norway.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁸ Institute for Genomics in Health, Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Health Sciences University, Brooklyn, New York, USA.
⁹ Life Sciences, Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, Richmond, Virginia, USA.
¹⁰ Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
¹¹ Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹² Faculty of Medicine, Queensland University , Brisbane, Queensland, Australia.
¹³ Bristol Medical School, Population Health Sciences, MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁴ Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹⁵ Division of Medicine, Human Genetics, Vanderbilt University, Nashville, Tennessee, USA.
¹⁶ Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹⁸ School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
¹⁹ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
²⁰ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
²¹ Department of Biomedicine, Human Genomics Research Group, University of Basel; University Hospital Basel, Basel, Switzerland.
²² Institute of Medical Genetics and Pathology, Medical Faculty, University Hospital Basel, Basel, Switzerland.
²³ Center for Human Genetics, University of Marburg, Marburg, Germany.
²⁴ Dept. of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
²⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁶ Helsinki Institute of Life Science, Institute for Molecular Medicine Finland - FIMM, University of Helsinki, Helsinki, Finland.
²⁷ Faculty of Medicine, Department of Psychology and Logopedics, SleepWell Research Program, University of Helsinki, Helsinki, Finland.
²⁸ School of Medicine, Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA.
²⁹ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
³⁰ College of Medicine and Veterinary Medicine, Institute of Genetics and Cancer; Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, UK.
³¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
³² HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
³³ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
³⁴ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
³⁵ Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway.
³⁶ Department of Public Health and Nursing, HUNT Center for Molecular and Clinical Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway.
³⁷ Department of Neurology, Oslo University Hospital, Oslo, Norway.
³⁸ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
³⁹ Division of Mental Health, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁴⁰ NORMENT Centre, University of Oslo, Oslo, Norway.
⁴¹ Centre of Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital and University of Oslo, Oslo, Norway.
⁴² Department of Psychiatry, Sørlandet Hospital, Kristiansand, Norway.
⁴³ Division of Clinical Neuroscience, Department of Research and Innovation; Musculoskeletal Health, Oslo University Hospital, Oslo, Norway.
⁴⁴ Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴⁵ National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
⁴⁶ Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom.
⁴⁷ Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
⁴⁸ PsychGen Centre for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁴⁹ Nic Waals Institute , Lovisenberg Diaconal Hospital, Oslo, Norway.
⁵⁰ Nic Waals Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
⁵¹ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.
⁵² Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
⁵³ Psychiatry, Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
⁵⁴ Department of Genes and Environment, Max-Planck Institute of Psychiatry, Munich, Germany.
⁵⁵ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.
⁵⁶ Psychiatry, Center for Precision Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁷ Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁸ Psychiatric Epidemiology and Psychopathology Research Center, Department of Psychiatry, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland.
⁵⁹ ARAMIS laboratory, Paris Brain Institute, Paris, France.
⁶⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
⁶¹ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶² Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁶³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶⁴ School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
⁶⁵ Department of Statistics, Miami University, Oxford, Ohio, USA.
⁶⁶ Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁶⁷ Faculty of Nursing and Health Science, Nord University, Levanger, Norway.
⁶⁸ Department of Psychiatry, Hospital Namsos, Nord-Trøndelag Health Trustt, Namsos, Norway.
⁶⁹ Department of Psychiatry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
⁷⁰ Child Psychiatry, National Institute of Developmental Psychiatry, São Paulo, Brazil.
⁷¹ Tanenbaum Centre for Pharmacogenetics, Molecular Brain Sciences Department, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁷² Department of Psychiatry, Division of Neurosciences and Clinical Translation, University of Toronto, Toronto, Ontario, Canada.
⁷³ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
⁷⁴ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷⁵ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁷⁶ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
⁷⁷ Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
⁷⁸ Psychological Medicine, University of Otago, Christchurch, New Zealand.
⁷⁹ Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia.
⁸⁰ Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia.
⁸¹ National Institute of Mental Health, Human Genetics Branch, National Institutes of Health, Bethesda, Maryland, USA.
⁸² Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁸³ National Institute of Mental Health, Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health, Bethesda, Maryland, USA.
⁸⁴ Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, USA.
⁸⁵ Department of Psychology, Zentrum für Psychotherapie, Humboldt-Universität zu Berlin, Berlin, Germany.
⁸⁶ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁸⁷ Social and Behavioral Science, T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁸⁸ Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, Netherlands.
⁸⁹ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹⁰ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹¹ 23andMe, Sunnyvale, CA, USA.
⁹² Department of Psychiatry, University of Oxford, Oxford, UK.
⁹³ UCL Division of Psychiatry, University College London, London, UK.
⁹⁴ Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁹⁵ Department of Neuroscience, Laboratory of Neural Plasticity, University of Copenhagen, Copenhagen, Denmark.
⁹⁶ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁹⁷ Faculty of Medicine, Department of Psychology and Logopedics and SleepWell Research Program, University of Helsinki, Helsinki, Finland.
⁹⁸ UVM Medical Center, Department of Psychiatry, University of Vermont, Burlington, Vermont, USA.
⁹⁹ Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
¹⁰⁰ K. G. Jebsen Center for Neurodevelopmental disorders, University of Oslo, Oslo, Norway.
¹⁰¹ Department of Psychiatry, Psychosis Research Unit, Aarhus University Hospital, Aarhus, Denmark.
¹⁰² The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.
¹⁰³ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
¹⁰⁴ Center for Genomics and Personalised Medicine, Aarhus University, Aarhus, Denmark.
¹⁰⁵ The National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
¹⁰⁶ Faculty of Medicine, School of Public Health, University of Queensland, Herston, Queensland, Australia.
¹⁰⁷ Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁰⁸ School of Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰⁹ Psychiatry Research, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA.
¹¹⁰ Departments of Genetics and Neuroscience, Yale University of Medicine, New Haven, Connecticut, USA.
¹¹¹ Amsterdam Neuroscience; Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, Netherlands.
¹¹² Twin Register and Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
¹¹³ Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, Netherlands.
¹¹⁴ Psychiatry, University of Tartu, Tartu, Estonia.
¹¹⁵ Department of Medicine, Centre for Neuropsychopharmacology,, Division of Brain Sciences, Imperial College London, London, UK.
¹¹⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
¹¹⁷ Department of Psychiatry, University of Marburg, Marburg, Germany.
¹¹⁸ Psychology, Clinical Psychology, Experimental Psychopathology and Psychotherapy, University of Marburg, Marburg, Germany.
¹¹⁹ Psychology, Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany.
¹²⁰ School of Social Sciences, Department of Psychology, University of Mannheim, Mannheim, Germany.
¹²¹ Department of Mental Health, Institute for Translational Psychiatry, University of Muenster, Muenster, Germany.
¹²² Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹²³ German Center for Mental Health (DZPG), Partner Site Berlin, Berlin, Germany.
¹²⁴ Faculty of Health, Queensland University of technology, Queensland, Australia.
¹²⁵ Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.
¹²⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt - Goethe University, Frankfurt, Germany.
¹²⁷ Psychiatry, Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
¹²⁸ School of Medicine, Psychiatry, University of Utah, Salt Lake City, Utah, USA.
¹²⁹ School of Medicine, Psychiatry; Huntsman Mental Health Institute, University of Utah, Salt Lake City, Utah, USA.
¹³⁰ Department of Psychosomatic Medicine and Psychotherapy, University Hospital Münster, Münster, Germany.
¹³¹ Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³² Computer Science, Dalhousie University, Halifax, Nova Scotia, Canada.
¹³³ Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, Texas, USA.

PMID: 39006447
PMCID: PMC11245051
DOI: 10.1101/2024.07.03.24309466

Abstract

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.

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Conflict of interest statement

Per Hoffmann receives Salary from the Life & Brain GmbH, Bonn, Germany. James L. Kennedy is a member of the Scientific Advisory Board for Myriad Neuroscience Inc. Ian B. Hickie was an inaugural Commissioner on Australia’s National Mental Health Commission (2012-18). He is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. He is the Chief Scientific Advisor to, and a 5% equity shareholder in, InnoWell Pty Ltd. InnoWell was formed by the University of Sydney (45% equity) and PwC (Australia; 45% equity) to deliver the $30 M Australian Government-funded Project Synergy (2017-20; a three-year program for the transformation of mental health services) and to lead transformation of mental health services internationally through the use of innovative technologies. Andrew M. Mcintosh has received research support from Eli Lilly, Janssen, and The Sackler Trust. AMM has also received speaker fees from Illumina and Janssen. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, Boehringer Ingelheim, Bionomics, BioXcel Therapeutics, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He is paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). He has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. He is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America. Joel Gelernter is named as an inventor on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018 and issued on January 26, 2021 as U.S. Patent No. 10,900,082; and is paid for editorial work for the journal “Complex Psychiatry.” Iiris Hovatta received speaker’s honoraria from Lundbeck. Ole A. Andreassen received speaker’s honorarium from Lundbeck and Sunovion, consultant for Cortechs.ai and Precision Health AS. Katharina Domschke has been a member of the Steering Committee Neurosciences, Janssen, Inc. until 2022 and is currently a member of the Board of the German National Society of Psychiatry (DGPPN) and the Neurotorium Editorial Board of the Lundbeck Foundation. Jordan W. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received an honorarium for an internal seminar Tempus Labs. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. Eduard Maron has received research support and has also received speaker fees from Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Indorsia, Neuraxpharm, Servier and Janssen Cilag. Henrik Larsson has served as a speaker for Evolan Pharma, Medici and Shire/Takeda and has received research grants from Shire/Takeda; all outside the submitted work. Gerome Breen is an advisory board member for Compass Pathways. Jürgen Deckert is a member of the board of the German Society of Biological Psychiatry and is on the scientific advisory boards of non-profit organizations and foundations. Volker Arolt worked as an advisor for Sanofi-Adventis Germany. Zach Fuller and Xin Wang are employees of 23andMe and hold stock or stock options in 23andMe. All other authors have no competing interests to declare.

Figures

**Figure 1:**
Manhattan plot of the main ANX GWAS (122,341 ANX cases and 729,881 unaffected controls) showing 58 genome-wide significant loci. The x-axis shows the position in the genome (chromosome 1 to 22), the y-axis represents –log10 p-values for the association of variants with ANX from the meta-analysis using an inverse-variance weighted fixed effects model. The horizontal red line shows the threshold for genome-wide significance (P = 5×10⁻⁰⁸). Dots represent each SNP that was tested in the GWAS with a green diamond indicating the lead SNP of a genome-wide significant locus and green dots below representing SNPs within the locus with high levels of LD with the lead SNP.

**Figure 2:**
List of 66 of the most highly-supported ANX genes that were implicated in at least three of the five SNP-(eQTL, HiC) or gene-based (MAGMA, M-SMR, P-SMR, T-SMR) tests. The left side indicates the position of the gene in the genome. Significance is indicated by a coloured dot. eQTL (blue dots) comparing results from brain-related eQTL studies for overlap in significance between our GWAS and the eQTL studies. HiC (green dots) used brain-related HiC information available through FUMA to functionally annotate our results. MAGMA (gray dots) tested genetic associations at the gene level for the combined effect of SNPs in or near protein coding genes. M/P/T-SMR (yellow, red, and pink dots, respectively) refers to transcriptome/proteome/methylome -wide analyses that assessed likely causal association between traits and gene/proteins/genomic regions by inferring the association between trait and gene expression/protein concentration/methylation, as predicted from genomic data.

**Figure 3A:**
The (rotated) Manhattan plot of the -log₁₀ p-values of the ANX meta-analysis (left) and PheWAS alluvial plot of the pleiotropic variants (right). The colored ribbons depict variants that are pleiotropically associated with at least one other published GWAS finding and correspond with the color of the ribbon in the alluvial plot. The red diamonds in the Manhattan plot depict the most significant variant in the region corresponding with potentially ANX specific SNPs, i.e., a variant that reached the genome-wide significance threshold for ANX but not in any other published GWAS.

**Figure 3B:**
Dendrogram-based heatmap indicating the numbers of unduplicated reports of genome-wide psychiatric or personality associations among 24 pleiotropic SNPs. Shading indicates the number of GWAS reporting associations between a specific SNP and the outcomes. Symptom Dimensions (mood disturbance, mania, psychosis) and Self-Report Professional Diagnoses (depression, anxiety, distress) are from the UK Biobank.

**Figure 4:**
Genetic correlations (rg) between the main ANX GWAS and 112 psychiatric, substance use, cognition/socioeconomic status (SES), personality, psychological, neurological, autoimmune, cardiovascular, anthropomorphic/diet, fertility, and other phenotypes. References of the corresponding summary statistics of the GWAS studies can be found in Supplementary Table S24. Bars represent 95% confidence intervals, red circles indicate significant associations after FDR correction for multiple testing. Black circles indicate associations that are not significant after FDR correction.

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References

1. Bandelow B, Baldwin D, Abelli M, Bolea-Alamanac B, Bourin M, Chamberlain SR, et al. (2017): Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry 18: 162–214. - PMC - PubMed
1. Ask H, Cheesman R, Jami ES, Levey DF, Purves KL, Weber H (2021): Genetic contributions to anxiety disorders: where we are and where we are heading. Psychol Med 51: 2231–2246. - PubMed
1. Ressler KJ (2020): Translating Across Circuits and Genetics Toward Progress in Fear- and Anxiety-Related Disorders. Am J Psychiatry 177: 214–222. - PMC - PubMed
1. Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, Wittchen H-U (2017): Anxiety disorders [no. 1]. Nat Rev Dis Primers 3: 1–19. - PMC - PubMed
1. Hasin DS, Grant BF (2015): The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Waves 1 and 2: review and summary of findings. Soc Psychiatry Psychiatr Epidemiol 50: 1609–1640. - PMC - PubMed

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Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

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Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

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