Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Andreas J Forstner^#^{1

2

3

4}, Swapnil Awasthi^#⁵, Christiane Wolf^#⁶, Eduard Maron^{7

8

9}, Angelika Erhardt¹⁰, Darina Czamara¹⁰, Elias Eriksson¹¹, Catharina Lavebratt¹², Christer Allgulander¹³, Nina Friedrich², Jessica Becker², Julian Hecker¹⁴, Stefanie Rambau¹⁵, Rupert Conrad¹⁵, Franziska Geiser¹⁵, Francis J McMahon¹⁶, Susanne Moebus¹⁷, Timo Hess¹, Benedikt C Buerfent¹, Per Hoffmann^{2

4}, Stefan Herms^{2

4}, Stefanie Heilmann-Heimbach², Ingrid Kockum¹⁸, Tomas Olsson¹⁸, Lars Alfredsson¹⁹, Heike Weber^{6

20}, Georg W Alpers²¹, Volker Arolt²², Lydia Fehm²³, Thomas Fydrich²³, Alexander L Gerlach²⁴, Alfons Hamm²⁵, Tilo Kircher²⁶, Christiane A Pané-Farré^{25

27}, Paul Pauli²⁸, Winfried Rief²⁷, Andreas Ströhle²⁹, Jens Plag²⁹, Thomas Lang³⁰, Hans-Ulrich Wittchen^{31

32}, Manuel Mattheisen⁶, Sandra Meier³³, Andres Metspalu³⁴, Katharina Domschke^{35

36}, Andreas Reif²⁰, Iiris Hovatta^{37

38}, Nils Lindefors³⁹, Evelyn Andersson³⁹, Martin Schalling¹², Hamdi Mbarek⁴⁰, Yuri Milaneschi⁴¹, Eco J C de Geus⁴⁰, Dorret I Boomsma⁴⁰, Brenda W J H Penninx⁴¹, Thorgeir E Thorgeirsson⁴², Stacy Steinberg⁴², Kari Stefansson⁴², Hreinn Stefansson⁴², Bertram Müller-Myhsok^{10

43

44}, Thomas Folkmann Hansen^{45

46}, Anders D Børglum^{47

48

49}, Thomas Werge^{46

47

50}, Preben Bo Mortensen^{47

51

52}, Merete Nordentoft^{47

53}, David M Hougaard^{47

54}, Christina M Hultman⁵⁵, Patrick F Sullivan^{55

56

57}, Markus M Nöthen², David P D Woldbye⁵⁸, Ole Mors^{47

59}, Elisabeth B Binder^{10

60}, Christian Rück³⁹, Stephan Ripke^#^{5

61

62}, Jürgen Deckert^#⁶, Johannes Schumacher^#^{63

64}

Affiliations

¹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
² Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
⁷ Department of Psychiatry, University of Tartu, Tartu, Estonia.
⁸ Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia.
⁹ Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
¹⁰ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
¹¹ Department of Pharmacology, Institute of Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹³ Karolinska Institutet, Stockholm, Sweden.
¹⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Psychosomatic Medicine and Psychotherapy, University of Bonn, Bonn, Germany.
¹⁶ Human Genetics Branch, National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA.
¹⁷ Centre for Urban Epidemiology, IMIBE, University Duisburg-Essen, Essen, Germany.
¹⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
²¹ Clinical and Biological Psychology, School of Social Sciences and Otto-Selz-Institute, University of Mannheim, Mannheim, Germany.
²² Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
²³ Department of Psychology, Humboldt-University Berlin, Berlin, Germany.
²⁴ Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
²⁵ Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany.
²⁶ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
²⁷ Psychologie, Philipps- Universität Marburg, Marburg, Germany.
²⁸ Department of Psychology and Center of Mental Health, University of Würzburg, Würzburg, Germany.
²⁹ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
³⁰ IPP Bremen GmbH, Bremen, Germany.
³¹ Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
³² Psychiatric University Hospital, LMU, München, Germany.
³³ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³⁴ Institute of Genomics and Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁵ Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁶ Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁷ Research Program of Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.
³⁸ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
³⁹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Huddinge, Sweden.
⁴⁰ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴¹ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit/GGZ inGeest, Amsterdam, The Netherlands.
⁴² deCODE Genetics / Amgen, Reykjavik, Iceland.
⁴³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁴ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁴⁵ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁶ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
⁴⁷ iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁴⁸ Center for Genomics and Personalized Medicine, Aarhus University and Central Region Denmark, Aarhus, Denmark.
⁴⁹ Department of Biomedicine, and iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁵⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁵¹ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
⁵² Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
⁵³ Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁵⁴ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
⁵⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁷ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁸ Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
⁵⁹ Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
⁶⁰ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁶¹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research and Medical and Population Genetics Program, Cambridge, MA, USA.
⁶² Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Analytic and Translational Genetics Unit, Boston, MA, USA.
⁶³ Centre for Human Genetics, University of Marburg, Marburg, Germany. johannes.schumacher@uni-marburg.de.
⁶⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. johannes.schumacher@uni-marburg.de.

^# Contributed equally.

PMID: 31712720
DOI: 10.1038/s41380-019-0590-2

Meta-Analysis

Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

Andreas J Forstner et al. Mol Psychiatry. 2021 Aug.

. 2021 Aug;26(8):4179-4190.

doi: 10.1038/s41380-019-0590-2. Epub 2019 Nov 11.

Authors

Affiliations

¹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
² Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
³ Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.
⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany.
⁶ Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
⁷ Department of Psychiatry, University of Tartu, Tartu, Estonia.
⁸ Department of Psychiatry, North Estonia Medical Centre, Tallinn, Estonia.
⁹ Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK.
¹⁰ Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany.
¹¹ Department of Pharmacology, Institute of Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
¹³ Karolinska Institutet, Stockholm, Sweden.
¹⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Psychosomatic Medicine and Psychotherapy, University of Bonn, Bonn, Germany.
¹⁶ Human Genetics Branch, National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA.
¹⁷ Centre for Urban Epidemiology, IMIBE, University Duisburg-Essen, Essen, Germany.
¹⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁰ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany.
²¹ Clinical and Biological Psychology, School of Social Sciences and Otto-Selz-Institute, University of Mannheim, Mannheim, Germany.
²² Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
²³ Department of Psychology, Humboldt-University Berlin, Berlin, Germany.
²⁴ Institute of Clinical Psychology and Psychotherapy, University of Cologne, Cologne, Germany.
²⁵ Department of Biological and Clinical Psychology, University of Greifswald, Greifswald, Germany.
²⁶ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
²⁷ Psychologie, Philipps- Universität Marburg, Marburg, Germany.
²⁸ Department of Psychology and Center of Mental Health, University of Würzburg, Würzburg, Germany.
²⁹ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
³⁰ IPP Bremen GmbH, Bremen, Germany.
³¹ Department of Psychology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
³² Psychiatric University Hospital, LMU, München, Germany.
³³ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
³⁴ Institute of Genomics and Estonian Genome Center, University of Tartu, Tartu, Estonia.
³⁵ Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁶ Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁷ Research Program of Molecular and Integrative Biosciences, University of Helsinki, Helsinki, Finland.
³⁸ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland.
³⁹ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Huddinge, Sweden.
⁴⁰ Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴¹ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit/GGZ inGeest, Amsterdam, The Netherlands.
⁴² deCODE Genetics / Amgen, Reykjavik, Iceland.
⁴³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁴ Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
⁴⁵ Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
⁴⁶ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
⁴⁷ iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
⁴⁸ Center for Genomics and Personalized Medicine, Aarhus University and Central Region Denmark, Aarhus, Denmark.
⁴⁹ Department of Biomedicine, and iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
⁵⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁵¹ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
⁵² Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
⁵³ Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁵⁴ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
⁵⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁷ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵⁸ Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
⁵⁹ Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
⁶⁰ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁶¹ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research and Medical and Population Genetics Program, Cambridge, MA, USA.
⁶² Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Analytic and Translational Genetics Unit, Boston, MA, USA.
⁶³ Centre for Human Genetics, University of Marburg, Marburg, Germany. johannes.schumacher@uni-marburg.de.
⁶⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. johannes.schumacher@uni-marburg.de.

^# Contributed equally.

PMID: 31712720
DOI: 10.1038/s41380-019-0590-2

Abstract

Panic disorder (PD) has a lifetime prevalence of 2-4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0-34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10^-4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10 × 10^-7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Trial registration: ClinicalTrials.gov NCT01323556.

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References

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Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

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Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

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