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

Andreas J. Forstner; Swapnil Awasthi; Christiane Wolf; Eduard Maron; Angelika Erhardt; Darina Czamara; Elias Eriksson; Catharina Lavebratt; Christer Allgulander; Nina Friedrich; Jessica Becker; Julian Hecker; Stefanie Rambau; Rupert Conrad; Franziska Geiser; Francis J. Mcmahon; Susanne Moebus; Timo Hess; Benedikt C. Buerfent; Per Hoffmann; Stefan Herms; Stefanie Heilmann-heimbach; Ingrid Kockum; Tomas Olsson; Lars Alfredsson; Heike Weber; Georg W. Alpers; Volker Arolt; Lydia Fehm; Thomas Fydrich; Alexander L. Gerlach; Alfons Hamm; Tilo Kircher; Christiane A. Pané-farré; Paul Pauli; Winfried Rief; Andreas Ströhle; Jens Plag; Thomas Lang; Hans-ulrich Wittchen; Manuel Mattheisen; Sandra Meier; Andres Metspalu; Katharina Domschke; Andreas Reif; Iiris Hovatta; Nils Lindefors; Evelyn Andersson; Martin Schalling; Hamdi Mbarek; Yuri Milaneschi; Eco J. C. De Geus; Dorret I. Boomsma; Brenda W. J. H. Penninx; Thorgeir E. Thorgeirsson; Stacy Steinberg; Kari Stefansson; Hreinn Stefansson; Bertram Müller-myhsok; Thomas Folkmann Hansen; Anders D. Børglum; Thomas Werge; Preben Bo Mortensen; Merete Nordentoft; David M. Hougaard; Christina M. Hultman; Patrick F. Sullivan; Markus M. Nöthen; David P. D. Woldbye; Ole Mors; Elisabeth B. Binder; Christian Rück; Stephan Ripke; Jürgen Deckert; Johannes Schumacher

doi:10.1038/s41380-019-0590-2

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

Andreas J. Forstner, Swapnil Awasthi, Christiane Wolf, Eduard Maron, Angelika Erhardt, Darina Czamara, Elias Eriksson, Catharina Lavebratt, Christer Allgulander, Nina Friedrich, Jessica Becker, Julian Hecker, Stefanie Rambau, Rupert Conrad, Franziska Geiser, Francis J. Mcmahon, Susanne Moebus, Timo Hess, Benedikt C. Buerfent, Per HoffmannStefan Herms, Stefanie Heilmann-heimbach, Ingrid Kockum, Tomas Olsson, Lars Alfredsson, Heike Weber, Georg W. Alpers, Volker Arolt, Lydia Fehm, Thomas Fydrich, Alexander L. Gerlach, Alfons Hamm, Tilo Kircher, Christiane A. Pané-farré, Paul Pauli, Winfried Rief, Andreas Ströhle, Jens Plag, Thomas Lang, Hans-ulrich Wittchen, Manuel Mattheisen, Sandra Meier, Andres Metspalu, Katharina Domschke, Andreas Reif, Iiris Hovatta, Nils Lindefors, Evelyn Andersson, Martin Schalling, Hamdi Mbarek, Yuri Milaneschi, Eco J. C. De Geus, Dorret I. Boomsma, Brenda W. J. H. Penninx, Thorgeir E. Thorgeirsson, Stacy Steinberg, Kari Stefansson, Hreinn Stefansson, Bertram Müller-myhsok, Thomas Folkmann Hansen, Anders D. Børglum, Thomas Werge, Preben Bo Mortensen, Merete Nordentoft, David M. Hougaard, Christina M. Hultman, Patrick F. Sullivan, Markus M. Nöthen, David P. D. Woldbye, Ole Mors, Elisabeth B. Binder, Christian Rück, Stephan Ripke, Jürgen Deckert, Johannes Schumacher

4 Citations (Scopus)

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.

Original language	English
Journal	Molecular Psychiatry
Number of pages	12
ISSN	1359-4184
DOIs	https://doi.org/10.1038/s41380-019-0590-2
Publication status	Published - Aug 2021

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Forstner, A. J., Awasthi, S., Wolf, C., Maron, E., Erhardt, A., Czamara, D., Eriksson, E., Lavebratt, C., Allgulander, C., Friedrich, N., Becker, J., Hecker, J., Rambau, S., Conrad, R., Geiser, F., Mcmahon, F. J., Moebus, S., Hess, T., Buerfent, B. C., ... Schumacher, J. (2021). Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression. Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0590-2

Forstner, AJ, Awasthi, S, Wolf, C, Maron, E, Erhardt, A, Czamara, D, Eriksson, E, Lavebratt, C, Allgulander, C, Friedrich, N, Becker, J, Hecker, J, Rambau, S, Conrad, R, Geiser, F, Mcmahon, FJ, Moebus, S, Hess, T, Buerfent, BC, Hoffmann, P, Herms, S, Heilmann-heimbach, S, Kockum, I, Olsson, T, Alfredsson, L, Weber, H, Alpers, GW, Arolt, V, Fehm, L, Fydrich, T, Gerlach, AL, Hamm, A, Kircher, T, Pané-farré, CA, Pauli, P, Rief, W, Ströhle, A, Plag, J, Lang, T, Wittchen, H, Mattheisen, M, Meier, S, Metspalu, A, Domschke, K, Reif, A, Hovatta, I, Lindefors, N, Andersson, E, Schalling, M, Mbarek, H, Milaneschi, Y, De Geus, EJC, Boomsma, DI, Penninx, BWJH, Thorgeirsson, TE, Steinberg, S, Stefansson, K, Stefansson, H, Müller-myhsok, B, Hansen, TF, Børglum, AD, Werge, T, Mortensen, PB, Nordentoft, M, Hougaard, DM, Hultman, CM, Sullivan, PF, Nöthen, MM, Woldbye, DPD, Mors, O, Binder, EB, Rück, C, Ripke, S, Deckert, J & Schumacher, J 2021, 'Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression', Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0590-2

@article{3d927d6b28824b59a294ab5e66b7989f,

title = "Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression",

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.",

author = "Forstner, {Andreas J.} and Swapnil Awasthi and Christiane Wolf and Eduard Maron and Angelika Erhardt and Darina Czamara and Elias Eriksson and Catharina Lavebratt and Christer Allgulander and Nina Friedrich and Jessica Becker and Julian Hecker and Stefanie Rambau and Rupert Conrad and Franziska Geiser and Mcmahon, {Francis J.} and Susanne Moebus and Timo Hess and Buerfent, {Benedikt C.} and Per Hoffmann and Stefan Herms and Stefanie Heilmann-heimbach and Ingrid Kockum and Tomas Olsson and Lars Alfredsson and Heike Weber and Alpers, {Georg W.} and Volker Arolt and Lydia Fehm and Thomas Fydrich and Gerlach, {Alexander L.} and Alfons Hamm and Tilo Kircher and Pan{\'e}-farr{\'e}, {Christiane A.} and Paul Pauli and Winfried Rief and Andreas Str{\"o}hle and Jens Plag and Thomas Lang and Hans-ulrich Wittchen and Manuel Mattheisen and Sandra Meier and Andres Metspalu and Katharina Domschke and Andreas Reif and Iiris Hovatta and Nils Lindefors and Evelyn Andersson and Martin Schalling and Hamdi Mbarek and Yuri Milaneschi and {De Geus}, {Eco J. C.} and Boomsma, {Dorret I.} and Penninx, {Brenda W. J. H.} and Thorgeirsson, {Thorgeir E.} and Stacy Steinberg and Kari Stefansson and Hreinn Stefansson and Bertram M{\"u}ller-myhsok and Hansen, {Thomas Folkmann} and B{\o}rglum, {Anders D.} and Thomas Werge and Mortensen, {Preben Bo} and Merete Nordentoft and Hougaard, {David M.} and Hultman, {Christina M.} and Sullivan, {Patrick F.} and N{\"o}then, {Markus M.} and Woldbye, {David P. D.} and Ole Mors and Binder, {Elisabeth B.} and Christian R{\"u}ck and Stephan Ripke and J{\"u}rgen Deckert and Johannes Schumacher",

year = "2021",

month = aug,

doi = "10.1038/s41380-019-0590-2",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "nature publishing group",

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TY - JOUR

T1 - Genome-wide association study of panic disorder reveals genetic overlap with neuroticism and depression

AU - Forstner, Andreas J.

AU - Awasthi, Swapnil

AU - Wolf, Christiane

AU - Maron, Eduard

AU - Erhardt, Angelika

AU - Czamara, Darina

AU - Eriksson, Elias

AU - Lavebratt, Catharina

AU - Allgulander, Christer

AU - Friedrich, Nina

AU - Becker, Jessica

AU - Hecker, Julian

AU - Rambau, Stefanie

AU - Conrad, Rupert

AU - Geiser, Franziska

AU - Mcmahon, Francis J.

AU - Moebus, Susanne

AU - Hess, Timo

AU - Buerfent, Benedikt C.

AU - Hoffmann, Per

AU - Herms, Stefan

AU - Heilmann-heimbach, Stefanie

AU - Kockum, Ingrid

AU - Olsson, Tomas

AU - Alfredsson, Lars

AU - Weber, Heike

AU - Alpers, Georg W.

AU - Arolt, Volker

AU - Fehm, Lydia

AU - Fydrich, Thomas

AU - Gerlach, Alexander L.

AU - Hamm, Alfons

AU - Kircher, Tilo

AU - Pané-farré, Christiane A.

AU - Pauli, Paul

AU - Rief, Winfried

AU - Ströhle, Andreas

AU - Plag, Jens

AU - Lang, Thomas

AU - Wittchen, Hans-ulrich

AU - Mattheisen, Manuel

AU - Meier, Sandra

AU - Metspalu, Andres

AU - Domschke, Katharina

AU - Reif, Andreas

AU - Hovatta, Iiris

AU - Lindefors, Nils

AU - Andersson, Evelyn

AU - Schalling, Martin

AU - Mbarek, Hamdi

AU - Milaneschi, Yuri

AU - De Geus, Eco J. C.

AU - Boomsma, Dorret I.

AU - Penninx, Brenda W. J. H.

AU - Thorgeirsson, Thorgeir E.

AU - Steinberg, Stacy

AU - Stefansson, Kari

AU - Stefansson, Hreinn

AU - Müller-myhsok, Bertram

AU - Hansen, Thomas Folkmann

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Mortensen, Preben Bo

AU - Nordentoft, Merete

AU - Hougaard, David M.

AU - Hultman, Christina M.

AU - Sullivan, Patrick F.

AU - Nöthen, Markus M.

AU - Woldbye, David P. D.

AU - Mors, Ole

AU - Binder, Elisabeth B.

AU - Rück, Christian

AU - Ripke, Stephan

AU - Deckert, Jürgen

AU - Schumacher, Johannes

PY - 2021/8

Y1 - 2021/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41380-019-0590-2

DO - 10.1038/s41380-019-0590-2

M3 - Journal article

C2 - 31712720

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

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